TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

作者：Elena Vendrame, C. Seiler, T. Ranganath, Nancy Q. Zhao, Rosemary Vergara, M. Alary, A. Labbé, F. Guédou, J. Poudrier, Susan P. Holmes, M. Roger, C. Blish · 发表于：bioRxiv · 年份：2019 · DOI：10.1097/qad.0000000000002488 · 被引用次数：52 · 研究领域：Biology、Medicine

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 i...