Modelling the impact of iKIRs in adaptive immune responses

Abstract

Inhibitory killer cell immunoglobulin-like receptors (iKIRs) are a family of inhibitory receptors that are expressed by natural killer cells and late-stage differentiated T cells. iKIRs are well- known for their function during innate responses but there is evidence that they also regulate T cell-mediated immunity. Importantly, recent immunogenetic studies indicate that iKIRs en- hance T cell-mediated control in chronic viral infections in humans. Whether iKIRs play an analogous role in other contexts is currently unknown. This thesis aims to tackle that ques- tion by combining immunogenetic analysis, mathematical modelling and iKIR expression data analysis in the context of type 1 diabetes (T1D). In autoimmunity, an enhanced T cell response might be considered detrimental and so iKIRs might have an opposite effect and exacerbate self-reactive T cell responses. The immunogenetic analysis of two T1D cohorts confirms this hypothesis and reveals a large detrimental effect of iKIR genes in T1D. Specifically, the pro- tection conferred by some HLA class II genotypes is weakened in individuals carrying a high number of iKIR genes together with their ligand genes. Mathematical modelling shows that an iKIR-mediated increase of CD8+ and CD4+ T cell survival can explain the effect of iKIR genes in individuals carrying protective HLA class II genotypes. Finally, the iKIR expressing CD4+ and CD8+ T cell populations are relatively small and not expanded in blood in T1D patients, suggesting that crosstalk between autoreactive T cells and other iKIR expressing immune pop- ulations is more likely to explain the observed iKIR effect. Overall, this thesis expands the iKIR modulatory role of T cells during antiviral responses to autoimmune responses, hinting at a core and widespread function of iKIRs in adaptive human immunity.