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 (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. Immunology and Cell Biology (2012) 90, 802-811; doi:10.1038/icb.2012.17; published online 10 April 2012