NK cells negatively regulate CD8 T cells via natural cytotoxicity receptor (NCR) 1 during LCMV infection

Besides their function in recognizing cancerous and virally infected cells, natural killer (NK) cells have the potential to shape adaptive immune responses. However, the mechanisms employed by NK cells to negatively regulate virus-specific CD8 T cell responses remain to be fully defined. Using activating receptor natural cytotoxicity receptor (NCR) 1 deficient (NCR1(gfp/gfp)) mice, we found increased numbers of virus-specific CD8 T cells, leading to enhanced virus control during acute LCMV infection. Furthermore, virus-specific CD8 T cells were more activated in the absence of NCR1, resulting in exacerbated immunopathology, documented by weight loss, and superior virus control early during chronic LCMV infection. Transfer experiments of virus-specific CD8 T cells into NCR1 deficient hosts revealed a direct cross talk between NK and CD8 T cells. Studies on the splenic microarchitecture revealed pronounced disorganization of T cells in infected NCR1(gfp/gfp) mice, resulting in enhanced immunopathology and disruption of the T cell niche upon chronic LCMV infection. Our data show a novel pathway employed by NK cells to regulate antiviral CD8 T cell responses, namely direct recognition and elimination of activated CD8 T cells via NCR1 early during infection to protect the host from an overshooting T cell response. Author summary LCMV, which is part of the Arenaviridae family, is a well-established mouse model for acute and chronic virus infections, and it has allowed the identification of many immunological principles that were subsequently confirmed in human infections, such as CTL escape or CD8 T cell exhaustion. NK cells belong to the first line defense, being activated early following infection or exposure to malignant cells, and mediate their antiviral or anti-tumoral effect by direct cytotoxicity and inflammatory cytokine secretion. While NK cells are dispensable for control of LCMV, NK cells have the potential to shape adaptive immunity by regulating T cell responses. The absence of NK cells leads to increased T cell immunity and thereby, to faster eradication of the virus. However, the detailed mechanisms of how NK cells control antiviral T cell responses is still poorly defined. Here, we identified the activating NK cell receptor NCR1 to be involved in the regulation of CD8 T cell responses during acute and chronic LCMV infection. The absence of NCR1 led to a more robust CD4 and CD8 T cell response and to superior viral control in acute and chronic LCMV infections. However, the increased CD8 T cell responses led to severe immunopathology in the setting of chronic infection. Hence, NK cells curtail CD8 T cell responses to protect the host from immunopathological damage in an NCR1 dependent manner.