IL-6 triggers IL-21 production by human CD4(+) T cells to drive STAT3-dependent plasma cell differentiation in B cells

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 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 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 antibody production by IL-6. In IL-21–treated B cells, signal transducer and activator of transcription (STAT)3 was required for optimal Ig production and upregulation of 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, while not sufficient, may serve as a platform for the acquisition of a T(FH)–like phenotype by human CD4(+) T cells.