Distinct and overlapping roles for cell intrinsic IL-6 and IL-27 signaling in promoting virus specific CD4+ T cell numbers and function during acute and chronic viral infections (VIR7P.1055)

Abstract

Abstract Chronic viral infections such as human immunodeficiency virus 1 and hepatitis C virus represent a significant global health burden. Virus specific CD4+ T cell number and function are critical in determining the outcome of these chronic viral infections, but little is known about the signals that can promote their survival or helper functions in this environment. By studying both acute and chronic variants of lymphocytic choriomeningitis virus infection of mice we found that the IL-6 cytokine family signal transduction molecule gp130 expression on CD4+ T cells was essential for long term viral control in chronic, but not acute infection. It was critical for virus specific CD4+ T cell survival, differentiation and the production of IL-21, factors which are critical in the control of chronic infections. Dissection of the individual IL-6 family of cytokines revealed that IL-6 was critical for the upregulation of the transcriptional regulator Bcl6 and subsequent escalation in T follicular helper cell responses and development of antiviral antibody. Contrastingly IL-27 was uniquely required in the survival of these virus specific CD4+ T cells at late stages of chronic infection. Use of Il6ra-/-;Il27ra-/- ¬mice showed however that IL-6 and IL-27 had an overlapping role in the production of IL-21. Our data situates the IL-6 cytokine family as central orchestrators of anti-viral CD4+ T cell responses and subsequent immune responses vital during established chronic viral infections.