title: Role of retinoic acid in the stability of the T-helper-type 1 lineage and implications for autoimmunity.
abstract: BACKGROUND
  CD4 T cells with features of both T-helper-type 1 (Th1) and 17 (Th17) cells have been implicated in several autoimmune diseases suggesting that plasticity among CD4 T-cell lineages is potentially pathogenic. However, the factors that regulate T-cell lineage stability are largely unknown. Retinoic acid (RA) is synthesised at sites of inflammation. We hypothesised that retinoic acid, a profound epigenetic modifier, could regulate T-cell lineage stability.
  
  
  METHODS
  We used a mouse model in which retinoic acid signalling is specifically ablated within the T-cell compartment through overexpression of a dominant negative retinoic acid receptor α (RARα) (dnRARα mice) to investigate its role in the regulation of Th1 lineage stability. Genome-wide ChIP-seq analysis was done to identify RARα targets. In parallel, we performed global mapping of regulatory regions, termed enhancers, to gain mechanistic insight into retinoic acid regulation of T-cell fate. The in-vivo relevance of our findings was determined in a model of oral antigen-induced intestinal inflammation.
  
  
  RESULTS
  We found that retinoic acid is crucial for maintenance of the Th1 lineage. Abrogation of retinoic acid signalling in Th1 cells resulted in loss of T-bet expression and STAT4 activity. Th1 cells from dnRARα mice showed enhanced plasticity with the emergence of hybrid Th1-Th17 and Th17 effector cells. Global analysis of RARα binding and enhancer mapping revealed that RA-RARα directly regulated enhancer activity at Th1 lineage defining genes while repressing genes that regulate Th17 cell fate. Retinoic acid inhibition of Th1 plasticity was essential for maintaining appropriate Th cell responses in vivo and preventing autoimmune intestinal inflammation.
  
  
  CONCLUSIONS
  Our study has identified RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1 cells and defines a new pathway for the development of pathogenic Th17 cells. Retinoids might be novel therapeutic agents for Th17-associated autoimmune diseases.
  
  
  BACKGROUND
  Wellcome Trust.
authors: Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK. Electronic address: chrysothemis.brown@kcl.ac.uk.
authors: Chrysothemis
authors: C
authors: Brown
authors: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA.
authors: Daria
authors: D
authors: Esterhazy
authors: Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK.
authors: Aurelien
authors: A
authors: Sarde
authors: National Institute for Health Research Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London, UK.
authors: Venu
authors: V
authors: Pullabhatla
authors: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA.
authors: Mariya
authors: M
authors: London
authors: Genomics Centre, King's College London, London, UK.
authors: Matthew
authors: M
authors: Arno
authors: National Institute for Health Research Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London, UK.
authors: Emanuele
authors: E
authors: de Rinaldis
authors: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA.
authors: Daniel
authors: D
authors: Mucida
authors: Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK.
authors: Graham
authors: G
authors: Lord
authors: Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK.
authors: Randolph
authors: R
authors: Noelle