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Context-specific roles for IL-17 in tuberculosis

Abstract

The number 17 is considered unlucky by some Italians as its Roman numerals – XVII – can be rearranged as Vixi, a Latin expression that can be interpreted as “my life is over”. In other contexts, the number 17 is associated with wisdom and success. This paradox holds true when it comes to the role of interleukin 17 (IL-17) in tuberculosis (TB). On one hand, immune correlates of protection studies have consistently identified IL-17 responses as key players in natural and vaccine induced protection against infection and disease. On the other, IL-17 has been proposed as a main driver of the immunopathology that underlies TB morbidity and mortality. Thus, while some researchers seek to develop novel TB vaccine approaches that promote IL-17 responses, others hunt for host-directed therapeutic approaches that block its activity. In this article, we attempt to address this conundrum and synthesise the main arguments supporting a role for IL-17 in the protection and pathogenesis of this deadly human infectious disease. Ultimately, as with superstition, whether the 17th interleukin is friend or foe in human TB is likely to depend on the context.

Citation: Maseeme M, Tezera LB, Noursadeghi M, Leslie A, Pollara G (2026) Context-specific roles for IL-17 in tuberculosis. PLoS Pathog 22(4): e1014054. https://doi.org/10.1371/journal.ppat.1014054

Editor: Antje Blumenthal, University of Queensland, AUSTRALIA

Published: April 21, 2026

Copyright: © 2026 Maseeme et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: M.M. is supported by Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) grant from Gates foundation (INV-033558). L.B.T. is supported by the Springboard Award from the Academy of Medical Sciences (SBF0010\1085). M.N. is supported by the Wellcome Trust (207511/Z/17/Z and 306550/Z/23/Z) and from the National Institute for Health Research UCLH Biomedical Research Centre. A.L. is supported by Wellcome Trust (201433/A/16/A, 210662/Z/18/Z and 317454/Z/24/Z). G.P. is supported by the National Institute for Health Research UCLH Biomedical Research Centre and Dioraphte Foundation (20230576). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The bacillus Mycobacterium tuberculosis (Mtb) is the human pathogen that causes tuberculosis (TB) infection and disease. Active, symptomatic, TB disease still accounts for ≈10 million cases and almost two million deaths annually, making it the most common infectious cause of death worldwide (World Health Organisation 2024). TB disease predominantly affects the lungs and initiates a robust host immune response involving multiple cellular components and cytokines, characterised by a pathognomonic histopathological feature, the TB granuloma, an aggregate of cells surrounding Mtb bacilli, necrotic tissue or calcification [1].

The clinical outcome of Mtb infection is likely dependent on the fate of host-pathogen interactions within individual granuloma [2], with both the lack of bacteriologic containment and immunopathology contributing to the manifestation of clinical symptoms. Determining which immune components play protective or deleterious roles in the natural history of TB disease is critical to establish desirable properties of efficacious TB vaccines and targets for adjuvant host-directed therapies in TB. For TNFα, genetic deletion and pharmacologic inhibition have revealed a key role in preventing TB disease [3,4]. However, unmasking of TB disease by checkpoint inhibitor therapy [5] has also exemplified that exaggerated cytokine activity, such as through IL-6 signalling, can also contribute to TB disease manifestation [6].

Several lines of evidence now point to the cytokine IL-17 playing a pivotal role in TB, and in this review, we will focus on summarising the key aspects of IL-17 cell biology that relate to Mtb infection, integrating in vitro and in vivo work from both human and non-human studies that highlight the beneficial and detrimental roles for IL-17 cytokine activity in Mtb infection. By offering polarised views, we aim to challenge readers’ pre-conceptions in either direction, before concluding with an overarching context-specific model for the role IL-17 cytokines play in TB.

The IL-17 cytokine family

It has been almost three decades since the proinflammatory IL-17 cytokine family was identified as an important player in both health and disease [7]. Although often referred to in the singular, there are 6 currently known isoforms of IL-17, giving rise to the homo- and heterodimeric cytokine family IL-17A to F. These IL-17 family members in turn signal via five IL-17 heterodimeric receptors, termed IL-17RA to E, which are composed of the widely expressed IL-17RA and another receptor, depending on the cell type. The signalling mechanisms employed by the IL-17 cytokine family have been extensively reviewed elsewhere [7].

Conventional αβ CD4 T cells differentiated to secrete IL-17A/F (Th17 cells) are a significant source of IL-17 in vivo, and the cytokines IL-1β, IL-6, IL-23 and TGF-β play a role in this process [7]. However, IL-17 cytokines also originate from CD8+  T cells, γδ T cells, NK cells, iNK cells, innate lymphoid cells (ILC), neutrophils, and mast cells [7–10]. Most studies investigating the role of IL-17 cytokines focus on IL-17A and IL-17F due to the high level of homology and the proximity of their gene loci in humans and mice. IL-17A & F bind the same receptor complex (IL-17RA and IL-17RC), which translates into highly overlapping biological function, including promoting the expression of antimicrobial peptides, upregulating production of neutrophil chemokines, and inducing the expression of tissue remodelling enzymes, such as matrix metalloproteinases (MMPs) [7]. Therefore, in this review, we will refer to both IL-17A and IL-17F as IL-17, unless specified.

A protective role for IL-17 in TB

IL-17 cytokine activity has shown protective roles in the context of non-TB infections, including Candida infection in which both mice and in humans with a deficiency in IL-17 cytokine activity, either through genetic deletions or pharmacological inhibition, who consistently show severe susceptibility to mucocutaneous candidiasis [11]. The mechanisms underlying this protection include the recruitment and bactericidal enhancement of neutrophils [12], as well as the induction of antimicrobial peptides [13,14].

Mouse studies

Mouse models of TB infection support a critical role played by IL-17 in controlling Mtb infection and preventing disease. Using an outbred, genetically diverse population of mice, low bacterial burden was associated with Th17 signatures, and it was notable that Th1 responses were low in the mice with Th17-associated protection [15]. A BCG vaccination study using similar models also found that mice protected from Mtb challenge following BCG vaccination had enhanced IL-17 responses, although in this case with IFNy co-expression [16]. Conversely, mice lacking Mtb-specific Th17 responses due to absence of the p19 subunit of the Th17-inducing IL-23 cytokine, were highly susceptible to TB disease at high inoculum doses after infection with the lab-adapted H37Rv Mtb strain [17], associated with a delay in neutrophil infiltration [18]. Separately, IL-17 responses were essential for protection from the virulent Mtb strain HN878 in mouse models, by signalling via the IL-17 receptor on non-haematopoietic cells to promote CXCL13 activity and T cell aggregation [19]. These findings in mouse models mirror Mtb strain-dependent differences in IL-17 cytokine production by human PBMC stimulated in vitro [20].

Further support for the importance of IL-17 activity stems from evidence that Mtb may have evolved a mechanism to limit Th17 development. Bone marrow-derived mouse dendritic cells infected with Mtb were observed to down-regulate the co-stimulatory molecule CD40, preventing Th17 polarisation in vivo [21]. Restoration of CD40 signalling on DCs enhanced Mtb-specific Th17 generation and reduced pathogen burden. Importantly, the Mtb-derived protease Hip1 was found to attenuate expression of the Th17-associated Notch ligand, Delta-like ligand 4 (DLL4) [22], suggesting that suppressing Th17 polarisation confers a survival benefit to the pathogen.

A protective role for IL-17 responses early in mouse Mtb infection is further strengthened by the pivotal role in vaccine protection played by this cytokine [23]. Greater protection offered by subcutaneous co-administration of BCG with a liposomal adjuvant was associated with the expansion of Mtb-specific lung Th17 cells and sustained IL-17 responses [24]. Similarly, subcutaneous vaccination with Mtb ESAT-6 peptide formulated with mycobacterial lipid adjuvant induced markedly superior Th17 responses in the lung and greater Mtb control, but these mice also experienced greater weight loss, indicating the careful balance between IL-17 immunity and pathology (addressed later in the review) [25]. Mucosal vaccination has gained significant traction, with the goal of promoting tissue memory responses. In the case of TB, intranasal BCG vaccination was superior to subcutaneous routes in protecting mice from subsequent Mtb challenge in an IL-17A- and neutrophil-dependent but IFNg-independent manner [26]. Similarly, protection against TB disease following mucosal vaccination adjuvanted by type II heat-labile enterotoxin, STING-activating cyclic dinucleotides or delta inulin microparticles was also found to be dependent on IL-17 [27–29]. Overall, the consistent association between protection and induction of IL-17 responses upon Mtb challenge strongly supports a protective role for early IL-17 responses following in vivo Mtb infection, at least in mouse models of TB.

