Table 1.
Immune characteristics of γδ T cells in flavivirus infections. Human γδ T cells can primarily be divided into three main subsets: Vδ1, Vδ2, and Vδ3. γδ T EMRA cells, as effector T cells, can directly kill virus-infected cells, while γδ TEM cells, as central memory cells, often secrete cytokines such as IFN-γ to exert indirect antiviral effects.
Table 2.
The mechanisms of γδ T cells function in flavivirus infections. After flavivirus infection, γδ T cells can be activated through various recognition mechanisms of the γδ TCR and TLR signaling pathways. Subsequently, they secrete cytokines (IFN-γ, IL-17A, or TNF-α), enhancing the systemic immune response. However, we must be cautious, as the prolonged presence of certain cytokines may exacerbate tissue damage. Additionally, they can directly kill virus-infected cells.
Fig 1.
γδ T cells in flavivirus infections. A. Mechanical contact between tissue-resident γδ TCR and endothelial protein C receptor (EPCR). Following footpad injection of Dengue virus (DENV) in mice, skin-resident γδ T cells are the first to be activated. This activation occurs through mechanical interaction between their T cell receptor (TCR) and EPCR, which is upregulated on the surface of DENV-infected mast cells, thereby initiating their protective function. B. Protective mechanism of γδ T cells in peripheral blood. γδ T cell activation is primarily mediated through their TCR, which recognizes BTN proteins on the surface of infected cells. These BTN proteins undergo conformational changes in response to the intracellular accumulation of phosphoantigens, enabling TCR engagement. Furthermore, TLR7, a pattern recognition receptor that detects single-stranded RNA, has also been implicated in γδ T cell activation under certain conditions. Upon activation, γδ T cells execute their antiviral functions via two distinct mechanisms: direct and indirect pathways. The direct antiviral mechanism involves surface molecules such as NKG2D, TRAIL, and FasL, which detect the upregulation of corresponding ligands on infected cells. This interaction facilitates the targeted release of cytotoxic mediators, including perforin and granzyme B, resulting in the lytic destruction of infected cells. Conversely, the indirect antiviral mechanism is characterized by the secretion of IFN-γ, a cytokine that plays a pivotal role in facilitating the adaptive immune response, thereby augmenting viral clearance and immune defense. NKG2D, natural killer group 2 member D; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; FasL, Fas ligand; Created in BioRender.
Table 3.
γδ T cell-based anti-flaviviral potential therapies. Currently, there are five types of γδ T cell-based immunotherapies. These methods primarily utilize the specific recognition and activation mechanisms of γδ T cells to enhance their secretion of interferons and their cytotoxic ability against infected cells.
Fig 2.
γδ T cell-based potential therapies for flavivirus infections.
Current immunotherapies based on γδ T cells primarily include four main strategies. The first strategy involves the use of expanded γδ T cells, which is mainly based on the activation mechanism of γδ TCR. Zoledronic acid (ZOL) and pamidronate (PAM) can promote the accumulation of phosphoantigens within infected cells, which in turn induces conformational changes in BTN2A1 and BTN3A1, allowing them to interact with γδ TCR and activate γδ T cells. Additionally, the BTN3A1 activator ICT01 can directly induce conformational changes in BTN3A1, thereby activating γδ T cells through a phosphoantigen-independent pathway. The second strategy involves the use of bispecific antibodies, which are designed based on two approaches: the first approach aims to direct γδ T cells toward flavivirus-infected cells to enhance their specificity; the second utilizes the recognition properties of γδ TCR to target αβ T cells to the site of infected cells. The third strategy builds upon γδ T cells by introducing artificially engineered chimeric antigen receptors (CARs) designed to target flavivirus antigens or NKG2D ligands specifically upregulated in infected cells, thereby further enhancing the cytotoxic function of γδ T cells. The fourth strategy leverages the unique recognition characteristics of γδ TCR to modify αβ T cells, endowing them with similar recognition capabilities to γδ T cells, thereby increasing their ability to kill infected cells. NKG2D, natural killer group 2 member D. Created in BioRender.