title: Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile.
abstract: The transcription factors T-bet and Bcl-6 are required for the establishment of a T helper type 1 cell (T(H)1 cell) and follicular helper T cell (T(FH) cell) gene-expression profile, respectively. Here we found that high concentrations of interleukin 2 (IL-2) inhibited Bcl-6 expression in polarized T(H)1 cells. Mechanistically, the low concentrations of Bcl-6 normally found in effector T(H)1 cells did not repress its target genes because a T-bet-Bcl-6 complex masked the Bcl-6 DNA-binding domain. T(H)1 cells increased their Bcl-6/T-bet ratio in response to limiting IL-2 conditions, which allowed excess Bcl-6 to repress its direct target Prdm1 (which encodes the transcriptional repressor Blimp-1). The Bcl-6-dependent repression of Blimp-1 effectively induced a partial T(FH) profile because Blimp-1 directly repressed a subset of T(FH) signature genes, including Cxcr5. Thus, IL-2-signaling regulates the Bcl-6-Blimp-1 axis in T(H)1 cells to maintain flexibility with a T(FH) cell-like gene profile.
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Oestreich
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Mohn
authors.forename: Amy S
authors.initials: AS
authors.lastname: Weinmann
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D000098815:T-bet Transcription Factor
chemical_list: C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1