Non-human primate studies

A limitation of the evidence from mouse studies is that Mtb is not a natural pathogen of mice, and therefore this in vivo model may not faithfully recapitulate the pathophysiological spectrum of human Mtb infection. In contrast, the non-human primate model of Mtb infection more closely reflects the natural history of Mtb infection, including the immunological components of the TB granuloma and the development of lung cavities [2]. Moreover, paucibacillary Mtb infection of macaques can result in asymptomatic infection, commonly observed in humans [30]. This is associated with greater expansion of IL-17 and IFNγ co-expressing Th17 cells (also termed Th17.1 cells) predominantly in the lungs compared to blood [31], a response proportional to the inoculum dose [32]. Investigators have also leveraged the autonomy of individual TB granuloma responses in NHP, relating elevated IL-17 responses (especially Th17.1) in granulomas with better bacteriologic control (lower Mtb burden) [33]. These findings have been recapitulated with greater resolution using single-cell RNA-seq approaches, again demonstrating that a greater frequency of Th17.1-like cells is associated with lower granuloma-associated bacterial load [34]. More recently, the same group has narrowed these observations down to Mtb-specific T-cells using MHC class II tetramers, observing Mtb-specific T-cells enriched in NHP granuloma, with frequency of these cells expressing the Th1 and Th17 transcription factors T-bet and RORγT inversely correlating with bacterial burden [35].

Like the findings in mice, vaccine studies in the NHP model of TB support a protective role for IL-17. Standard intradermal injection of BCG provides some level of protection in NHPs although it does not appear to induce sterilising immunity. Nevertheless, NHPs with relatively good disease control were found to have elevated Th17 and Th1 responses in restimulated PBMC compared to non-controllers [36]. More recently, intravenous administration of BCG (ivBCG) has emerged as an exciting vaccine model of protective immunity in NHPs, generating sterilising immunity in some vaccinated animals. Like the above study, restimulated airway cells from NHPs that received a protective (high) ivBCG dose displayed elevated Th1 and Th17 signalling [37]. In dose-ranging ivBCG experiments, in which not all animals are protected, airway CD4 T-cells producing IL-17 were identified as a key correlate of immune protection [38]. Importantly, these responses were much less evident in blood, highlighting the importance of studying the site of disease where possible. Another alternative vaccination route for BCG, via the airways, has also been explored by several groups. Although not always successful [39], sterilising immunity to repeated low-dose pulmonary Mtb challenge has been achieved via mucosal BCG vaccination [40]. In this case, protection was again associated with an expansion of polyfunctional Th17 cells in the lung. Together with the mouse studies highlighted, NHP data are consistent with a potentially central role for a Th17-like response in both natural infection and vaccine-induced immunity under controlled experimental settings.

Human studies

IL-17 production is a feature of human recall responses following Mtb infection, and it can be detected following ex vivo stimulation, in circulating aβ T cells, invariant T cells, MAIT cells, and γδ T cells [10, 41,42]. However, causal evidence supporting its protective role in human Mtb infection is limited. Several studies have shown lower circulating frequency of IL-17-producing T cell subsets in active TB compared to healthy controls [42,43], and greater IL-17 production following mitogen-stimulation of blood seen following culture conversion on TB antibiotic treatment [44]. Likewise, isoniazid preventative therapy of TB-exposed individuals (IGRA positive) restores Mtb-specific IL-17 responses [45]. More recently, a multimodal strategy including single-cell RNA-seq and flow cytometry demonstrated depletion of Th17-like cells in individuals prior to development of TB disease [46]. A similar Th17 signature was found to be significantly depleted in published bulk blood RNAseq data from Mtb-exposed adolescents in South Africa 1 year prior to the development of active TB disease [47]. Conversely, Mtb-specific, CD4+ T cell Th17 responses were found to be a feature of “resister” individuals that do not develop TB infection/disease despite prolonged exposure, although whether this IL-17 activity directly prevented the development of TB disease and through which mechanism remains unclear [48].

Human data on IL-17 responses from the site of TB disease is harder to obtain, but a greater frequency of IL-17-producing T cells was observed in pleural TB from mononuclear cells in the pleural space compared to blood [49], implying enrichment of these cells at the site of disease. More recently, lung explants from TB patients requiring surgery demonstrated evidence of lung tissue-resident CD4 T cells secreting IL-17, whereas the frequency of IL-17 production in the peripheral blood of these same patients was significantly lower [50]. In addition, the frequency of Mtb-specific IL-17-producing T-cells was inversely correlated with severity of TB disease [50]. In the same study, addition of exogenous IL-17 to a human granuloma model was associated with elevated levels of nitric oxide and attenuation of Mtb growth [50], suggesting a potential mechanism for promoting microbiological control in humans.

Finally, there is evidence from natural genetic variation that IL-17 activity plays a protective role in TB. Several case-control studies have identified associations between single-nucleotide polymorphisms (SNPs) in IL-17A and IL-17F gene promoters and the risk of developing TB disease [51–55]. Specifically, for the IL17A gene SNP rs2275913, the minor A allele results in greater IL-17 production by stimulated PBMC and is found with lower frequency in patients with TB disease compared to controls [55,56]. This observation has been reproduced in the Chinese Han population using an alternative IL17A SNP (rs8193036) that also affects IL-17 production and TB disease susceptibility [54]. These genetic associations support the notion that overall IL-17 cytokines form an important cornerstone of the host response to Mtb infection contributing to control of early or paucibacillary infection, and thus the prevention of disease.

A detrimental role for IL-17 in TB

Despite the arguments supporting a protective role for IL-17 responses in Mtb infection, this section will put forward a counter view, centred on the absence of disease risk in individuals with attenuated IL-17 signalling activity, as well as the potential for IL-17 responses and its downstream effectors to drive significant tissue pathology, promoting lung damage and disease transmission [57]. Indeed, IL-17-mediated pathology has been proposed as a significant contributor to disease in mouse models of the chronic fungal infection paracoccidiomycosis, a condition also associated with granulomatous lung inflammation [58].

Lack of protection offered by IL-17 in TB

Inborn errors of immunity have increasingly demonstrated the dependence on specific immunological components for protection against certain infectious diseases [59]. Complete autosomal recessive deficiency of IL-17 receptor subunits, IL-17RA or IL-17RC, which ablates IL-17 cytokine signalling, is associated with an increased risk of mucocutaneous candidiasis and staphylococcal, but not mycobacterial, infections [60,61]. A similar clinical phenotype has been described for individuals with genetic deficiencies in IL-17F cytokine [62] and mutations in the IL-17 receptor adaptor molecule ACT1 [63]. Gain-of-function mutations in STAT1 and bi-allelic loss-of-function mutations in RORC, the gene encoding the transcriptional factor for the Th17 lineage RORγT, both impair the differentiation of Th17 cells and are associated with increased risk of mycobacterial infections, but these defects also inhibit the activity of IFNγ [64], a cytokine indispensable for protection to mycobacterial diseases [65]. Genetic defects in the signalling of cytokine receptors that promote Th17 differentiation, IL-1 and IL-6, are associated with increased risk of pyogenic, but not mycobacterial, infections [6,59,66]. Comparable to the effect of inborn deficiencies in these pathways, autoantibodies to cytokines have recently been identified as playing a potentially significant causative role in the susceptibility of infectious diseases, illustrated by the association between IFNγ-targeting autoantibodies and increased risk of mycobacteria disease, including TB [67]. However, individuals with autoantibodies to IL-17 or IL-6, while susceptible to some infections, including mucocutaneous candidiasis for IL-17, are not susceptible to mycobacterial diseases [67].

The associations between IL-17 SNPs and protection from TB disease described earlier need to be interpreted with caution due to uncertainty around generalisability in all populations, as well as the lack of functional correlation between most SNPs and cytokine production. Moreover, the ‘protective’ rs2275913 SNP A allele that results in greater IL-17 production [68] is also associated with radiologically more severe TB disease [56], hyperinflammatory responses in other mycobacterial infections, such as BCG-induced osteitis [69], leprosy type 1 reactions [70], giant cell arteritis [71], ulcerative colitis [72] and chronic periodontitis [73]. Similarly, genetic variants that increase activity of the IL-1 & IL-6 pathways have also been associated with more severe TB disease [66,74]. More recently, a meta-analysis of 17 genome-wide association studies (GWAS) studies used Mendelian randomisation to attribute lower risk of TB disease with the IL-6 receptor allele that attenuates in vivo IL-6 signalling and closely phenocopies the effect of pharmacologic IL-6 antagonism [6]. This further supports the notion that elevated IL-6 activity may contribute to TB disease risk, although a functional relationship between this phenotype and greater IL-17 activity has not been established.

Biologic agents that inhibit the activity of IL-17 and cytokine regulators of Th17 differentiation have been used extensively to treat chronic inflammatory conditions, such as psoriasis and ankylosing spondylitis. However, despite extensive and ongoing post-licensing surveillance, an increased risk of TB disease has not been observed with secukinumab (targeting IL-17A) as well as biologics targeting Th17-differentiating cytokines [75], unlike TNF-blocking biologics [3]. Moreover, an in vitro model of Mtb dormancy showed reactivation using anti-TNF therapy (adalimumab), but not secukinumab [76], and IL-17 blockade in Mtb-infected mice does not result in elevated bacterial growth, unlike the effects of TNF inhibition [77].

