학술논문
A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function.
Document Type
Academic Journal
Author
Larange A; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Takazawa I; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Kakugawa K; Laboratory for Immune Crosstalk, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan.; Thiault N; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Ngoi S; School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.; Olive ME; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.; Iwaya H; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Seguin L; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Vicente-Suarez I; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Becart S; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Verstichel G; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Balancio A; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Altman A; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Chang JT; School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.; Taniuchi I; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan.; Lillemeier B; Immunobiology and Microbial Pathogenesis Laboratory, IMPL-L, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Kronenberg M; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA; Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.; Myers SA; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Laboratory for Immunochemical Circuits, La Jolla Institute for Immunology, La Jolla, CA 92037, USA. Electronic address: sam@lji.org.; Cheroutre H; Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Laboratory for Immune Crosstalk, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan. Electronic address: hilde@lji.org.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE
Subject
Language
English
Abstract
Ligation of retinoic acid receptor alpha (RARα) by RA promotes varied transcriptional programs associated with immune activation and tolerance, but genetic deletion approaches suggest the impact of RARα on TCR signaling. Here, we examined whether RARα would exert roles beyond transcriptional regulation. Specific deletion of the nuclear isoform of RARα revealed an RARα isoform in the cytoplasm of T cells. Extranuclear RARα was rapidly phosphorylated upon TCR stimulation and recruited to the TCR signalosome. RA interfered with extranuclear RARα signaling, causing suboptimal TCR activation while enhancing FOXP3 + regulatory T cell conversion. TCR activation induced the expression of CRABP2, which translocates RA to the nucleus. Deletion of Crabp2 led to increased RA in the cytoplasm and interfered with signalosome-RARα, resulting in impaired anti-pathogen immunity and suppressed autoimmune disease. Our findings underscore the significance of subcellular RA/RARα signaling in T cells and identify extranuclear RARα as a component of the TCR signalosome and a determinant of immune responses.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2023 Elsevier Inc. All rights reserved.)