title: TGF-β induces the differentiation of human CXCL13-producing CD4(+) T cells.
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.
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Shio
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: The Tazuke-Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of the Control for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Furu
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Juichi
authors.initials: J
authors.lastname: Ito
authors.affiliation: Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshitomi
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D054382:Chemokine CXCL13 / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*; D055815:Young Adult
chemical_list: D054382:Chemokine CXCL13; D018836:Inflammation Mediators; D016212:Transforming Growth Factor beta
keywords: CXCL13; Follicular helper T cells; FoxP3; Proinflammatory cytokines; TGF-β ⋅ Treg cells