A CD8α- subpopulation of macaque circulatory natural killer cells can mediate both antibody-dependent and antibody-independent cytotoxic activities

Natural killer (NK) cells are important components of the innate immune system that mediate effector and regulatory functions. As effector cells, NK cells help control virus-infected cells through cell-mediated antibody-dependent mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). Although macaques are an important and reliable animal model for the study of retrovirus-induced human diseases, and despite the crucial role played by NK cells in innate and adaptive immune responses against simian immunodeficiency virus (SIV), only a few studies have attempted to characterize different macaque NK cell subpopulations. In the present study, we identified a subpopulation of circulatory CD8 alpha(-) macaque NK cells that express NK lineage markers and exhibit cytotoxic potential. CD8 alpha(-) NK cells were phenotypically characterized as CD3(-) CD14(-) CD20(-) CD8 alpha(-) cells that express NK cell markers including CD16, CD56, granzyme B, perforin, NKG2D and KIR2D. Based on their CD56/CD16 expression patterns, cells within the CD8 alpha(-) gate can be divided into four subpopulations: CD56(dim) CD16(bright), CD56(dim) CD16(-), CD56(bright) CD16(-), and CD56(-) CD16(-) cells. In contrast, CD8 alpha+ NK cells are 95% CD56(dim) CD16(bright), which correlates with their high cytotoxic potential. Upon interleukin-15 activation, CD8 alpha(-) cells up-regulated CD69 expression and produced low levels of interferon-gamma and tumour necrosis factor-a. Sorted CD8 alpha(-) NK cells were capable of killing MHC-I-devoid target cells and mediated ADCC responses against SIV gp120-coated target cells in the presence of macaque anti-gp120 antibodies. Taking into account CD8 alpha(-) myeloid dendritic cells, we show that about 35% of macaque CD8 alpha(-) cells represent a novel, functional population of circulatory NK cells that possesses cytotoxic potential and is capable of mediating anti-viral immune responses.