IL-17 as a driver of pathology in TB disease

Once TB disease is established, exaggerated activity of the IL-17 cytokine axis, including drivers of Th17 differentiation, may promote excessive inflammation and tissue pathology.

Several human chronic diseases are characterised by elevated IL-17 activity at the site of disease, including psoriasis and inflammatory bowel disease, and the central role played by this cytokine in driving pathological inflammation is illustrated by robust and sustained clinical responses achieved by biologics blocking the IL-17 cytokine axis [78]. Moreover, Th17 cells in TB lesions make up a greater proportion of the total T cell population than that observed in other diseases [79], and crucially this appears to translate into functional IL-17 activity within and beyond the macroscopic edge of human TB granuloma [80]. Nevertheless, these cross-sectional assessments cannot negate confounding from differences in disease duration and antigenic burden, an aspect overcome in studies using an antigen challenge model to interrogate in vivo human immune recall responses in TB patients. Repurposing the tuberculin skin test (TST) from use as a diagnostic investigation into a research tool [79,81,82] revealed that standardised in vivo antigen stimulation induced greater IL-17 responses at the site of TSTs in TB patients compared to healthy individuals with past Mtb exposure or cured TB [79]. Notably, this difference was not observed for other inflammatory cytokines such as IFNγ or TNFα [79]. The elevated IL-17 activity was accompanied by greater IL-1 and IL-6 cytokine responses at the site of TST, as well as from ex vivo-stimulated monocytes in active TB [79], indicating that monocytic infiltration to the site of host-pathogen interactions may generate a cytokine environment that favours in situ Th17 differentiation and IL-17 cytokine activity [79,83–86].

Parallels between mouse models and human TB allude to common mechanisms of immunopathology. Robert Koch’s attempt to treat TB disease with inoculation of mycobacterial extracts was not only clinically ineffective but also resulted in harmful exaggerated inflammation both at the site of inoculation and established disease [87]. Similarly, repeated mycobacterial antigen challenge through BCG vaccination of mice with established Mtb infection amplified inflammatory responses to the detriment of the host through exaggerated IL-17 and neutrophil activity [88]. IL-17 responses also drive pathological inflammation following Mtb infection of mice deficient in IFNγ or IL-27 signalling [89–92], and mouse Mtb infection in the context of a chronic viral infection also promotes Th17-mediated neutrophilic immunopathology [93]. In turn, this observation may explain the association between elevated IL-17 activity and hyperinflammatory responses seen with immune reconstitution in HIV [94].

IL-17 induces the expression of traditional neutrophil chemokine molecules (e.g., CXCL8/IL8) as well as calprotectin, a heterodimer of S100A8/9 proteins, and beta defensins, both of which promote neutrophil chemotaxis alongside their antimicrobial properties [95–97]. In Mtb-infected mice, calprotectin promotes neutrophil accumulation and tissue pathology without additional benefit in antimicrobial function [90,98]. S100A8/9 protein expression is observed in human TB granuloma [90], and in the human TST challenge model both S100A8/9 and beta defensins, as well as CXCL8, are overexpressed in response to standardised in vivo antigen stimulation in active TB patients relative to controls [79]. These observations may explain the presence of neutrophils in human TB granuloma [80,99], and accumulation in greater numbers at the site of the human TST challenge in active TB [79]. Human neutrophil stimulation by Mtb can generate neutrophil extracellular traps (NETs) that contain tissue-damaging matrix MMPs [99]. This process, termed NETosis, is closely linked with IL-17, which promotes NETosis and drives further Th17 differentiation, amplifying neutrophil recruitment [100,101]. Importantly, elevated blood neutrophil counts predict radiological severity of lung damage at the end of treatment and mortality in human TB [102,103].

Independent of its role in neutrophil recruitment, IL-17 can also promote tissue damage through the direct induction of MMP secretion by epithelial cells and fibroblasts [104,105]. These enzymes can degrade airway tissue and promote cavitation and are found in elevated levels in the airway of patients with TB disease [106]. The activity of these proteases relates to the extent of human lung disease, and recently use of doxycycline, an inhibitor of MMP activity, as an adjunct to antibiotics showed promise in reducing inflammation and cavitation of pulmonary TB disease [107]. In this context, it is striking that in the human TST challenge model, genes that showed the greatest differential induction in active TB patients compared to controls were MMP-1, -3 and -9, indicating that TB disease may polarise tissue responses to induce further tissue destruction at the site of host-pathogen interactions through the activity of these enzymes [79].

A detrimental role for the IL-17 axis cytokine activity in TB disease is further supported by associations with disease severity. Elevated IL-6 levels and increased frequency of Th17 cells are found in the pleural space of patients with more extensive TB lung lesions [108,109], and stimulation of granuloma-derived T cells induces greater IL-17 production in macaques with extrapulmonary TB dissemination, compared to those with disease restricted to the lungs [110]. IL-17 responses also play a central role in hyper-inflammatory, immune reconstitution responses seen in HIV-TB co-infection [94]. Moreover, the antigen-mediated expansion in blood of IL-17-IFNγ co-expressing Th17.1 cells, strongly associated with tissue pathology in other inflammatory conditions [111–115], correlates with more advanced TB lung disease in humans [116]. In diabetes, which is associated with more radiologically advanced lung disease [117], elevated TB-specific Th17 responses are evident in individuals that fail to control dysglycemia following TB treatment [118], and lack of microbiological clearance at 2 months of TB treatment is specifically associated with elevated circulating IL-17 levels [119].

Although these cross-sectional assessments ultimately cannot truly establish pathological causality, further evidence for excessive inflammation driving TB disease comes from human interventional data. Anakinra, a recombinant form of the human soluble IL-1R, has shown some clinical benefit in dampening excessive inflammation in cases of HIV-associated TB-IRIS [120,121], as well as reduced lung inflammation with no deleterious effect in both TB-infected mice and macaques [122]. Instead, drugs that target the T cell checkpoint molecule PD-1 can unmask and exacerbate TB disease [5,123], and both in vivo and ex vivo attenuation of PD-1 activity is associated with elevated IL-17, as well as IFNγ, responses by CD4+ T cells [116,124–126].

Model for the role of IL-17 in TB

Collating the polarised arguments presented in this review, we conclude that IL-17 plays a dichotomous role in the context of human Mtb infections. Data from the paucibacillary, subclinical stages of the infection, human genetic polymorphisms, in vitro Mtb infections of myeloid cells, and animal models of early infection or vaccination support IL-17 responses accelerating bacterial clearance and preventing disease. We speculate this occurs by promoting infiltration of activated neutrophils that support bacterial clearance through induction of reactive oxygen species and antimicrobial proteins, although the effect of IL-17 on macrophage microbicidal activity cannot be excluded, possibly in conjunction with other cytokines. Moreover, the precise mechanism by which Th17.1 cells confer protection is not clear, especially whether there is genuine synergy in the activity of IL-17 and IFNγ, or if this phenotype is simply reflective of the functional plasticity of Th17 cell types. Nevertheless, the absence of a TB susceptibility phenotype in individuals with no IL-17 signalling suggests that this cytokine is unlikely to be essential in the resolution of early human Mtb infection or maintenance of latency. In contrast, in the presence of established TB disease, effector functions downstream of persistent and exaggerated IL-17 activity may not provide additional benefit in bacterial clearance but instead promote bystander tissue damage detrimental to host health even beyond antibiotic cure of disease, exemplified by the syndrome of post-TB lung disease (PTLD) [127].

It remains unclear whether IL-17-mediated processes that favour the resolution of early infection are the same as the ones that later drive pathology. This possibility is exemplified by IL-17 and IFNγ co-expressing Th17.1 cells being associated with both granuloma sterilisation in early macaque TB [33,34], and tissue destruction in chronic, non-resolving inflammatory diseases [111–113]. Similarly, in mice, type I IFN, despite promoting neutrophil infiltration, can antagonise macrophage accumulation and CD4 T cell activation, making mice susceptible to TB [128], whereas in established human TB tissue, type I IFN activity may limit the extent of tissue pathology [129]. Both these examples illustrate the importance of interpreting the functional and kinetic effects of cytokines in the context of the wider microenvironment around Mtb infection, which may ultimately determine the balance between protection and pathology.

Overall, we propose that IL-17 activity in TB infections may relate to bacterial burden and granuloma size, with small and/or paucibacillary lesions inducing sufficient IL-17 activity, likely in the context of other cytokines, to enhance additive bactericidal function and contribute to local control. However, rising or persistent bacterial load and granuloma necrosis further amplifies IL-17 responses to the point where benefit from bactericidal activity is greatly outweighed by tissue damage. The resultant chronic inflammatory state may also impact the function of monocytes and their myeloid progenitors [130,131], increasing their potential to promote Th17 differentiation and chemoattract neutrophils [79]. Similar models of disease pathogenesis have been proposed in the granulomatous disease sarcoidosis [132], and may explain the positive association between the size of the Mtb infection inoculum and IL-17 responses in macaques [32].

