title: 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.
authors.affiliation: Department of Medicine-Immunobiology, University of Vermont, Burlington, VT 05405, USA. sean.diehl@uvm.edu
authors.forename: Sean A
authors.initials: SA
authors.lastname: Diehl
authors.forename: Heike
authors.initials: H
authors.lastname: Schmidlin
authors.forename: Maho
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Bianca
authors.initials: B
authors.lastname: Blom
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D015850:Interleukin-6 / Q000494:pharmacology*; D007378:Interleukins / Q000096:biosynthesis*; D051379:Mice; D010950:Plasma Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: C084103:BCL6 protein, human; D015415:Biomarkers; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D015850:Interleukin-6; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21