KIR-HLA interactions extend human CD8+ T cell lifespan in vivo
Yan Zhang, Ada W.C. Yan, Lies Boelen, Linda Hadcocks, Arafa Salam, Daniel Padrosa Gispert, Loiza Spanos, Laura Mora Bitria, Neda Nemat-Gorgani, James A. Traherne, Chrissy Roberts, Danai Koftori, Graham P. Taylor, Daniel Forton, Paul J. Norman, Steven G.E. Marsh, Robert Busch, Derek C. Macallan, Becca Asquith
Yan Zhang, Ada W.C. Yan, Lies Boelen, Linda Hadcocks, Arafa Salam, Daniel Padrosa Gispert, Loiza Spanos, Laura Mora Bitria, Neda Nemat-Gorgani, James A. Traherne, Chrissy Roberts, Danai Koftori, Graham P. Taylor, Daniel Forton, Paul J. Norman, Steven G.E. Marsh, Robert Busch, Derek C. Macallan, Becca Asquith
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Clinical Research and Public Health Immunology

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

Abstract

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.

Authors

Yan Zhang, Ada W.C. Yan, Lies Boelen, Linda Hadcocks, Arafa Salam, Daniel Padrosa Gispert, Loiza Spanos, Laura Mora Bitria, Neda Nemat-Gorgani, James A. Traherne, Chrissy Roberts, Danai Koftori, Graham P. Taylor, Daniel Forton, Paul J. Norman, Steven G.E. Marsh, Robert Busch, Derek C. Macallan, Becca Asquith

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Figure 3

Label enrichment in CD8+ T cell subpopulations expressing functional iKIRs.

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Label enrichment in CD8+ T cell subpopulations expressing functional iKI...
Plots show, for each individual, the label enrichment in the DNA of sorted T cell subpopulations during and following labeling for 49 days. CD8+ Tcm and Temra cells were sorted on the basis of their iKIR expression and the individual’s HLA ligand genotype into functional iKIR (Func KIR) (cells expressing an iKIR, in which the individual carried 1 or more allele encoding a ligand); nonfunctional iKIR (Non Func KIR) (cells expressing an iKIR whose ligand is absent from the genome); and KIR– (KIR Neg) (not expressing any of the iKIRs studied). This figure depicts label enrichment in cells expressing functional iKIRs; the remaining data are shown in Figure 4. Circles represent data, and the blue line indicates the best fit of the model to the data. Because of low or absent cell frequencies, it was not possible to collect all cell populations for all individuals.