title: LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6.
abstract: Follicular helper T cells (T(FH) cells) are specialized effector CD4(+) T cells that help B cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate the differentiation of T(FH) cells remain incompletely understood. Here we report that selective loss of Lef1 or Tcf7 (which encode the transcription factor LEF-1 or TCF-1, respectively) resulted in T(FH) cell defects, while deletion of both Lef1 and Tcf7 severely impaired the differentiation of T(FH) cells and the formation of GCs. Forced expression of LEF-1 enhanced T(FH) differentiation. LEF-1 and TCF-1 coordinated such differentiation by two general mechanisms. First, they established the responsiveness of naive CD4(+) T cells to T(FH) cell signals. Second, they promoted early T(FH) differentiation via the multipronged approach of sustaining expression of the cytokine receptors IL-6Rα and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor Bcl6.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Youn Soo
authors.initials: YS
authors.lastname: Choi
authors.affiliation: 1] Department of Microbiology, University of Iowa, Iowa City, Iowa, USA. [2] Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Gullicksrud
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Xing
authors.affiliation: Department of Physics, The George Washington University, Washington, DC, USA.
authors.forename: Zhouhao
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shan
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Fengyin
authors.initials: F
authors.lastname: Li
authors.affiliation: Section on Cellular and Developmental Biology, NICHD, NIH, Bethesda, Maryland, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Love
authors.affiliation: Department of Physics, The George Washington University, Washington, DC, USA.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.affiliation: 1] Department of Microbiology, University of Iowa, Iowa City, Iowa, USA. [2] Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Xue
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Shane
authors.identifier: 0000000264846262
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000276:immunology*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D051560:Proto-Oncogene Proteins c-bcl-6; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C494200:Il6st protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130