Cell-Intrinsic IL-27 and gp130 Cytokine Receptor Signaling Regulates Virus-Specific CD4+ T Cell Responses and Viral Control during Chronic Infection

•T cell-specific gp130 signaling is vital for clearance of chronic infection•Intrinsic gp130-IL27 signaling promotes the survival of virus specific CD4+ T cells•Intrinsic gp130 signaling controls the IL-21 production from CD4+ T cells•IL-27 is critical for the clearance of chronic viral infection

SummaryThe outcome of chronic viral infections, which affect millions of people worldwide, is greatly dependent on CD4+ T cells. Here we showed that T cell-specific ablation of the common interleukin-6 (IL-6) family receptor, gp130, profoundly compromised virus-specific CD4+ T cell survival, T follicular helper responses, and IL-21 production at late stages of chronic lymphocytic choriomeningitis virus (LCMV) infection. These effects were cell intrinsic for CD4+ T cells and were accompanied by a reduction of CD8+ T cells, antibodies, and a severe failure in viral control. We identified IL-27 as a gp130 cytokine that promoted antiviral CD4+ T cell accumulation in vivo and that rapidly induced IL-21 ex vivo. Furthermore, IL-27R was critical for control of persistent LCMV in vivo. These results reveal that gp130 cytokines (particularly IL-27) are key regulators of CD4+ T cell responses during an established chronic viral infection, empowering both humoral and cytotoxic immunity.