TGF‐β induces the differentiation of human CXCL13‐producing CD4+ T cells. Issue 2 (24th November 2015)

• Record Type: Journal Article
• Authors: Kobayashi, Shio; Watanabe, Takeshi; Suzuki, Ryo; Furu, Moritoshi; Ito, Hiromu; Ito, Juichi; Matsuda, Shuichi; Yoshitomi, Hiroyuki
• Is Part Of: European journal of immunology. Volume 46:Issue 2(2016)
• Page Start: 360
• Page End: 371
• Publication Date: 2015-11-24
• Subjects: CXCL13 -- Follicular helper T cells -- FoxP3 -- Proinflammatory cytokines -- TGF‐β ⋅ Treg cells; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201546043
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract : In the ectopic lymphoid‐like structures present in chronic inflammatory conditions such as rheumatoid arthritis, a subset of human effector memory CD4 + T cells that lacks features of follicular helper T (Tfh) cells produces CXCL13. Here, we report that TGF‐β induces the differentiation of human CXCL13‐producing CD4 + T cells from naïve CD4 + T cells. The TGF‐β‐induced CXCL13‐producing CD4 + T cells do not express CXCR5, B‐cell lymphoma 6 (BCL6), and other Tfh‐cell markers. Furthermore, expression levels of CD25 (IL‐2Rα) in CXCL13‐producing CD4 + T cells are significantly lower than those in FoxP3 + in vitro induced Treg cells. Consistent with this, neutralization of IL‐2 and knockdown of STAT5 clearly upregulate CXCL13 production by CD4 + T cells, while downregulating the expression of FoxP3. Furthermore, overexpression of FoxP3 in naïve CD4 + T cells downregulates CXCL13 production, and knockdown of FoxP3 fails to inhibit the differentiation of CXCL13‐producing CD4 + T cells. As reported in rheumatoid arthritis, proinflammatory cytokines enhance secondary CXCL13 production from reactivated CXCL13‐producing CD4 + T cells. Our findings demonstrate that CXCL13‐producing CD4 + T cells lacking Tfh‐cell features differentiate via TGF‐β signaling but not via FoxP3, and exert their function in IL‐2‐limited but TGF‐β‐rich and proinflammatory cytokine‐rich inflammatory conditions.