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.