Implications for clinical translation

The increased awareness of the role played by IL-17 in TB biology has been harnessed for therapeutic benefit. In vaccination, efforts are now focused on inducing Th17 responses via novel vaccine adjuvants. In particular, the pattern recognition receptor Mincle appears to be crucial for promoting Th17 polarisation [133], and its ligands include trehalose dimycolate (TDM), a major cell wall component of Mtb [134]. A range of synthetic Mincle ligands have been developed that promote Th17 expansion [135], several of which are being explored for TB vaccines. For example, the synthetic Mincle agonist UM-1098 promotes Th17 and Th1 responses in mice when combined with M72 vaccine antigens on silica nanoparticles [136], though protection was inferior to BCG. In addition, Mincle can be combined with other agonists, as in the CAF10b liposome adjuvant, which combines Mincle and a TLR9 agonist. This strongly promotes Th17 and Th1 Mtb-specific response in conjunction with the novel TB vaccine antigen H107 [137] and is currently in a first-in-human trial (ClinicalTrials.gov ID NCT06050356). In addition, several groups have demonstrated that mucosal delivery of various TB vaccines promotes Mtb-specific Th17 responses [29,138,139], which are closely associated with vaccine-induced protection against TB disease [38].

In contrast, the strongest rationale for modulating IL-17 activity in TB disease is to inhibit its function in the context of established disease to minimise immunopathology. In pulmonary TB, the most common disease form, PTLD is increasingly being recognised as a major contributor to chronic lung disease among >155 million TB survivors worldwide, impacting quality of life and economic productivity, but without preventative treatments [127]. Host-directed therapeutic strategies to improve PTLD are currently focussed on interventions that are adjunctive to standard antibiotic therapy [140]. To date no study has proposed direct attenuation of IL-17 activity itself, although monoclonal antibodies that neutralise IL-17A are licenced (secukinumab) and could be repurposed [76]. Indirect attenuation of the IL-17 axis may also prove beneficial, with inhibition of IL-1 or IL-6 activity reducing hyperinflammation and the risk of PTLD by preventing downstream Th17 differentiaon [79,121], whereas direct MMP inhibition in cavitary lung TB diseases may be beneficial by blocking processes downstream of exaggerated IL-17 activity [107]. The benefit of IL-17 blockade may be greatest in extrapulmonary TB where non-specific corticosteroid therapy has known adjunctive therapeutic benefit [141–143]. Ultimately, it’s likely that interventional experimental medicine studies will be required to determine the mechanistic and clinical effects of intervening on the IL-17 axis, as well as the subset of patients that may most benefit [6,144].

Conclusions

We have summarised the proposed dual role of IL-17 in TB both in Table 1 and Fig 1. Future work will need to define the cellular effectors involved in IL-17 associated protection and pathology, requiring in vivo, ex vivo and in situ assessments at the single-cell level. In addition, it will be important to develop correlates of tissue IL-17 activity to permit their rapid quantification following vaccination, as well as in the context of established TB disease. Nevertheless, our proposed model implies that disease context is key to understanding and harnessing the role of IL-17 in TB. Vaccines that yield IL-17-generating T cell memory responses are likely to contribute to protection from TB disease by promoting rapid eradication of paucibacillary inocula. In contrast, in established TB disease, attenuation of the pathologic functions of IL-17, or cytokines involved in inducing signalling through this axis, such as IL-1 or IL-6, may be beneficial. The use of host-directed biologics that target these cytokines, administered in adjunctive fashion alongside antibiotics, may safely accelerate the resolution of pathological processes, minimise long term tissue damage, and reduce transmission.

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Table 1. Summary of mechanisms associated with IL-17 activity, and how these impact outcomes in TB.

https://doi.org/10.1371/journal.ppat.1014054.t001

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Fig 1. Dual role of IL-17 responses and associated clinical outcomes at different stages of TB.

Protective role of Th17 – IL-17 in the early stages of Mtb infection (blue/left) and detrimental effects in the context of symptomatic active disease (red/right), and the IL-17-mediated mechanisms associated with these outcomes. Below, the drivers of IL-17 induction and the functional consequences of the ensuing IL-17 signalling activity: (1) dendritic cells (DCs) and macrophages (Mϕ) immune activation by Mtb, (2) release of IL-23, IL-1β, IL-6 and TGF-β to differentiate Th17 cells from naïve T cells (T0), CD40 expression on DCs is central to enhance Th17 polarisation, (3) release of IL-17 and IL-22 by activated Th17, which (4) triggers release of neutrophil chemokines and antimicrobial peptides from epithelial cells and alveolar macrophages that may control Mtb replication. (5) Neutrophils recruited to the site of infection contribute to ROS production which may be protective, but in established disease may also contribute to (6) induction of matrix metalloproteases that promote tissue damage. Figure generated using BioRender. Maseeme, M. (2026) https://BioRender.com/anzbb6v.

https://doi.org/10.1371/journal.ppat.1014054.g001

Learning points

  • IL-17 responses prevent disease in early-stage TB infection and following effective vaccination in animal models.
  • In established TB disease, persistent and exaggerated IL-17 activity may drive immunopathology.
  • Vaccines that generate IL-17-producing T cell memory responses are likely to contribute to protection from TB disease.
  • Attenuation of IL-17 activity, or upstream cytokines such as IL-1 or IL-6, may accelerate TB disease resolution and minimise long-term tissue damage.

Key papers in the field

  1. Mills, K. H. G. IL-17 and IL-17-producing cells in protection versus pathology. Nat. Rev. Immunol. 23, 38–54 (2023).
  2. Darrah, P. A. et al. Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature 577, 95–102 (2020).
  3. Ogongo, P. et al. Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung. The Journal of Clinical Investigation (2021).
  4. Cruz, A. et al. Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis. J. Exp. Med. 207, 1609–1616 (2010).
  5. Pollara, G. et al. Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease. Sci. Transl. Med. 13, (2021).

