NK cell-intrinsic Fc epsilon RI gamma limits CD8(+) T-cell expansion and thereby turns an acute into a chronic viral infection

During viral infection, tight regulation of CD8(+) T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8(+) T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcR gamma, Fc epsilon RI gamma, Fcer1g(-/-) mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8(+) T-cell regulation. We found that the lack of FcR gamma on NK cells limits their ability to restrain virus-specific CD8(+) T cells and that the lack of FcR gamma in Fcer1g(-/-) mice leads to enhanced CD8(+) T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcR gamma stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcR gamma did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8(+) T-cell functions. In conclusion, we determined that FcR gamma plays an important role in regulating CD8(+) T-cell functions during chronic LCMV infection. Author summary FcR gamma is a signaling molecule for Fc receptors and NK cell killer activating receptor (KAR) complex. FcR gamma is highly expressed by NK cells and involved in NK cell activity. NK cells are widely defined to regulate the expansion of T cells. Here using chronic LCMV model, we described the role of FcR gamma in NK cell mediated shaping of CD8(+) T cell response and viral control. We observed that FcR gamma does not affect the early activity of NK cells which is mainly innate immune cytokines driven, but rather the specific activation due to NKp46 inadequacy. We detected that FcR gamma stabilizes NKp46 protein by preventing it from proteasomal degradation. Due to lack of NKp46 expression in absence of FcR gamma, we observed strong CD8(+) T cell response and faster viral clearance during chronic LCMV infection. These data demonstrate that FcR gamma is crucial for specific activity of NK cells for regulation of CD8(+) T cell response during viral infection.