Abstract
CD49a+ tissue resident NK cells have been implicated in memory-like NK cell responses, but while this population is well-characterized in mice and in humans, they are poorly described in non-human primates (NHP) which are particularly critical for modeling human viral infections. Others and we have shown that memory-like NK cells are enriched in the liver and because of the importance of NHP in modeling HIV infection, understanding the immunobiology of CD49a+ NK cells in SIV-infected rhesus macaques is critical to explore the role of this cell type in retroviral infections. In this study mononuclear cells isolated from livers, spleens, and peripheral whole blood were analyzed in acutely and chronically lentivirus-infected and experimentally-naïve Indian rhesus macaques (RM). NK cells were then identified as CD45+CD14−CD20−CD3−NKG2A/C+ cells and characterized using multiparametric flow-cytometry. Our data show that in RM, CD49a+ NK cells increase in the liver following retroviral infections [median = 5.2% (naïve) vs. median = 9.48% (SIV+) or median = 16.8% (SHIV+)]. In contrast, there is little change in CD49a+ NK frequencies in whole blood or spleens of matched animals. In agreement with human and murine data we also observed that CD49a+ NK cells were predominantly Eomeslow T-betlow, though these frequencies are elevated in infected animal cohorts. Functionally, our data suggests that infection alters TNF-α, IFN-γ, and CD107a expression in stimulated CD49a+ NK cells. Specifically, our analyses found a decrease in CD49a+ CD107a+ TNFα+ IFNγ− NK cells, with a simultaneous increase in CD49a+ CD107a+ TNFα− IFNγ+ NK cells and the non-responsive CD49a+ CD107a− TNFα− IFNγ− NK cell population following infection, suggesting both pathogenic and inflammatory changes in the NK cell functional profile. Our data also identified significant global differences in polyfunctionality between CD49a+ NK cells in the naïve and chronic (SHIV+) cohorts. Our work provides the first characterization of CD49a+ NK cells in tissues from RM. The significant similarities between CD49a+ NK cells from RM and what is reported from human samples justifies the importance of studying CD49a+ NK cells in this species to support preclinical animal model research.
Highlights
Natural killer (NK) cells are considered as the prototypic innate immune effector cell capable of rapid and broad responses to several agents—including viral infections and cancerous cells
Quantification of CD49a±b± NK cells revealed that the majority of NK cells in the liver did not express CD49a or CD49b, but interestingly there was a significant increase in the frequencies of CD49a+b− NK cells from acute SIV+ or chronic SHIV+ infected animals as compared to the naïve group
CD49a+ NK cells are still poorly characterized in any tissue from non-human primates (NHP)
Summary
Natural killer (NK) cells are considered as the prototypic innate immune effector cell capable of rapid and broad (non-specific) responses to several agents—including viral infections and cancerous cells. Adaptive NK cells have been shown to be enriched in the livers of mice [7] and non-human primates (NHP) [5], and recently in human livers from BLT mice [8]. The α1β1 integrin CD49a ( VLA-1) has been shown to be associated with liver-resident lymphocytes and is further described as one of several markers for adaptive NK cells that accumulate in the liver [7, 9, 10]. Ligation of CD49a has been shown to influence tyrosine kinase signaling leading to IL-2 dependent NK cell activation [16]. CD49a has been shown to interact with Galectins 1, 3, and 8 [21, 22] and semaphorin 7A [23], which has been implicated in cytokine-induced NK cell memory responses [24]
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