title: Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages.
abstract: After activation, CD4(+) helper T (Th) cells differentiate into distinct effector subsets. Although chemokine (C-X-C motif) receptor 5-expressing T follicular helper (Tfh) cells are important in humoral immunity, their developmental regulation is unclear. Here we show that Tfh cells had a distinct gene expression profile and developed in vivo independently of the Th1 or Th2 cell lineages. Tfh cell generation was regulated by ICOS ligand (ICOSL) expressed on B cells and was dependent on interleukin-21 (IL-21), IL-6, and signal transducer and activator of transcription 3 (STAT3). However, unlike Th17 cells, differentiation of Tfh cells did not require transforming growth factor beta (TGF-beta) or Th17-specific orphan nuclear receptors RORalpha and RORgamma in vivo. Finally, naive T cells activated in vitro in the presence of IL-21 but not TGF-beta signaling preferentially acquired Tfh gene expression and promoted germinal-center reactions in vivo. This study thus demonstrates that Tfh is a distinct Th cell lineage.
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center and Graduate School of Biomedical Sciences, Houston, TX 77030, USA. rnurieva@mdanderson.org
authors.forename: Roza I
authors.initials: RI
authors.lastname: Nurieva
authors.forename: Yeonseok
authors.initials: Y
authors.lastname: Chung
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.forename: Xuexian O
authors.initials: XO
authors.lastname: Yang
authors.forename: Hong Soon
authors.initials: HS
authors.lastname: Kang
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Yi-hong
authors.initials: YH
authors.lastname: Wang
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tian
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology*; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology; D007150:Immunohistochemistry; D060945:Inducible T-Cell Co-Stimulator Ligand; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D011506:Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D000098546:Interleukin-21