Interferon regulatory factor-1 (irf-1) shapes both innate and cd8 + t cell immune responses against west nile virus infection

Interferon regulatory factor (irf)-1 is an immunomodulatory transcription factor that functions downstream of pathogen recognition receptor signaling and has been implicated as a regulator of type i interferon (ifn)-αβ expression and the immune response to virus infections. however,this role for irf-1 remains controversial because altered type i ifn responses have not been systemically observed in irf-1 -/- mice. to evaluate the relationship of irf-1 and immune regulation,we assessed west nile virus (wnv) infectivity and the host response in irf-1 -/- cells and mice. irf-1 -/- mice were highly vulnerable to wnv infection with enhanced viral replication in peripheral tissues and rapid dissemination into the central nervous system. ex vivo analysis revealed a cell-type specific antiviral role as irf-1 -/- macrophages supported enhanced wnv replication but infection was unaltered in irf-1 -/- fibroblasts. irf-1 also had an independent and paradoxical effect on cd8 + t cell expansion. although markedly fewer cd8 + t cells were observed in naïve animals as described previously,remarkably,irf-1 -/- mice rapidly expanded their pool of wnv-specific cytolytic cd8 + t cells. adoptive transfer and in vitro proliferation experiments established both cell-intrinsic and cell-extrinsic effects of irf-1 on the expansion of cd8 + t cells. thus,irf-1 restricts wnv infection by modulating the expression of innate antiviral effector molecules while shaping the antigen-specific cd8 + t cell response. © 2011 brien et al.