References

  1. 1. Cohen SB, Gern BH, Urdahl KB. The tuberculous granuloma and preexisting immunity. Annu Rev Immunol. 2022;40:589–614. pmid:35130029
  2. 2. Flynn JL, Chan J. Immune cell interactions in tuberculosis. Cell. 2022;185(25):4682–702. pmid:36493751
  3. 3. Zhang Z, Fan W, Yang G, Xu Z, Wang J, Cheng Q, et al. Risk of tuberculosis in patients treated with TNF-α antagonists: a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2017;7(3):e012567. pmid:28336735
  4. 4. Arias AA, Neehus A-L, Ogishi M, Meynier V, Krebs A, Lazarov T, et al. Tuberculosis in otherwise healthy adults with inherited TNF deficiency. Nature. 2024;633(8029):417–25. pmid:39198650
  5. 5. Barber DL, Sakai S, Kudchadkar RR, Fling SP, Day TA, Vergara JA, et al. Tuberculosis following PD-1 blockade for cancer immunotherapy. Sci Transl Med. 2019;11(475):eaat2702. pmid:30651320
  6. 6. Hamilton F, Schurz H, Yates TA, Gilchrist JJ, Möller M, Naranbhai V, et al. Altered IL-6 signalling and risk of tuberculosis: a multi-ancestry mendelian randomisation study. Lancet Microbe. 2025;6(1):100922. pmid:39579785
  7. 7. Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. 2023;23(1):38–54. pmid:35790881
  8. 8. Pan L, Chen X, Liu X, Qiu W, Liu Y, Jiang W, et al. Innate lymphoid cells exhibited IL-17-expressing phenotype in active tuberculosis disease. BMC Pulm Med. 2021;21(1):318. pmid:34641843
  9. 9. Ardain A, Domingo-Gonzalez R, Das S, Kazer SW, Howard NC, Singh A, et al. Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis. Nature. 2019;570(7762):528–32. pmid:31168092
  10. 10. Coulter F, et al. IL-17 production from T helper 17, mucosal-associated invariant T, and γδ cells in tuberculosis infection and disease. Front Immunol. 2017;8:1252.
  11. 11. Li J, Vinh DC, Casanova J-L, Puel A. Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals. Curr Opin Microbiol. 2017;40:46–57. pmid:29128761
  12. 12. Jiang L, Su Z, Zhang Y, Liu H, Wang H. LPS promotes the production of ROS in neutrophils to regulate their killing activity against Mycobacterium tuberculosis. Sci Rep. 2025;15(1):26785. pmid:40702070
  13. 13. Conti HR, Bruno VM, Childs EE, Daugherty S, Hunter JP, Mengesha BG, et al. IL-17 receptor signaling in oral epithelial cells is critical for protection against oropharyngeal candidiasis. Cell Host Microbe. 2016;20(5):606–17. pmid:27923704
  14. 14. Huppler AR, Conti HR, Hernández-Santos N, Darville T, Biswas PS, Gaffen SL. Role of neutrophils in IL-17-dependent immunity to mucosal candidiasis. J Immunol. 2014;192(4):1745–52. pmid:24442441
  15. 15. Proulx MK, Wiggins CD, Reames CJ, Wu C, Kiritsy MC, Xu P, et al. Noncanonical T cell responses are associated with protection from tuberculosis in mice and humans. J Exp Med. 2025;222(7):e20241760. pmid:40192640
  16. 16. Lai R, Gong DN, Williams T, Ogunsola AF, Cavallo K, Lindestam Arlehamn CS, et al. Host genetic background is a barrier to broadly effective vaccine-mediated protection against tuberculosis. J Clin Invest. 2023;133(13):e167762. pmid:37200108
  17. 17. Khader SA, Pearl JE, Sakamoto K, Gilmartin L, Bell GK, Jelley-Gibbs DM, et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-gamma responses if IL-12p70 is available. J Immunol. 2005;175(2):788–95. pmid:16002675
  18. 18. Freches D, Korf H, Denis O, Havaux X, Huygen K, Romano M. Mice genetically inactivated in interleukin-17A receptor are defective in long-term control of Mycobacterium tuberculosis infection. Immunology. 2013;140(2):220–31. pmid:23721367
  19. 19. Gopal R, Monin L, Slight S, Uche U, Blanchard E, Fallert Junecko BA, et al. Unexpected role for IL-17 in protective immunity against hypervirulent Mycobacterium tuberculosis HN878 infection. PLoS Pathog. 2014;10(5):e1004099. pmid:24831696
  20. 20. Ranaivomanana P, Rabodoarivelo MS, Ndiaye MDB, Rakotosamimanana N, Rasolofo V. Different PPD-stimulated cytokine responses from patients infected with genetically distinct Mycobacterium tuberculosis complex lineages. Int J Infect Dis. 2021;104:725–31. pmid:33556615
  21. 21. Sia JK, Bizzell E, Madan-Lala R, Rengarajan J. Engaging the CD40-CD40L pathway augments T-helper cell responses and improves control of Mycobacterium tuberculosis infection. PLoS Pathog. 2017;13(8):e1006530. pmid:28767735
  22. 22. Enriquez AB, Sia JK, Dkhar HK, Goh SL, Quezada M, Stallings KL, et al. Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection. iScience. 2022;25(5):104305. pmid:35586066
  23. 23. Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8(4):369–77. pmid:17351619
  24. 24. Woodworth JS, Clemmensen HS, Battey H, Dijkman K, Lindenstrøm T, Laureano RS, et al. A Mycobacterium tuberculosis-specific subunit vaccine that provides synergistic immunity upon co-administration with Bacillus Calmette-Guérin. Nat Commun. 2021;12(1):6658. pmid:34795205
  25. 25. Sulman S, Savidge BO, Alqaseer K, Das MK, Nezam Abadi N, Pearl JE, et al. Balance between protection and pathogenic response to aerosol challenge with Mycobacterium tuberculosis (Mtb) in mice vaccinated with TriFu64, a fusion consisting of three Mtb antigens. Vaccines (Basel). 2021;9(5):519. pmid:34070048
  26. 26. Aguilo N, Alvarez-Arguedas S, Uranga S, Marinova D, Monzón M, Badiola J, et al. Pulmonary but not subcutaneous delivery of BCG vaccine confers protection to tuberculosis-susceptible mice by an interleukin 17-dependent mechanism. J Infect Dis. 2016;213(5):831–9. pmid:26494773
  27. 27. Gopal R, Rangel-Moreno J, Slight S, Lin Y, Nawar HF, Fallert Junecko BA, et al. Interleukin-17-dependent CXCL13 mediates mucosal vaccine-induced immunity against tuberculosis. Mucosal Immunol. 2013;6(5):972–84. pmid:23299616
  28. 28. Jong RM, Van Dis E, Berry SB, Nguyenla X, Baltodano A, Pastenkos G, et al. Mucosal vaccination with cyclic dinucleotide adjuvants induces effective T cell homing and IL-17-dependent protection against Mycobacterium tuberculosis infection. J Immunol. 2022;208(2):407–19. pmid:34965963
  29. 29. Counoupas C, Ferrell KC, Ashhurst A, Bhattacharyya ND, Nagalingam G, Stewart EL, et al. Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependent protection against pulmonary tuberculosis. NPJ Vaccines. 2020;5(1):105. pmid:33298977
  30. 30. Dheda K, Perumal T, Fox GJ. Asymptomatic tuberculosis: undetected and underestimated, but not unimportant. Lancet. 2025;405(10492):1797–800. pmid:40127658
  31. 31. Shanmugasundaram U, Bucsan AN, Ganatra SR, Ibegbu C, Quezada M, Blair RV, et al. Pulmonary Mycobacterium tuberculosis control associates with CXCR3- and CCR6-expressing antigen-specific Th1 and Th17 cell recruitment. JCI Insight. 2020;5(14):e137858. pmid:32554933
  32. 32. Sharan R, Singh DK, Rengarajan J, Kaushal D. Characterizing early T cell responses in nonhuman primate model of tuberculosis. Front Immunol. 2021;12:706723. pmid:34484203
  33. 33. Gideon HP, Phuah J, Myers AJ, Bryson BD, Rodgers MA, Coleman MT, et al. Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization. PLoS Pathog. 2015;11(1):e1004603. pmid:25611466
  34. 34. Gideon HP, Hughes TK, Tzouanas CN, Wadsworth MH 2nd, Tu AA, Gierahn TM, et al. Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control. Immunity. 2022;55(5):827-846.e10. pmid:35483355
  35. 35. Grant NL, Kelly K, Maiello P, Abbott H, O’Connor S, Lin PL, et al. Mycobacterium tuberculosis-specific CD4 T cells expressing transcription factors T-Bet or RORγT associate with bacterial control in granulomas. mBio. 2023;14(3):e0047723. pmid:37039646
  36. 36. Wareham AS, Tree JA, Marsh PD, Butcher PD, Dennis M, Sharpe SA. Evidence for a role for interleukin-17, Th17 cells and iron homeostasis in protective immunity against tuberculosis in cynomolgus macaques. PLoS One. 2014;9(2):e88149. pmid:24505407
  37. 37. Peters JM, Irvine EB, Makatsa MS, Rosenberg JM, Wadsworth MH 2nd, Hughes TK, et al. High-dose intravenous BCG vaccination induces enhanced immune signaling in the airways. Sci Adv. 2025;11(1):eadq8229. pmid:39742484
  38. 38. Darrah PA, et al. Airway T cells are a correlate of i.v. Bacille Calmette-Guerin-mediated protection against tuberculosis in rhesus macaques. Cell Host Microbe 2023;31:962–77.e8. https://doi.org/10.1016/j.chom.2023.05.006 pmid:37267955
  39. 39. Darrah PA, Zeppa JJ, Maiello P, Hackney JA, Wadsworth MH 2nd, Hughes TK, et al. Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature. 2020;577(7788):95–102. pmid:31894150
