Functional STAT3 deficiency compromises the generation of human T follicular helper cells

作者：Cindy S. Ma, Danielle T. Avery, Anna Chan, Marcel Batten, Jacinta C. Bustamante, Stéphanie Boisson‐Dupuis, Peter D. Arkwright, Alexandra Y. Kreins, Diana Averbuch, Dan Engelhard, Klaus Magdorf, Sara Şebnem Kılıç, Yoshiyuki Minegishi, Shigeaki Nonoyama, Martyn A. French, Sharon Choo, Joanne M Smart, Jane Peake, Melanie Wong, Paul Edgar Gray, Matthew Cook, David A. Fulcher, Jean‐Laurent Casanova, Elissa K. Deenick, Stuart G. Tangye · 发表于：Blood · 年份：2012 · DOI：10.1182/blood-2011-11-392985 · 被引用次数：320 · 研究领域：Immunodeficiency and Autoimmune Disorders、T-cell and B-cell Immunology、Immune Cell Function and Interaction

T 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-12Rβ1, 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.