Decreased interferon‐γ production by NK cells from KIR haplotype B carriers in hepatitis C virus infection

摘要

Abstract Background and Aims Different population genetics studies showed that interactions between killer‐cell immunoglobulin‐like receptors (KIR) and HLA play a role in viral disease outcome, but functional correlates are missing. Building upon our previous work pointing to a regulatory role for KIR3DL1/DS1 in hepatitis C virus (HCV) infection, we analysed whether its expression may affect natural killer (NK) cell function in the presence or absence of its principal ligand HLA‐Bw4 in KIR haplotype A and B carriers, which are characterized by a different representation of activating and inhibitory KIRs. Methods We performed KIR and HLA class I genotypic analysis in 54 healthy donors (HD) and 50 HCV+ subjects and examined NK cell cytokine secretion and degranulation in the context of KIR3DL1‐HLA‐Bw4 match stratified by KIR haplotype. Results KIR3DL1‐HLA‐Bw4 match induced functional NK cell modulation, reflected by reduced interferon (IFN)γ production in haplotype B HCV+ patients compared to HD. This functional impairment could be ascribed to the KIR3DS1 negative HCV‐infected patient population, whose NK cells also showed a significantly decreased proportion of KIR3DL1. Haplotype A HCV‐infected patients showed increased NK cell degranulation compared with HD in the absence of KIR‐HLA‐Bw4 match and this activity was associated with increased phosphorylation of signal transducer and activator of transcription (STAT) 1. Conclusions Our data show that NK cells from HCV+ patients have an unbalanced ability to produce IFNγ and to kill target cells in haplotype A and B carriers, suggesting the existence of complex functional differences governed by KIR‐HLA interaction, particularly on KIR3DL1 expressing NK cells.