  40. 40. Dijkman K, Sombroek CC, Vervenne RAW, Hofman SO, Boot C, Remarque EJ, et al. Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques. Nat Med. 2019;25(2):255–62. pmid:30664782
  41. 41. Peng MY, Wang ZH, Yao CY, Jiang LN, Jin QL, Wang J, et al. Interleukin 17-producing gamma delta T cells increased in patients with active pulmonary tuberculosis. Cell Mol Immunol. 2008;5(3):203–8. pmid:18582402
  42. 42. Scriba TJ, et al. Distinct, specific IL-17- and IL-22-producing CD4 T cell subsets contribute to the human anti-mycobacterial immune response. J Immunol. 2008;180:1962–70. https://doi.org/10.4049/jimmunol.180.3.1962 pmid:18209095
  43. 43. Perreau M, Rozot V, Welles HC, Belluti-Enders F, Vigano S, Maillard M, et al. Lack of Mycobacterium tuberculosis-specific interleukin-17A-producing CD4+ T cells in active disease. Eur J Immunol. 2013;43(4):939–48. pmid:23436562
  44. 44. Feng J-Y, Ho L-I, Chuang F-Y, Pan S-W, Chen Y-Y, Tung C-L, et al. Depression and recovery of IL-17A secretion in mitogen responses in patients with active tuberculosis-a prospective observational study. J Formos Med Assoc. 2021;120(4):1080–9. pmid:33020006
  45. 45. Ssekamatte P, Sitenda D, Nabatanzi R, Nakibuule M, Kibirige D, Kyazze AP, et al. Isoniazid preventive therapy modulates Mycobacterium tuberculosis-specific T-cell responses in individuals with latent tuberculosis and type 2 diabetes. Sci Rep. 2025;15(1):10423. pmid:40140681
  46. 46. Nathan A, Beynor JI, Baglaenko Y, Suliman S, Ishigaki K, Asgari S, et al. Multimodally profiling memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment and disease. Nat Immunol. 2021;22(6):781–93. pmid:34031617
  47. 47. Scriba TJ, Penn-Nicholson A, Shankar S, Hraha T, Thompson EG, Sterling D, et al. Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease. PLoS Pathog. 2017;13(11):e1006687. pmid:29145483
  48. 48. Sun M, Phan JM, Kieswetter NS, Huang H, Yu KKQ, Smith MT, et al. Specific CD4+ T cell phenotypes associate with bacterial control in people who “resist” infection with Mycobacterium tuberculosis. Nat Immunol. 2024;25(8):1411–21. pmid:38997431
  49. 49. Chen X, Zhang M, Liao M, Graner MW, Wu C, Yang Q, et al. Reduced Th17 response in patients with tuberculosis correlates with IL-6R expression on CD4+ T Cells. Am J Respir Crit Care Med. 2010;181(7):734–42. pmid:20019339
  50. 50. Ogongo P, Tezera LB, Ardain A, Nhamoyebonde S, Ramsuran D, Singh A, et al. Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung. J Clin Invest. 2021;131(10):e142014. pmid:33848273
  51. 51. Ocejo-Vinyals JG, de Mateo EP, Hoz MÁ, Arroyo JL, Agüero R, Ausín F, et al. The IL-17 G-152A single nucleotide polymorphism is associated with pulmonary tuberculosis in northern Spain. Cytokine. 2013;64(1):58–61. pmid:23778030
  52. 52. Mansouri F, Heydarzadeh R, Yousefi S. The association of interferon‐gamma, interleukin‐4 and interleukin‐17 single‐nucleotide polymorphisms with susceptibility to tuberculosis. APMIS. 2018;126(3):227–33.
  53. 53. Eskandari-Nasab E, Moghadampour M, Tahmasebi A, Asadi-Saghandi A. Interleukin-17 A and F gene polymorphisms affect the risk of tuberculosis: an updated meta-analysis. Indian J Tuberc. 2018;65(3):200–7. pmid:29933861
  54. 54. Wang W, Deng G, Zhang G, Yu Z, Yang F, Chen J, et al. Genetic polymorphism rs8193036 of IL17A is associated with increased susceptibility to pulmonary tuberculosis in Chinese Han population. Cytokine. 2020;127:154956. pmid:31864094
  55. 55. Domingo-Gonzalez R, Das S, Griffiths KL, Ahmed M, Bambouskova M, Gopal R, et al. Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis. JCI Insight. 2017;2(19):e92973. pmid:28978810
  56. 56. Rolandelli A, Hernández Del Pino RE, Pellegrini JM, Tateosian NL, Amiano NO, de la Barrera S, et al. The IL-17A rs2275913 single nucleotide polymorphism is associated with protection to tuberculosis but related to higher disease severity in Argentina. Sci Rep. 2017;7:40666. pmid:28098168
  57. 57. Ong CWM, Elkington PT, Friedland JS. Tuberculosis, pulmonary cavitation, and matrix metalloproteinases. Am J Respir Crit Care Med. 2014;190(1):9–18. pmid:24713029
  58. 58. Puerta-Arias JD, Pino-Tamayo PA, Arango JC, González Á. Depletion of neutrophils promotes the resolution of pulmonary inflammation and fibrosis in mice infected with Paracoccidioides brasiliensis. PLoS One. 2016;11(9):e0163985. pmid:27690127
  59. 59. Conti F, Marzollo A, Moratti M, Lodi L, Ricci S. Inborn errors of immunity underlying a susceptibility to pyogenic infections: from innate immune system deficiency to complex phenotypes. Clin Microbiol Infect. 2022;28(11):1422–8. pmid:35640842
  60. 60. Lévy R, Okada S, Béziat V, Moriya K, Liu C, Chai LYA, et al. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. Proc Natl Acad Sci U S A. 2016;113(51):E8277–85. pmid:27930337
  61. 61. Ling Y, Cypowyj S, Aytekin C, Galicchio M, Camcioglu Y, Nepesov S, et al. Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J Exp Med. 2015;212(5):619–31. pmid:25918342
  62. 62. Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011;332(6025):65–8. pmid:21350122
  63. 63. Boisson B, Wang C, Pedergnana V, Wu L, Cypowyj S, Rybojad M, et al. An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity. 2013;39(4):676–86. pmid:24120361
  64. 64. Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, et al. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science. 2015;349(6248):606–13. pmid:26160376
  65. 65. Bogunovic D, Byun M, Durfee LA, Abhyankar A, Sanal O, Mansouri D, et al. Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency. Science. 2012;337(6102):1684–8. pmid:22859821
  66. 66. Zhang G, Zhou B, Li S, Yue J, Yang H, Wen Y, et al. Allele-specific induction of IL-1β expression by C/EBPβ and PU.1 contributes to increased tuberculosis susceptibility. PLoS Pathog. 2014;10(10):e1004426. pmid:25329476
  67. 67. Puel A, Bastard P, Bustamante J, Casanova J-L. Human autoantibodies underlying infectious diseases. J Exp Med. 2022;219(4):e20211387. pmid:35319722
  68. 68. Espinoza JL, Takami A, Nakata K, Onizuka M, Kawase T, Akiyama H, et al. A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation. PLoS One. 2011;6(10):e26229. pmid:22028838
  69. 69. Liehu-Martiskainen M, Korppi M, Teräsjärvi J, Vuononvirta J, Huhtala H, Nuolivirta K, et al. Interleukin 17A gene polymorphism rs2275913 is associated with osteitis after the Bacillus Calmette-Guérin vaccination. Acta Paediatr. 2017;106(11):1837–41. pmid:28731539
  70. 70. Aquino JS, Ambrosio-Albuquerque EP, Alves HV, Macedo LC, Visentainer L, Sell AM, et al. IL8 and IL17A polymorphisms associated with multibacillary leprosy and reaction type 1 in a mixed population from southern Brazil. Ann Hum Genet. 2019;83(2):110–4. pmid:30303246
  71. 71. Márquez A, Hernández-Rodríguez J, Cid MC, Solans R, Castañeda S, Fernández-Contreras ME, et al. Influence of the IL17A locus in giant cell arteritis susceptibility. Ann Rheum Dis. 2014;73(9):1742–5. pmid:24919468
  72. 72. Hayashi R, Tahara T, Shiroeda H, Saito T, Nakamura M, Tsutsumi M, et al. Influence of IL17A polymorphisms (rs2275913 and rs3748067) on the susceptibility to ulcerative colitis. Clin Exp Med. 2013;13(4):239–44. pmid:22955700
  73. 73. Zacarias JMV, Sippert EÂ, Tsuneto PY, Visentainer JEL, de Oliveira e Silva C, Sell AM. The influence of interleukin 17A and IL17F polymorphisms on chronic periodontitis disease in Brazilian patients. Mediators Inflamm. 2015;2015:147056. pmid:26339129
  74. 74. Delgobo M, Mendes DA, Kozlova E, Rocha EL, Rodrigues-Luiz GF, Mascarin L, et al. An evolutionary recent IFN/IL-6/CEBP axis is linked to monocyte expansion and tuberculosis severity in humans. Elife. 2019;8:e47013. pmid:31637998
  75. 75. Elewski BE, Baddley JW, Deodhar AA, Magrey M, Rich PA, Soriano ER, et al. Association of secukinumab treatment with tuberculosis reactivation in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. JAMA Dermatol. 2021;157(1):43–51. pmid:33001147
  76. 76. Kammüller M, Tsai T-F, Griffiths CE, Kapoor N, Kolattukudy PE, Brees D, et al. Inhibition of IL-17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections. Clin Transl Immunol. 2017;6(8):e152. pmid:28868144
  77. 77. Segueni N, Tritto E, Bourigault M-L, Rose S, Erard F, Le Bert M, et al. Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization. Sci Rep. 2016;6:36923. pmid:27853279
