RRC ID 54505
Author Kobayashi S, Watanabe T, Suzuki R, Furu M, Ito H, Ito J, Matsuda S, Yoshitomi H.
Title TGF-β induces the differentiation of human CXCL13-producing CD4(+) T cells.
Journal Eur J Immunol
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.
Volume 46(2)
Pages 360-71
Published 2016-2-1
DOI 10.1002/eji.201546043
PMID 26541894
PMC PMC5063156
MeSH Adolescent Adult Animals Arthritis, Rheumatoid / immunology* Cell Differentiation Cells, Cultured Chemokine CXCL13 / metabolism* Child Child, Preschool Female Gene Expression Regulation Humans Inflammation Mediators / metabolism Male Mice Middle Aged T-Lymphocyte Subsets / immunology* T-Lymphocytes, Helper-Inducer / immunology* Transforming Growth Factor beta / immunology* Young Adult
IF 4.695
Times Cited 21
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384) CS-RfA-EG (RDB04391) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) CSII-EF-IRES2-Venus_hFoxP3 (RDB17320) CSU6EG_sh7T-hFoxP3 (RDB17321) CSU6EG_sh2-hSTAT5AB (RDB17322)