KIR-HLA interactions extend human CD8+ T cell lifespan in vivo.

BACKGROUND: There is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell-mediated control of chronic virus infection and that these results are consistent with an increase in CD8+ T cell lifespan due to iKIR-ligand interactions. Here we test this prediction and investigate whether iKIRs affect T cell lifespan in humans in vivo. METHODS: We used stable isotope labelling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections. RESULTS: We showed that an individual's iKIR-ligand genotype is a significant determinant of CD8+ T cell lifespan: in individuals with two iKIR-ligand gene pairs, memory CD8+ T cells survived on average for 125 days, in individuals with four iKIR-ligand gene pairs then memory CD8+ T cell lifespan was doubled to 250 days. Additionally, we showed that this survival advantage is independent of iKIR expression by the T cell of interest and further that iKIR-ligand genotype altered CD8+ and CD4+ T cell immune aging phenotype. CONCLUSIONS: Together these data reveal an unexpectedly large impact of iKIR genotype on T cell survival. FUNDING: Wellcome Trust, Medical Research Council, EU Horizon 2020, EU FP7, Leukemia and Lymphoma Research, National Institute of Health Research Imperial Biomedical Research Centre, Imperial College Research Fellowship, National Institute of Health, Jefferiss Trust

Innate receptors modulating adaptive T cell responses: KIR-HLA interactions and T cell-mediated control of chronic viral infections

Killer-cell immunoglobulin-like receptors (KIRs) are mainly expressed on natural killer (NK) cells and are key regulators of innate immune responses. NK cells are the first responders in the face of infection and help promote placentation during pregnancy; the importance of KIRs in these NK-mediated processes is well-established. However, mounting evidence suggests that KIRs also have a prominent and long-lasting effect on the adaptive immune system. Here, we review the evidence for the impact of KIRs on T cell responses with a focus on the clinical significance of this interaction