KIR-HLA interactions extend human CD8+ T cell lifespan in vivo
Yan Zhang, … , Derek C. Macallan, Becca Asquith
Yan Zhang, … , Derek C. Macallan, Becca Asquith
Published April 18, 2023
Citation Information: J Clin Invest. 2023;133(12):e169496. https://doi.org/10.1172/JCI169496.
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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 6

CD57 expression increases with the number of functional iKIR genes carried by an individual.

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CD57 expression increases with the number of functional iKIR genes carri...
T cell subpopulations with measurable CD57 expression (median ≥150 events) are plotted. The proportion of cells expressing CD57 was significantly positively correlated with the functional iKIR count in CD4+ Tem cells (P = 0.036), CD8+ Tem cells (P = 0.018), and CD8+ Temra cells (P = 0.012). Multivariate regression was done with the age of the individual as a covariate (n = 63). Symbols denote experimental measurements, thin horizontal lines the median CD57 expression (for each subpopulation and each functional iKIR count), and thick lines the best fits line of regression.