Ma, CindyAvery, Danielle TChan, AnnaBatten, Marcel LBustamante, JacintaBoisson-Dupuis, StephanieArkwright, Peter DKreins, Alexandra YAverbuch, DianaEngelhard, DanCook, MatthewDeenick, ElissaTangye, Stuart2015-12-100006-4971http://hdl.handle.net/1885/61901T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4 + T cells to the Tfh lineage, because IL-12 induces naive human CD4 + T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4 + T cells from patients deficient in IL-12Rp1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4 + T cells. Defective expression of IL-21 by STAT3-deficient CD4 + T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4 +CXCR5 + T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.Keywords: chemokine receptor CXCR5; interleukin 12; interleukin 12 receptor beta1; interleukin 21; protein bcl 6; protein kinase TYK2; STAT1 protein; STAT3 protein; adolescent; adult; article; B lymphocyte; CD4+ T lymphocyte; cell line; cell lineage; cell maturatioFunctional STAT3 deficiency compromises the generation of human T follicular helper cells201210.1182/blood-2011-11-3929852016-06-14