Inhibitory killer cell immunoglobulin-like receptors strengthen CD8+ T cell–mediated control of HIV-1, HCV, and HTLV-1

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Science Immunology  09 Nov 2018:
Vol. 3, Issue 29, eaao2892
DOI: 10.1126/sciimmunol.aao2892

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Fine-tuning CD8+ T cell responses

Human cytotoxic CD8+ T cells are important for defense against viral infections. Boelen et al. investigated whether inhibitory killer cell immunoglobulin-like receptors (iKIRs) carried by patients with chronic viral infections affected the efficacy of their CD8+ T cell responses. Possession of an iKIR gene along with a gene encoding a KIR ligand enhanced protective and detrimental HLA class I associations for HIV-1, HCV, and HTLV-1. Analysis of virus dynamics, in vitro survival assays, and mathematical modeling suggested that iKIR ligation enhances HLA associations by increasing T cell survival. In contrast to many reported iKIR-disease associations, these observations applied to all iKIRs and the three viral infections studied. This analysis reveals a consistent ability of iKIRs to influence clinical outcomes in human chronic viral infection.


Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell–mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8+ T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple independent cohorts of HIV-1–, hepatitis C virus (HCV)–, and human T cell leukemia virus type 1 (HTLV-1)–infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression, and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8+ T cell response against HIV-1, HCV, and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections.

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