Programmed death (PD)-1-Deficient mice are extremely sensitive to murine hepatitis virus strain-3 (MHV-3) infection

The inhibitory receptor programmed death-1 (pd-1) has the capacity to maintain peripheral tolerance and limit immunopathological damage; however,its precise role in fulminant viral hepatitis (fh) has yet to be described. here,we investigated the functional mechanisms of pd-1 as related to fh pathogenesis induced by the murine hepatitis virus strain-3 (mhv-3). high levels of pd-1-positive cd4 +,cd8 + t cells,nk cells and macrophages were observed in liver,spleen,lymph node and thymus tissues following mhv-3 infection. pd-1-deficient mice exhibited significantly higher expression of the effector molecule which initiates fibrinogen deposition,fibrinogen-like protein 2 (fgl2),than did their wild-type (wt) littermates. as a result,more severe tissue damage was produced and mortality rates were higher. fluorescence double-staining revealed that fgl2 and pd-1 were not co-expressed on the same cells,while quantitative rt-pcr demonstrated that higher levels of ifn-γ and tnf-α mrna transcription occurred in pd-1-deficient mice in response to mhv-3 infection. conversely,in vivo blockade of ifn-γ and tnf-α led to efficient inhibition of fgl2 expression,greatly attenuated the development of tissue lesions,and ultimately reduced mortality. thus,the up-regulation of fgl2 in pd-1-deficient mice was determined to be mediated by ifn-γ and tnf-α. taken together,our results suggest that pd-1 signaling plays an essential role in decreasing the immunopathological damage induced by mhv-3 and that manipulation of this signal might be a useful strategy for fh immunotherapy. © 2011 chen et al.