Abstract
Abstract Persistent viral infections in mice (e.g. lymphocytic choriomeningitis virus, LCMV) and humans (e.g. HIV, hepatitis C virus) are characterized by chronic inflammation. This sustained inflammatory milieu promotes T cell exhaustion, which limits harmful tissue damage but prevents effective viral control. We found that natural killer (NK) cells aid in the establishment of this tolerogenic state through cytolytic elimination of antiviral T cells. In parallel, others shown that chronic infection encourages expansion of immunoregulatory IL-10-expressing myeloid cells and bona fide myeloid-derived suppressor cells (MDSCs) that contribute to T cell inhibition immune exhaustion and cell injury. We now report that depletion of NK cells prior to persistent infection with the clone 13 strain of LCMV abrogates the expansion of immunosuppressive myeloid cells. In the absence of NK cells, the levels of myelo-stimulatory cytokines, including TNF-a, MCP-1, and IL-6 were also reduced. Furthermore, frequencies of myeloid precursor cells were reduced in the bone marrow during infection in the absence of NK cells. Our results suggest that NK cells support an inflammatory milieu promoting expansion of the myeloid niche and specifically suppressive myeloid cells during chronic infection. This cross-talk between NK cells and myeloid cells during inflammation has the potential to contribute to immune dysfunction during both chronic infection and in cancer.