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

TY - JOUR

T1 - KIR-HLA interactions extend human CD8+ T cell lifespan in vivo

AU - Zhang, Yan

AU - Yan, Ada W C

AU - Boelen, Lies

AU - Busch, Robert

AU - Macallan, Derek

AU - Asquith, Becca

N1 - I have listed only first and last three authors; the attached file has the full list. The first three authors contributed equally, and the last three authors contributed equally, as noted in the ms. Previously submitted to Sci Immunol on 15 Dec, and subsequently to J Exp Med. Print/PDF version now at the link where the preprint was previously available.

PY - 2023/6/16

Y1 - 2023/6/16

N2 - 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 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.METHODS. We used stable isotope labelling 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 is a significant determinant of CD8+ T cell lifespan: in individuals with two iKIR-ligand gene pairs, memory CD8+ T cells survived on average for 125 days, in individuals with four iKIR-ligand gene pairs then memory CD8+ T cell lifespan was doubled to 250 days. Additionally, we showed that this survival advantage is independent of iKIR expression by the T cell of interest and further that iKIR-ligand genotype altered CD8+ and CD4+ T cell immune aging phenotype.CONCLUSIONS. Together these data reveal an unexpectedly large impact of iKIR genotype on T cell survival.

AB - 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 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.METHODS. We used stable isotope labelling 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 is a significant determinant of CD8+ T cell lifespan: in individuals with two iKIR-ligand gene pairs, memory CD8+ T cells survived on average for 125 days, in individuals with four iKIR-ligand gene pairs then memory CD8+ T cell lifespan was doubled to 250 days. Additionally, we showed that this survival advantage is independent of iKIR expression by the T cell of interest and further that iKIR-ligand genotype altered CD8+ and CD4+ T cell immune aging phenotype.CONCLUSIONS. Together these data reveal an unexpectedly large impact of iKIR genotype on T cell survival.

M3 - Article

SN - 0021-9738

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 12

M1 - e169496

ER -