Role of PKR and type I IFNs in viral control during primary and secondary infection

Type i interferons (ifns) are known to mediate viral control,and also promote survival and expansion of virus-specific cd8+ t cells. however,it is unclear whether signaling cascades involved in eliciting these diverse cellular effects are also distinct. one of the best-characterized anti-viral signaling mechanisms of type i ifns is mediated by the ifn-inducible dsrna activated protein kinase,pkr. here,we have investigated the role of pkr and type i ifns in regulating viral clearance and cd8+ t cell response during primary and secondary viral infections. our studies demonstrate differential requirement for pkr,in viral control versus elicitation of cd8+ t cell responses during primary infection of mice with lymphocytic choriomeningitis virus (lcmv). pkr-deficient mice mounted potent cd8+ t cell responses,but failed to effectively control lcmv. the compromised lcmv control in the absence of pkr was multifactorial,and linked to less effective cd8+ t cell- mediated viral suppression,enhanced viral replication in cells,and lower steady state expression levels of ifn-responsive genes. moreover,we show that despite normal expansion of memory cd8+ t cells and differentiation into effectors during a secondary response,effective clearance of lcmv but not vaccinia virus required pkr activity in infected cells. in the absence of type i ifn signaling,secondary effector cd8+ t cells were ineffective in controlling both lcmv and vaccinia virus replication in vivo. these findings provide insight into cellular pathways of type i ifn actions,and highlight the under- appreciated importance of innate immune mechanisms of viral control during secondary infections,despite the accelerated responses of memory cd8+ t cells. additionally,the results presented here have furthered our understanding of the immune correlates of anti-viral protective immunity,which have implications in the rational design of vaccines. © 2010 nakayama et al.