IL‐6 Triggers IL‐21 production by human CD4+ T cells to drive STAT3‐dependent plasma cell differentiation in B cells

Abstract

Interleukin (IL)‐21‐producing CD4⁺T cells are central to humoral immunity. Deciphering the signals that induce IL‐21 production in CD4⁺ T cells and those triggered by IL‐21 in B cells are, therefore, of importance for understanding the generation of antibody (Ab) responses. Here, we show that IL‐6 increased IL‐21 production by human CD4⁺ T cells, particularly in those that express the transcriptional regulator B cell lymphoma (BCL)6, which is required in mice for the development of C‐X‐C chemokine receptor type 5 (CXCR5⁺) IL‐21‐producing T follicular helper (T_FH) cells. However, retroviral overexpression of BCL6 in total human CD4⁺ T cells only transiently increased CXCR5, the canonical T_FH‐defining surface marker. We show here that IL‐21 was required for the induction of Ab production by IL‐6. In IL‐21‐treated B cells, signal transducer and activator of transcription (STAT)3 was required for optimal immunoglobulin production and upregulation of PR domain containing 1 (PRDM1⁺), the master plasma cell factor. These results, therefore, demonstrate the critical importance of STAT3 activation in B cells during IL‐21‐driven humoral immunity and suggest that BCL6 expression, although not sufficient, may serve as a platform for the acquisition of a T_FH‐like phenotype by human CD4⁺ T cells.