Retinoic Acid Is Essential for Th1 Cell Lineage Stability and Prevents Transition to a Th17 Cell Program

• Published in: Immunity (Cambridge, Mass.) Mass.), 2015-03, Vol.42 (3), p.499-511
• Main Authors: Brown, Chrysothemis C., Esterhazy, Daria, Sarde, Aurelien, London, Mariya, Pullabhatla, Venu, Osma-Garcia, Ines, al-Bader, Raya, Ortiz, Carla, Elgueta, Raul, Arno, Matthew, de Rinaldis, Emanuele, Mucida, Daniel, Lord, Graham M., Noelle, Randolph J.
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Biomedical research; Cell Differentiation - drug effects; Cell Differentiation - immunology; Cell Lineage - drug effects; Cell Lineage - immunology; Epigenetics; Gene expression; Gene Expression Regulation; Gene Regulatory Networks; Homeostasis - drug effects; Homeostasis - immunology; Integrases - genetics; Integrases - metabolism; Lymphocytes; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - immunology; Retinoic Acid Receptor alpha; Rodents; Signal Transduction; Stem cells; Studies; T cell receptors; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; Th1 Cells - cytology; Th1 Cells - drug effects; Th1 Cells - immunology; Th17 Cells - cytology; Th17 Cells - drug effects; Th17 Cells - immunology; Tretinoin - immunology; Tretinoin - pharmacology
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2015.02.003

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. [Display omitted] •Retinoic acid (RA) stabilizes Th1 fate commitment•Signaling through RA receptor α (RARα) activates enhancers of Th1-cell-lineage-specifying genes•RA-RARα represses Th17-cell genes in Th1 cells and constrains Th1-cell plasticity•RA-RARα prevents development of pathogenic Th17 cells in vivo Maintenance of T helper (Th)-cell identity is critical for appropriate immune responses; however, the factors that regulate Th-cell plasticity are unresolved. Brown et al. show that retinoic-acid signaling confers Th1 cell stability and restrains their conversion to Th17 cells.