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 1

The direct and indirect pathways that could explain iKIR enhancement of CD8+ T cell survival.

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The direct and indirect pathways that could explain iKIR enhancement of ...
iKIRs (purple) could increase T cell survival and lead to an enhancement of HLA class associations by a number of different pathways. In all diagrams, the HLA class I molecule associated with disease outcome is shown in yellow and is labeled “HLA risk molecule” (interacting with the TCR in blue), and the HLA molecule acting as the iKIR ligand is shown in red. (A) Direct hypothesis: iKIR expression on antigen-specific CD8+ T cells reduces activation-induced cell death and increases T cell lifespan upon ligation of the cognate KIR ligand. (B) Indirect hypotheses: iKIR ligation on other cells can affect CD8+ T cell lifespan through a range of mechanisms. (a) NK cells can interact with DCs and shape downstream T cell responses. (b) NK cells can directly kill activated CD4+ T cells. (c) Similarly, activated CD8+ T cells are also susceptible to NK cell killing. (d) Regulatory KIR+ CD8+ T cells can kill activated antigen-specific CD8+ T cells.