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Immunol Cell Biol. 2012 Sep;90(8):802-11. doi: 10.1038/icb.2012.17. Epub 2012 Apr 10.

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

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Department of Medicine-Immunobiology, University of Vermont, Burlington, VT 05405, USA.


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.

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