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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 Article has an altmetric score of 16

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

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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 2

Percentage of T cells expressing different inhibitory KIRs (cohort 1).

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Percentage of T cells expressing different inhibitory KIRs (cohort 1).
T...
The percentage of cells in each subpopulation that expressed each of 3 different iKIRs was quantified by flow cytometry for the participants in cohort 1 (n = 23). Multivariate regression analysis found that the following were highly significant predictors of increased iKIR expression: a more advanced cell differentiation stage (expressed as an ordinal), P = 4 × 10–14, CD8 coexpression P = 0.0007 and KIR2DL2/L3 P = 4 × 10–12; male sex was weakly predictive (P = 0.049). CMV serostatus and infection status were not significant predictors of iKIR expression. Note that the scale of the y axis is different between the rows. Boxes show the median and IQRs. The corresponding data are provided in Supplemental Table 1, and the details of the multivariate regression are given in Supplemental Table 2. n = 7 hypotheses tested. P value threshold for α = 0.05 is P = 0.009 (permutation test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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