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

Yan Zhang, Ada W C Yan, Lies Boelen, Robert Busch, Derek Macallan, Becca Asquith

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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 virus infection and that these results are consistent with an increase in CD8+ T cell lifespan due to iKIR-ligand interactions. Here we test this prediction and investigate whether iKIRs affect T cell lifespan in humans in vivo. We used stable isotope labelling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections. We show that an individual’s iKIR-ligand genotype is a significant determinant of CD8+ T cell lifespan: in individuals with two iKIR-ligand gene pairs, memory CD8+ T cells survive on average for 125 days, in individuals with four iKIR-ligand gene pairs then memory CD8+ T cell lifespan is doubled to 250 days. Additionally, we show that this survival advantage is independent of iKIR expression by the T cell of interest and further that iKIR-ligand genotype
alters CD8+ and CD4+ T cell immune aging phenotype. Together these data reveal an unexpectedly large impact of iKIR genotype on T cell survival.
Original languageEnglish
JournalJournal of Experimental Medicine
Publication statusSubmitted - 4 Jan 2023

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