title: Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling.
abstract: Receptors of the Notch family direct the differentiation of helper T cell subsets, but their influence on regulatory T cell (T(reg) cell) responses is obscure. We found here that lineage-specific deletion of components of the Notch pathway enhanced T(reg) cell-mediated suppression of type 1 helper T cell (T(H)1 cell) responses and protected against their T(H)1 skewing and apoptosis. In contrast, expression in T(reg) cells of a gain-of-function transgene encoding the Notch1 intracellular domain resulted in lymphoproliferation, exacerbated T(H)1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired T(reg) cell fitness and promoted the acquisition by T(reg) cells of a T(H)1 cell-like phenotype, whereas non-canonical Notch signaling dependent on the adaptor Rictor activated the kinase AKT-transcription factor Foxo1 axis and impaired the epigenetic stability of Foxp3. Our findings establish a critical role for Notch signaling in controlling peripheral T(reg) cell function.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Louis-Marie
authors.initials: LM
authors.lastname: Charbonnier
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Georgiev
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Esen
authors.initials: E
authors.lastname: Sefik
authors.affiliation: Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D061166:Peripheral Tolerance; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D059467:Transcriptome
chemical_list: D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C497762:Notch1 protein, mouse; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051881:Receptor, Notch1; D011993:Recombinant Fusion Proteins; C525637:rictor protein, mouse