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 5

Predicted and observed relationship between iKIRs and T cell lifespan.

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Predicted and observed relationship between iKIRs and T cell lifespan. (...
(A and B) Sketches of hypothetical data that depict predicted patterns in the data within individuals and between individuals, respectively, if the direct pathway operates. (C and D) Hypothetical data depicting predicted patterns within and between individuals if the indirect pathway operates. (E and F) Actual observed results within and between individuals. (E) n = 21 paired data sets. (F) n = 53 data points from 18 individuals. Boxes show the median and IQRs with all individual data points superimposed. It can be seen that the observed results are most consistent with the indirect pathway. Note that for the between-individuals comparison, the T cell lifespan has been adjusted (by linear regression coefficients) to allow for infection status of the individual and for cell subpopulation type (Tcm or Temra). This is not necessary for the within-individuals comparison, as this comparison is internally controlled (i.e., both points would be adjusted by the same factor, as both points come from the same individual and the same cell subpopulation (Tem or Temra). We found that the CD8+ T cell lifespan was independent of functional iKIR expression (P = 0.79, paired Wilcoxon test) and indeed was independent of iKIR expression in general (P = 0.50, paired Wilcoxon). In contrast, the CD8+ T cell lifespan was significantly determined by iKIR-HLA genotype (P = 3 × 10–6, multivariate regression).