OA04.01
Background: Natural killer (NK) cells provide rapid responses to viral infections and are typically considered to be nonspecific components of innate immunity. However, recent studies have shown that NK cells can also mediate antigen-specific memory in mice, but it remains unclear whether this phenomenon also exists in primates.
Methods: In this study we evaluated NK cells from a cohort of 8 rhesus macaques chronically infected with SIVmac251, 6 naïve controls, and 9 macaques vaccinated with replication-incompetent Ad26 vectors expressing either HIV-1 Env or SIVmac239 Gag. Using a novel flow cytometric assay we evaluated antigen-specific killing of autologous dendritic cells (DCs) by highly purified hepatic and splenic NK cells. Fluorochrome-labeled DCs were pulsed with intact SIV Gag or HIV-1 Env and non-pulsed DCs served as intra-well controls. Purified NK cells were co-cultured with DCs at multiple E:T ratios and specific lysis was used as a functional determination of antigen-specificity.
Results: Splenic NK cells from SIV-infected animals were highly reactive to Gag-pulsed DCs at a 10:1 NK:target ratio with a median specific lysis of 40% compared to 1% in naive controls, indicating the presence of antigen-specific NK cells in chronic infection. In our vaccinated, unchallenged macaques, at both 10:1 and 5:1 NK:target ratios, splenic and hepatic NK cells lysed antigen-matched targets at higher frequencies than they did antigen-mismatched targets (P=0.021, liver; P=0.040, spleen). Responses in peripheral blood were marginal, suggesting that memory NK cells likely reside in tissues.
Conclusions: Taken together, our data demonstrate the first evidence of NK cell memory in a primate species. Furthermore, antigen-specific NK cell responses to SIV antigens are induced in primates following both infection and vaccination. The longevity, functionality, and specificity of memory NK responses in primates suggest their functional relevance in developing vaccines against multiple pathogens, including HIV.
