Lack of TGFβR signaling confers more mature, activated, and educated phenotypes to NK cells leading to resistance to MCMV infection

Abstract

Abstract Natural Killer (NK) cells are crucial in early resistance to murine cytomegalovirus (MCMV) infection. In B6 mice, the activating Ly49H receptor recognizes the viral m157 glycoprotein on infected cells. Balb/c mice lacking LY49H are more susceptible to MCMV infection than B6 mice. Strikingly, CD11cdnR mice that lack TGFβR signaling in NK cells are protected from MCMV infection in both strains. It is established that unlicensed NK cells that are not inhibited by self-MHC class I can control viral infection more than licensed NK cells. We found that CD11cdnR mice have increased frequency of unlicensed (LY49G2+) NK cells and slightly decreased frequency of licensed (LY49C/I+) NK cells in B6 strain. Moreover, TGFβ-resistant NK cells showed more activated phenotypes such as increased granzyme B protein expression and more KLRG1+ expression than control NK cells in both licensed and unlicensed cells. Interestingly, in CD11cdnR mice even unlicensed NK cells have a significant capacity to produce IFN-γ when triggered by anti-NK1.1, but not in control mice. Our data suggest that inactivation of TGFβR signaling might have a critical role in the licensing of NK cell and lead to the resistance against MCMV infection.