Late interleukin-6 promotes T follicular helper cell response and resolution of chronic viral infection (105.8)

Abstract

Abstract Multiple inhibitory molecules create a profoundly immunuosuppressive environment during chronic viral infections in humans and mice, making generation of effective immunity in this context a challenge. Using murine chronic lymphocytic choriomeningitis virus (LCMV) infection we found that non-hematopoietic cells produced interleukin 6 (IL-6) in a unique biphasic manner, with later IL-6 playing an essential role for viral control. The underlying mechanism involved IL-6 upregulation of the transcription factor BCL6 in virus specific CD4 T cells during chronic (but not acute) infection. This resulted in escalation of T follicular helper cell, germinal center and antibody responses at late stages of chronic infection. Notably, while CD4 T cells showed intact IL6 signaling both early and late after chronic infection only late IL6 stimulation resulted in significant BCL6 up-regulation. Finally ablation of the common IL-6 cytokine family receptor gp130 not only curtailed BCL6 upregulation in CD4 T cells but also reduced their numbers and IL-21 expression in a cell-intrinsic fashion. Our results uncover a novel antiviral strategy that overcomes the immunosuppressive environment to promote CD4 helper functions and safely resolves a persistent infection in vivo. These findings could illuminate new therapies to control viral persistence in humans.