CD16− natural killer cells: enrichment in mucosal and secondary lymphoid tissues and altered function during chronic SIV infection

Abstract

Natural killer (NK) cells contribute to control of HIV/SIV infection. We defined macaque NK-cell subsets based on expression of CD56 and CD16 and found their distribution to be highly disparate. CD16⁺ NK cells predominated in peripheral blood, whereas most mucosal NK cells were CD56⁺, and lymph nodes contained both CD56⁺ and CD16⁻CD56⁻ (double-negative [DN]) subsets. Functional profiles were also distinct among subsets—CD16⁺ NK cells expressed high levels of cytolytic molecules, and CD56⁺ NK cells were predominantly cytokine-secreting cells, whereas DN NK possessed both functions. In macaques chronically infected with SIV, circulating CD16⁺ and DN NK cells were expanded in number and, although markers of cytoxicity increased, cytokine secretion decreased. Notably, CD56⁺ NK cells in SIV-infected animals up-regulated perforin, granzyme B, and CD107a. In contrast, the lymph node–homing molecules CD62 ligand (CD62L) and C-C chemokine receptor type 7 (CCR7), which are expressed primarily on CD56⁺ and DN NK cells, were significantly down-regulated on NK cells from infected animals. These data demonstrate that SIV infection drives a shift in NK-cell function characterized by decreased cytokine production, expanded cytotoxicity, and trafficking away from secondary lymphoid organs, suggesting that the NK-cell repertoire is not only heterogeneous but also plastic.