Proliferation promotes functional changes in NK cells during viral infection. (P6054)

Abstract

Abstract Following mouse cytomegalovirus (MCMV) challenge, NK cells control viral replication by killing infected cells and producing IFNγ in response to IL-12 induced at day 1.5 after infection. Previous work in our laboratory has demonstrated that under conditions of high viral replication, NK cells make significant amounts of IL-10 and deliver immunoregulatory functions at 3 to 4 days of infection (Lee et al., J. Exp. Med. 206:2235, 2009). The condition is accompanied by extensive NK cell proliferation. To test the hypothesis that proliferation is required for the changing function, culture systems were developed examining NK cell responses to IL-12 with and without division supported by high dose IL-2. Proliferating NK cells were induced to express the IL-10-reporter GFP in response to IL-12. One cell division was sufficient as was entrance into cell cycle measured by incorporation of BrdU. In contrast to intracellular IFNγ, proliferation was required for IL-10-GFP expression. Cell transfer studies into MCMV-infected mice demonstrated that IL-10-GFP levels were elevated with increasing divisions. When evaluated either in vitro or in vivo, decreasing intracellular IFNγ expression correlated with increasing IL-10-GFP expression as divisions progressed. Taken together, the studies reveal a previously unappreciated role for proliferation in shaping NK cell responses to infection. (Supported in part by the National Institutes of Health, USA.)