IL-6 induces IL-21 and B cell helper function in CD8 cells

Abstract

Abstract Interleukin 6 (IL-6) is a pro-inflammatory produced by various cell types in response to external stimuli including trauma, stress and infection. IL-6 signaling plays an important role in immune reaction and progression of several autoimmune diseases by programing CD4 cell differentiation and effector functions. CD8 cells was first believed to primarily function as cytotoxic effector cells, their helper cell effector function has been better understood till recently. During activation, CD8 cells can be primed in different cytokine environments to differentiate into different CD8 effector subtypes, including Tc1, Tc2 and recently identified Tc17. Although the role of IL-6 in CD4 cell differentiation and effector function is well known, how IL-6 may regulate CD8 cell differentiation is less studied. In this study, we show that IL-6 induces IL-21 production in CD8 cells during activation through the transcription factor Stat3. Importantly, IL-6 also differentiates CD8 cells to an effector subset producing high IL-21 but low IFN-γ and IL-2. IL-6R expression level in CD8 cells determines the subset of cells that capable of making IL-21. Similar to IL-21 producing CD4 cells, surprisingly, IL-21 producing CD8 cells provides B cell help by inducing isotype switching and promoting antibody production in vitro and in vivo during influenza A flu infection. Thus, our study suggests that IL-6 could differentiate CD8 cells into IL-21 producing B cell helper subset that may play a unique role in restricting infection and the progression of autoimmune diseases.