ABSTRACT
Objective Our objective was to investigate the mechanisms that govern natural killer (NK) cell responses to HIV, with a focus on specific receptor-ligand interactions involved in HIV recognition by NK cells.
Design and Methods We first performed a mass cytometry-based screen of NK cell receptor expression patterns in healthy controls and HIV+ individuals. We then focused mechanistic studies on the expression and function of T cell immunoreceptor with Ig and ITIM domains (TIGIT).
Results The mass cytometry screen revealed that TIGIT is upregulated on NK cells of untreated HIV+ women, but not in antiretroviral-treated women. TIGIT is an inhibitory receptor that is thought to mark exhausted NK cells; however, blocking TIGIT did not improve anti-HIV NK cell responses. In fact, the TIGIT ligands CD112 and CD155 were not upregulated on CD4+ T cells in vitro or in vivo, providing an explanation for the lack of benefit from TIGIT blockade. TIGIT expression marked a unique subset of NK cells that express significantly higher levels of NK cell activating receptors (DNAM-1, NTB-A, 2B4, CD2) and exhibit a mature/adaptive phenotype (CD57hi, NKG2Chi, LILRB1hi, FcRγlo, Syklo). Furthermore, TIGIT+ NK cells had increased responses to mock-infected and HIV-infected autologous CD4+ T cells, and to PMA/ionomycin, cytokine stimulation and the K562 cancer cell line.
Conclusions TIGIT expression is increased on NK cells from untreated HIV+ individuals. Although TIGIT does not participate directly in NK cell recognition of HIV, it marks a population of mature/adaptive NK cells with increased functional responses.
Footnotes
Disclosures/Grant Support: This work was supported by: NIH Ruth L. Kirschstein Institutional National Research Service Award T32AI007502 and TL1TR001084 (EV), NIH/NIAID K08 K08AI138640 (EV), ITI/Bill & Melinda Gates Foundation Pilot Grant (CAB), NIH/NIAID DP2 AI1219301 (CAB), NIH/NIDA Avant Garde Award for HIV Research DP1 DA045089 (CAB), Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases (CAB), Grant # PJT-148529 from the Canadian Institutes of Health Research and by the Réseau SIDA from the Fonds de Recherche du Québec en Santé (MR). CAB is an investigator of the Chan Zuckerberg Biohub. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.