  78. 78. Batta S, Khan R, Zaayman M, Limmer A, Kivelevitch D, Menter A. IL-17 and -23 inhibitors for the treatment of psoriasis. EMJ Allergy Immunol. 2023.
  79. 79. Pollara G, Turner CT, Rosenheim J, Chandran A, Bell LCK, Khan A, et al. Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease. Sci Transl Med. 2021;13(592):eabg7673. pmid:33952677
  80. 80. Dheda K, Lenders L, Srivastava S, Magombedze G, Wainwright H, Raj P, et al. Spatial network mapping of pulmonary multidrug-resistant tuberculosis cavities using RNA sequencing. Am J Respir Crit Care Med. 2019;200(3):370–80. pmid:30694692
  81. 81. Lachmandas E, Rios-Miguel AB, Koeken VACM, van der Pasch E, Kumar V, Matzaraki V, et al. Tissue metabolic changes drive cytokine responses to Mycobacterium tuberculosis. J Infect Dis. 2018;218(1):165–70. pmid:29618104
  82. 82. Bell LCK, Pollara G, Pascoe M, Tomlinson GS, Lehloenya RJ, Roe J, et al. In vivo molecular dissection of the effects of HIV-1 in active tuberculosis. PLoS Pathog. 2016;12(3):e1005469. pmid:26986567
  83. 83. Wang X, Barnes PF, Huang F, Alvarez IB, Neuenschwander PF, Sherman DR, et al. Early secreted antigenic target of 6-kDa protein of Mycobacterium tuberculosis primes dendritic cells to stimulate Th17 and inhibit Th1 immune responses. J Immunol. 2012;189(6):3092–103. pmid:22904313
  84. 84. van de Veerdonk FL, Teirlinck AC, Kleinnijenhuis J, Kullberg BJ, van Crevel R, van der Meer JWM, et al. Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1. J Leukoc Biol. 2010;88(2):227–32. pmid:20299682
  85. 85. Stephen-Victor E, Sharma VK, Das M, Karnam A, Saha C, Lecerf M, et al. IL-1β, but not programed death-1 and programed death ligand pathway, is critical for the human Th17 Response to Mycobacterium tuberculosis. Front Immunol. 2016;7:465. pmid:27867382
  86. 86. Liu Y, Wang R, Jiang J, Cao Z, Zhai F, Sun W, et al. A subset of CD1c+ dendritic cells is increased in patients with tuberculosis and promotes Th17 cell polarization. Tuberculosis (Edinb). 2018;113:189–99. pmid:30514502
  87. 87. Ligon BL. Robert Koch: nobel laureate and controversial figure in tuberculin research. Semin Pediatr Infect Dis. 2002;13(4):289–99. pmid:12491235
  88. 88. Cruz A, Fraga AG, Fountain JJ, Rangel-Moreno J, Torrado E, Saraiva M, et al. Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis. J Exp Med. 2010;207(8):1609–16. pmid:20624887
  89. 89. Desvignes L, Ernst JD. Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis. Immunity. 2009;31(6):974–85. pmid:20064452
  90. 90. Gopal R, Monin L, Torres D, Slight S, Mehra S, McKenna KC, et al. S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am J Respir Crit Care Med. 2013;188(9):1137–46. pmid:24047412
  91. 91. Nandi B, Behar SM. Regulation of neutrophils by interferon-γ limits lung inflammation during tuberculosis infection. J Exp Med. 2011;208(11):2251–62. pmid:21967766
  92. 92. Erdmann H, Behrends J, Ritter K, Hölscher A, Volz J, Rosenkrands I, et al. The increased protection and pathology in Mycobacterium tuberculosis-infected IL-27R-alpha-deficient mice is supported by IL-17A and is associated with the IL-17A-induced expansion of multifunctional T cells. Mucosal Immunol. 2018;11(4):1168–80. pmid:29728641
  93. 93. Xu W, Snell LM, Guo M, Boukhaled G, Macleod BL, Li M, et al. Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection. Immunity. 2021;54(3):526-541.e7. pmid:33515487
  94. 94. Bruyn ED, Fukutani KF, Rockwood N, Schutz C, Meintjes G, Arriaga MB, et al. Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis. Lancet Microbe. 2021;2(8):e375–85. pmid:34386782
  95. 95. Jukic A, Bakiri L, Wagner EF, Tilg H, Adolph TE. Calprotectin: from biomarker to biological function. Gut. 2021;70:1978–88.
  96. 96. Röhrl J, Yang D, Oppenheim JJ, Hehlgans T. Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2. J Immunol. 2010;184(12):6688–94. pmid:20483750
  97. 97. Hu S, He W, Du X, Yang J, Wen Q, Zhong X-P, et al. IL-17 production of neutrophils enhances antibacteria ability but promotes arthritis development during Mycobacterium tuberculosis infection. EBioMedicine. 2017;23:88–99. pmid:28821374
  98. 98. Scott NR, Swanson RV, Al-Hammadi N, Domingo-Gonzalez R, Rangel-Moreno J, Kriel BA, et al. S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis. J Clin Invest. 2020;130(6):3098–112. pmid:32134742
  99. 99. Ong CWM, Elkington PT, Brilha S, Ugarte-Gil C, Tome-Esteban MT, Tezera LB, et al. Neutrophil-derived MMP-8 drives AMPK-dependent matrix destruction in human pulmonary tuberculosis. PLoS Pathog. 2015;11(5):e1004917. pmid:25996154
  100. 100. Zhang Y, Chandra V, Riquelme Sanchez E, Dutta P, Quesada PR, Rakoski A, et al. Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer. J Exp Med. 2020;217(12):e20190354. pmid:32860704
  101. 101. Su D, Li L, Xie H, Ai L, Wang Y, Yang B, et al. IL-17A drives a fibroblast-neutrophil-NET axis to exacerbate immunopathology in the lung with diffuse alveolar damage. Front Immunol. 2025;16:1574246. pmid:40568586
  102. 102. Lowe DM, Bandara AK, Packe GE, Barker RD, Wilkinson RJ, Griffiths CJ, et al. Neutrophilia independently predicts death in tuberculosis. Eur Respir J. 2013;42(6):1752–7. pmid:24114967
  103. 103. Jones TPW, Dabbaj S, Mandal I, Cleverley J, Cash C, Lipman MCI, et al. The blood neutrophil count after 1 month of treatment predicts the radiologic severity of lung disease at treatment end. Chest. 2021;160(6):2030–41. pmid:34331904
  104. 104. Singh S, Maniakis-Grivas G, Singh UK, Asher RM, Mauri F, Elkington PT, et al. Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis. J Pathol. 2018;244(3):311–22. pmid:29210073
  105. 105. Wu Y, Zhu L, Liu L, Zhang J, Peng B. Interleukin-17A stimulates migration of periodontal ligament fibroblasts via p38 MAPK/NF-κB -dependent MMP-1 expression. J Cell Physiol. 2014;229(3):292–9. pmid:23929359
  106. 106. Elkington P, Shiomi T, Breen R, Nuttall RK, Ugarte-Gil CA, Walker NF, et al. MMP-1 drives immunopathology in human tuberculosis and transgenic mice. J Clin Invest. 2011;121(5):1827–33. pmid:21519144
  107. 107. Miow QH, Vallejo AF, Wang Y, Hong JM, Bai C, Teo FS, et al. Doxycycline host-directed therapy in human pulmonary tuberculosis. J Clin Invest. 2021;131(15):e141895. pmid:34128838
  108. 108. Losada PX, Perdomo-Celis F, Castro M, Salcedo C, Salcedo A, DeLaura I, et al. Locally-secreted interleukin-6 is related with radiological severity in smear-negative pulmonary tuberculosis. Cytokine. 2020;127:154950. pmid:31864093
  109. 109. Morais-Papini TF, Coelho-Dos-Reis JGA, Wendling APB, do Vale Antonelli LR, Wowk PF, Bonato VLD, et al. Systemic Immunological changes in patients with distinct clinical outcomes during Mycobacterium tuberculosis infection. Immunobiology. 2017;222(11):1014–24. pmid:28619539
  110. 110. Lin PL, Maiello P, Gideon HP, Coleman MT, Cadena AM, Rodgers MA, et al. PET CT identifies reactivation risk in cynomolgus macaques with latent M. tuberculosis. PLoS Pathog. 2016;12(7):e1005739. pmid:27379816
  111. 111. Ramesh R, Kozhaya L, McKevitt K, Djuretic IM, Carlson TJ, Quintero MA, et al. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med. 2014;211(1):89–104. pmid:24395888
  112. 112. Misra DP, Agarwal V. Th17.1 lymphocytes: emerging players in the orchestra of immune-mediated inflammatory diseases. Clin Rheumatol. 2022;41(8):2297–308. pmid:35546376
  113. 113. Park E, Ciofani M. Th17 cell pathogenicity in autoimmune disease. Exp Mol Med. 2025;57(9):1913–27. pmid:40887501
  114. 114. Nizzoli G, Burrello C, Cribiù FM, Lovati G, Ercoli G, Botti F, et al. Pathogenicity of in vivo generated intestinal Th17 lymphocytes is IFNγ dependent. J Crohns Colitis. 2018;12(8):981–92. pmid:29697763
  115. 115. Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A. 2015;112(22):7061–6. pmid:26038559
  116. 116. Jurado JO, Pasquinelli V, Alvarez IB, Peña D, Rovetta AI, Tateosian NL, et al. IL-17 and IFN-γ expression in lymphocytes from patients with active tuberculosis correlates with the severity of the disease. J Leukoc Biol. 2012;91(6):991–1002. pmid:22416258
  117. 117. Zhan S, Juan X, Ren T, Wang Y, Fu L, Deng G, et al. Extensive radiological manifestation in patients with diabetes and pulmonary tuberculosis: a cross-sectional study. Ther Clin Risk Manag. 2022;18:595–602. pmid:35645562
