Figure 1.
CD8+ T cells recognise virally infected cells via their T cell receptor (TCR).
The TCR binds complexes of viral peptides and HLA class I molecules at the surface of virus-infected cells. Following CD8+ T cell recognition of the infected cell, the CD8+ T cell effector mechanisms are triggered. CD8+ effector mechanisms can be lytic (killing of the infected cell) and/or non-lytic (secretion of cytokines such as IFNg and TNFa which reduce the probability of cell infection and viral production).
Figure 2.
Proposed mechanism to explain inhibitory KIR enhancement of HLA class I associations.
KIR-HLA associations are typically attributed to direct NK action (a). However, Seich al Basatena's observations do not appear to be compatible with direct NK killing for four reasons. Firstly, most of the HLA molecules which were enhanced do not bind KIR2DL2. Secondly, both protective and detrimental HLA associations were enhanced. Thirdly, KIR2DL2 with or without its C1 ligand (i.e., not in the context of a particular protective or detrimental HLA allele) had no effect on any outcome for HCV or HTLV-1. And finally, the protective effect of binding HBZ was enhanced, and NK cells display some peptide specificity, but such marked protein specificity is more reminiscent of T cells [56]. Instead they hypothesise that the downstream effectors are CD8+ T cells (b). They postulate that KIR2DL2 enhances CD8+ T cell responses by increasing the survival of memory CD8+ T cells. Either because (i) inhibitory KIR on CD8+ T cells are associated with reduced activation induced cell death and protection from exhaustion [77]–[79] or (ii) inhibitory KIR on NK cells reduce NK-killing of activated CD8+ T cells [80], [81].
Figure 3.
The variation in outcome that can be explained by individual HLA class I alleles in HIV-1, HTLV-1 and HCV infections.
The explained fraction (EF) was calculated following Nelson [82]; data for HCV and HTLV-1 were taken from [56], and data for HIV-1 were taken from [40], [83]. 95% confidence intervals were estimated by bootstrapping the data 5,000 times, trimming the 5% extremes, and then calculating the range in which 95% of the remaining data lay. Due to linkage between the HLA alleles, the EF is not additive; so for instance, in HTLV-1 infection, the three alleles HLA-A*02, C*08, and B*54 together only explain 6.6% of the outcome. The outcomes explained are HCV: spontaneous clearance v persistence; HTLV-1: asymptomatic carriage v HAM/TSP; HIV-1: elite control v viremic control v progression.