The Study Of Hepatic CD49a~+CD49b~+NK Cells During Viral Infection

Natural killer(NK)cells are important innate effectors that play a pivotal role in defense against tumors and infections.In addition to their key role in innate immunity,NK cells also act as important regulators in adaptive immunity through direct cytotoxicity to immune cells or secreting various cytokines.Based on their potent function and wide distribution,NK cells have shown to participate in diverse physiological and pathological processes.As an organ with predominant innate immunity,the liver is enriched with heterogeneous NK cells,among which two transcriptionally and phenotypically distinct NK cell subsets have been identified:CD49a-CD49b+conventional NK(cNK)cells and CD49a+CD49b-liver-resident NK(LrNK)cells.Previous studies have focused on bulk liver NK cells,however,the dynamic composition and respective roles of the different hepatic NK cell subsets during infection remain unclear.Here,using a mouse model of lymphocytic choriomeningitis virus(LCMV)infection,we observed that CD49a+CD49b+NK(double positive NK,DP NK)cells emerged and underwent vigorous expansion in the liver early after infection,but then decreased progressively.These viral infection-induced DP NK cells were highly activated with high expression of the activation marker CD69 and activating receptors CD226,NKG2D and NKp46,and mainly composed of CD11bhiCD27hi mature NK cells.These DP NK cells underwent a rapid turnover during LCMV infection with increased proliferation and apoptosis.Moreover,compared with LrNK and cNK cells,DP NK cells were more functionally competent,as evidenced by higher amounts of IFN-? production and stronger cytotoxic capabilities during viral infection.These DP NK cells were EomesintT-bethi,and their generation was independent on T-bet.Adoptive transfer experiments revealed that cNK cells,not LrNK cells,could convert into DP NK cells after infection.The expansion of DP NK cells was impaired in IFN-y deficient mice during viral infection,whereas overexpression of IFN-y in vivo promoted the expansion of this subset.Collectively,our study reveals that there is a transient appearance of liver CD49a+CD49b+NK cells in response to viral infection-induced inflammation,and this subset represents a cNK cell-derived and functional competent subset.