Negative Impact of IFN-γ on Early Host Immune Responses to Retroviral Infection

The immune system is tasked with defending against a myriad of microbial infections, and its response to a given infectious microbe may be strongly influenced by coinfection with another microbe. It was shown that infection of mice with lactate dehydrogenase-elevating virus (LDV) impairs early adaptive immune responses to Friend virus (FV) coinfection. To investigate the mechanism of this impairment, we examined LDV-induced innate immune responses and found LDV-specific induction of IFN-alpha and IFN-gamma. LDV-induced IFN-alpha had little effect on FV infection or immune responses, but unexpectedly, LDV-induced IFN-gamma production dampened Th1 adaptive immune responses and enhanced FV infection. Two distinct effects were identified. First, LDV-induced IFN-gamma signaling indirectly modulated FV-specific CD8(+) T cell responses. Second, intrinsic IFN-gamma signaling in B cells promoted polyclonal B cell activation and enhanced early FV infection, despite promotion of germinal center formation and neutralizing Ab production. Results from this model reveal that IFN-gamma production can have detrimental effects on early adaptive immune responses and virus control. The Journal of Immunology, 2012, 189: 2521-2529.