Natural killer cells in HIV controller patients express an activated effector phenotype and do not up-regulate NKp44 on IL-2 stimulation

Francesco Marras, Elena Nicco, Federica Bozzano, Antonio Di Biagio, Chiara Dentone, Emanuele Pontali, Silvia Boni, Maurizio Setti, Giancarlo Orofino, Eugenio Mantia, Valentina Bartolacci, Francesca Bisio, Agostino Riva, Roberto Biassoni, Lorenzo Moretta, Andrea De Maria

Research output: Contribution to journalArticle

Abstract

Control of HIV replication in elite controller (EC) and long-term nonprogressor (LTNP) patients has been associated with efficient CD8+cytotoxic T-lymphocyte function. However, innate immunity may play a role in HIV control. We studied the expression of natural cytotoxicity receptors (NKp46, NKp30, and NKp44) and their induction over a short time frame (2-4 d) on activation of natural killer (NK) cells in 31 HIV controller patients (15 ECs, 16 LTNPs). In EC/LTNP, induction of NKp46 expression was normal but short (2 d), and NKp30 was induced to lower levels vs. healthy donors. Notably, in antiretroviral-treated aviremic progressor patients (TAPPs), no induction of NKp46 or NKp30 expression occurred. More importantly, EC/LTNP failed to induce expression of NKp44, a receptor efficiently induced in activated NK cells in TAPPs. The specific lack of NKp44 expression resulted in sharply decreased capability of killing target cells by NKp44, whereas TAPPs had conserved NKp44-mediated lysis. Importantly, conserved NK cell responses, accompanied by a selective defect in the NKp44-Activating pathway, may result in lack of killing of uninfected CD4 +NKp44Ligand+ cells when induced by HIVgp41 peptide-S3, representing a relevant mechanism of CD4+ depletion. In addition, peripheral NK cells from EC/LTNP had increased NKG2D expression, significant HLA-DR up-regulation, and a mature (NKG2A-CD57+killer cell Ig-like receptor+CD85j+) phenotype, with cytolytic function also against immature dendritic cells. Thus, NK cells in EC/LTNP can maintain substantially unchanged functional capabilities, whereas the lack of NKp44 induction may be related to CD4 maintenance, representing a hallmark of these patients.

Original languageEnglish
Pages (from-to)11970-11975
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number29
DOIs
Publication statusPublished - Jul 16 2013

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