  118. 118. Krause R, Warren CM, Simmons JD, Rebeiro PF, Maruri F, Karim F, et al. Failure to decrease HbA1c levels following TB treatment is associated with elevated Th1/Th17 CD4+ responses. Front Immunol. 2023;14:1151528. pmid:37313404
  119. 119. Brake J, Ajie M, Sumpter NA, Koesoemadinata RC, Soetedjo NNM, Santoso P, et al. Inflammation and dyslipidaemia in combined diabetes and tuberculosis; a cohort study. iScience. 2025;28(6):112760. pmid:40568317
  120. 120. Keeley AJ, Parkash V, Tunbridge A, Greig J, Collini P, McKane W, et al. Anakinra in the treatment of protracted paradoxical inflammatory reactions in HIV-associated tuberculosis in the United Kingdom: a report of two cases. Int J STD AIDS. 2020;31(8):808–12. pmid:32631210
  121. 121. van Arkel C, et al. Interleukin-1 receptor antagonist anakinra as treatment for paradoxical responses in HIV-negative tuberculosis patients: a case series. MED. 2022;3:603-611.e2.
  122. 122. Winchell CG, et al. Evaluation of IL-1 blockade as a host-directed therapy for tuberculosis in mice and macaques. BioRxiv. 2019.
  123. 123. Liu K, Wang D, Yao C, Qiao M, Li Q, Ren W, et al. Increased tuberculosis incidence due to immunotherapy based on PD-1 and PD-L1 blockade: a systematic review and meta-analysis. Front Immunol. 2022;13:727220. pmid:35663958
  124. 124. Kauffman KD, Sakai S, Lora NE, Namasivayam S, Baker PJ, Kamenyeva O, et al. PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques. Sci Immunol. 2021;6(55):eabf3861. pmid:33452107
  125. 125. Bandaru A, Devalraju KP, Paidipally P, Dhiman R, Venkatasubramanian S, Barnes PF, et al. Phosphorylated STAT3 and PD-1 regulate IL-17 production and IL-23 receptor expression in Mycobacterium tuberculosis infection. Eur J Immunol. 2014;44(7):2013–24. pmid:24643836
  126. 126. Zhang Y-B, Liu S-J, Hu Z-D, Zhou J-X, Wang Y-Z, Fang B, et al. Increased Th17 activation and gut microbiota diversity are associated with pembrolizumab-triggered tuberculosis. Cancer Immunol Immunother. 2020;69(12):2665–71. pmid:32761425
  127. 127. Auld SC, Barczak AK, Bishai W, Coussens AK, Dewi IMW, Mitini-Nkhoma SC, et al. Pathogenesis of post-tuberculosis lung disease: defining knowledge gaps and research priorities at the second international post-tuberculosis symposium. Am J Respir Crit Care Med. 2024;210(8):979–93. pmid:39141569
  128. 128. Branchett WJ, Stavropoulos E, Shields J, Al-Dibouni A, Cardoso M, Fernandes AI, et al. Type I IFN drives neutrophil swarming, impeding lung T cell-macrophage interactions and TB control. J Exp Med. 2025;222(12):e20250466. pmid:40986319
  129. 129. Szydlo-Shein A, et al. Type I interferon responses contribute to immune protection against mycobacterial infection. 2025. https://doi.org/10.7554/eLife.106799.1
    • 130. Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonça LE, Pacis A, et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172(1–2):176–90.e19. pmid:29328912
    • 131. Khan N, et al. M. tuberculosis reprograms hematopoietic stem cells to limit myelopoiesis and impair trained immunity. Cell 2020;183:752–70.e22.
    • 132. Talreja J, Talwar H, Bauerfeld C, Grossman LI, Zhang K, Tranchida P, et al. HIF-1α regulates IL-1β and IL-17 in sarcoidosis. Elife. 2019;8:e44519. pmid:30946009
    • 133. Martínez-López M, Iborra S, Conde-Garrosa R, Mastrangelo A, Danne C, Mann ER, et al. Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity. Immunity. 2019;50(2):446–61. https://doi.org/10.1016/j.immuni.2018.12.020
    • 134. Lee W-B, Deretic V, Kang J-S, Yan J-J, Lee MS, Jeon B-Y, et al. Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway. PLoS Pathogens. 2012;8(4):e1002614. https://doi.org/10.1371/journal.ppat.1002614
    • 135. Weth AF, Dangerfield EM, Timmer MSM, Stocker BL, et al. Recent Advances in the Development of Mincle-Targeting Vaccine Adjuvants. Vaccines. 2024;12(12):1320. https://doi.org/10.3390/vaccines12121320
    • 136. Rungelrath V, Ahmed M, Hicks L, Miller SM, Ryter KT, Montgomery K, et al. Vaccination with Mincle agonist UM-1098 and mycobacterial antigens induces protective Th1 and Th17 responses. npj Vaccines. 2024;9(1):null. https://doi.org/10.1038/s41541-024-00897-x
    • 137. Woodworth JS, Contreras V, Christensen D, Naninck T, Kahlaoui N, Gallouët A-S, et al. MINCLE and TLR9 agonists synergize to induce Th1/Th17 vaccine memory and mucosal recall in mice and non-human primates. Nature Communications. 2024;15(1):null. https://doi.org/10.1038/s41467-024-52863-9
    • 138. Sefat KMSR, Kumar M, Kehl S, Kulkarni R, Leekha A, Paniagua M-M, et al. An intranasal nanoparticle vaccine elicits protective immunity against Mycobacterium tuberculosis. Vaccine. 2024;42(22):125909. https://doi.org/10.1016/j.vaccine.2024.04.055
    • 139. Dijkman K, Aguilo N, Boot C, Hofman SO, Sombroek CC, Vervenne RA, et al. Pulmonary MTBVAC vaccination induces immune signatures previously correlated with prevention of tuberculosis infection. Cell Reports Medicine. 2021;2(1):100187. https://doi.org/10.1016/j.xcrm.2020.100187
    • 140. Wallis RS, Ginindza S, Beattie T, Arjun N, Likoti M, Edward VA, et al. Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial. The Lancet Respiratory Medicine. 2021;9(8):897–908. https://doi.org/10.1016/S2213-2600(20)30448-3
    • 141. Kurver L, Seers T, van Dorp S, van Crevel R, Pollara G, van Laarhoven A, et al. Tuberculosis-Associated Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and Determinants of Outcome. Open Forum Infectious Diseases. 2024;11(4):null. https://doi.org/10.1093/ofid/ofad697
    • 142. Wiysonge CS, Ntsekhe M, Thabane L, Volmink J, Majombozi D, Gumedze F, et al. Interventions for treating tuberculous pericarditis. Cochrane Database of Systematic Reviews. 2017;2017(9):null. https://doi.org/10.1002/14651858.CD000526.pub2
    • 143. Thwaites GE, Bang ND, Dung NH, Quy HT, Oanh DTT, Thoa NTC, et al. Dexamethasone for the Treatment of Tuberculous Meningitis in Adolescents and Adults. New England Journal of Medicine. 2004;351(17):1741–51. https://doi.org/10.1056/NEJMoa040573
    • 144. Donovan J, Duc Bang N, Dong HKT, Ho DTN, Nguyen TAT, Nguyen TTH, et al. Genotype-stratified adjunctive dexamethasone for tuberculous meningitis in HIV-negative adults: a randomized controlled phase 3 trial. Nature Medicine. 2026;32(3):849–58. https://doi.org/10.1038/s41591-025-04138-z
    • 145. Wu L, Awaji M, Saxena S, Varney ML, Sharma B, Singh RK. IL-17-CXC chemokine receptor 2 axis facilitates breast cancer progression by up-regulating neutrophil recruitment. Am J Pathol. 2020;190(1):222–33. pmid:31654638
    • 146. Morelli MP, Martin C, Pellegrini JM, Blanco F, Bigi F, Ciallella L, et al. Neutrophils from tuberculosis patients are polarized toward pro-inflammatory and anti-inflammatory phenotypes according to the disease severity. J Immunol. 2025;214(6):1173–86. pmid:40184042
    • 147. Moreira-Teixeira L, Stimpson PJ, Stavropoulos E, Hadebe S, Chakravarty P, Ioannou M, et al. Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis. Nat Commun. 2020;11(1):5566. pmid:33149141
    • 148. Zlatar L, Knopf J, Singh J, Wang H, Muñoz-Becerra M, Herrmann I, et al. Neutrophil extracellular traps characterize caseating granulomas. Cell Death Dis. 2024;15(7):548. pmid:39085192
    • 149. Zhang Q, Atsuta I, Liu S, Chen C, Shi S, Shi S, et al. IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws. Clin Cancer Res. 2013;19(12):3176–88. pmid:23616636
    • 150. Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M, Hwang JY, Kusser K, Hartson L, et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol. 2011;12(7):639–46. pmid:21666689
    • 151. Conlon TM, John-Schuster G, Heide D, Pfister D, Lehmann M, Hu Y, et al. Inhibition of LTβR signalling activates WNT-induced regeneration in lung. Nature. 2020;588(7836):151–6. pmid:33149305
    • 152. Monin L, Griffiths KL, Slight S, Lin Y, Rangel-Moreno J, Khader SA. Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge. Mucosal Immunol. 2015;8(5):1099–109. pmid:25627812
    • 153. Dixon BREA, Radin JN, Piazuelo MB, Contreras DC, Algood HMS. IL-17a and IL-22 induce expression of antimicrobials in gastrointestinal epithelial cells and may contribute to epithelial cell defense against Helicobacter pylori. PLoS One. 2016;11(2):e0148514. pmid:26867135