title: Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program.
abstract: CD4(+) T cells differentiate into phenotypically distinct T helper cells upon antigenic stimulation. Regulation of plasticity between these CD4(+) T-cell lineages is critical for immune homeostasis and prevention of autoimmune disease. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes, as well as repressing genes that instruct Th17-cell fate. RA signaling is essential for limiting Th1-cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our study identifies RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1-cell fate and defines an additional pathway for the development of Th17 cells.
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK. Electronic address: chrysothemis.brown@kcl.ac.uk.
authors.forename: Chrysothemis C
authors.initials: CC
authors.lastname: Brown
authors.affiliation: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Esterhazy
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.
authors.forename: Aurelien
authors.initials: A
authors.lastname: Sarde
authors.affiliation: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Mariya
authors.initials: M
authors.lastname: London
authors.affiliation: National Institute for Health Research Biomedical Research Centre at Guy's & St Thomas' National Health Service Foundation Trust and King's College London, London SE1 9RT, UK.
authors.forename: Venu
authors.initials: V
authors.lastname: Pullabhatla
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.
authors.forename: Ines
authors.initials: I
authors.lastname: Osma-Garcia
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.
authors.forename: Raya
authors.initials: R
authors.lastname: Al-Bader
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.
authors.forename: Carla
authors.initials: C
authors.lastname: Ortiz
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.
authors.forename: Raul
authors.initials: R
authors.lastname: Elgueta
authors.affiliation: Genomics Centre, King's College London, London SE1 9NH, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Arno
authors.affiliation: National Institute for Health Research Biomedical Research Centre at Guy's & St Thomas' National Health Service Foundation Trust and King's College London, London SE1 9RT, UK; Division of Cancer Studies, School of Medicine, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: de Rinaldis
authors.affiliation: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mucida
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK; National Institute for Health Research Biomedical Research Centre at Guy's & St Thomas' National Health Service Foundation Trust and King's College London, London SE1 9RT, UK.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK; Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA. Electronic address: rjn@dartmouth.edu.
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D019070:Cell Lineage / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000276:immunology; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014212:Tretinoin / Q000276:immunology / Q000494:pharmacology*
chemical_list: C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C045073:Cre recombinase; D019426:Integrases