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 viral infection and that these results are consistent with an increase in the CD8(+) T cell lifespan due to iKIR-ligand interactions. Here, we tested this prediction and investigated whether iKIRs affect T cell lifespan in humans in vivo. METHODS: We used stable isotope labeling 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 was a significant determinant of CD8(+) T cell lifespan: in individuals with 2 iKIR-ligand gene pairs, memory CD8(+) T cells survived, on average, for 125 days; in individuals with 4 iKIR-ligand gene pairs, the memory CD8(+) T cell lifespan doubled to 250 days. Additionally, we showed that this survival advantage was independent of iKIR expression by the T cell of interest and, further, that the iKIR-ligand genotype altered the CD8(+) and CD4(+) T cell immune aging phenotype. CONCLUSIONS: Together, these data reveal an unexpectedly large effect 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 (NIHR) Imperial Biomedical Research Centre; Imperial College Research Fellowship; National Institutes of Health; Jefferiss Trust.