title: TGF-β enhanced IL-21-induced differentiation of human IL-21-producing CD4+ T cells via Smad3.
abstract: IL-21 has pleiotropic effects on innate and adaptive immune response, and plays an important role in the development of autoimmune disease and antitumor activity. It has been reported that IL-21 is produced by CD4(+) T cells and NKT cells. However, the differentiation of IL-21-producing CD4(+) T cells in humans remains largely unclear. In the present study, we showed that cytokines of IL-1β, IL-6 or IL-21 induced differentiation of human IL-21-producing CD4(+) T cells, and TGF-β enhanced the effect of inflammatory cytokines on the development of IL-21-producing CD4(+) T cells. Furthermore, we found that the majority of IL-21-producing cells were distinct from Th17 cells and Th1 cells since they did not co-express IL-17 and IFN-γ. TGF-β significantly inhibited the production of IFN-γ and enhanced the effect of IL-21 on the development of IL-21-producing CD4(+) T cells. In addition, we found that IL-21 inhibited the differentiation of CD4(+) Foxp3(+) T cells induced by TGF-β. Further study indicated that IL-21 induced phosphorylation of transcriptional factors of STAT1, STAT3 and STAT5, and TGF-β induced phosphorylation of Smad3 in CD4(+) T cells. Taken together, our data indicated that TGF-β enhanced IL-21-induced differentiation of IL-21-producing CD4(+) T cells, and the majority of IL-21-producing cells were different from Th17 and Th1 cells. Our results provide a new sight regarding the differentiation of human CD4(+) T cells.
authors.affiliation: Institute of Immunology, Zhongshan School of Medicine, Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Sifei
authors.initials: S
authors.lastname: Yu
authors.forename: Zitao
authors.initials: Z
authors.lastname: Li
authors.forename: Jiangjun
authors.initials: J
authors.lastname: Ma
authors.forename: Yannan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Binyan
authors.initials: B
authors.lastname: Yang
authors.forename: Changyou
authors.initials: C
authors.lastname: Wu
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis / Q000494:pharmacology*; D061251:Primary Cell Culture; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000098546:Interleukin-21
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D007378:Interleukins; C497790:SMAD3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D000098546:Interleukin-21