A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function

Immunity. 2023 Sep 12;56(9):2054-2069.e10. doi: 10.1016/j.immuni.2023.07.017. Epub 2023 Aug 18.

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.

Keywords: FOXP3(+) regulatory T cells; T cell receptor; ZAP-70; anti-pathogen immunity; autoimmune disease; cellular-retinoic-acid-binding protein; effector differentiation; extranuclear; nuclear receptor; proliferation; retinoic acid; retinoic acid receptor alpha; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Autoimmune Diseases*
  • Cell Membrane
  • Humans
  • Lymphocyte Activation*
  • Receptors, Antigen, T-Cell
  • Retinoic Acid Receptor alpha / genetics

Substances

  • Retinoic Acid Receptor alpha
  • Receptors, Antigen, T-Cell