Retinoic acid suppresses IL-17 production and pathogenic activity of γδ T cells in CNS autoimmunity

Immunol Cell Biol. 2016 Sep;94(8):763-73. doi: 10.1038/icb.2016.39. Epub 2016 May 10.

Abstract

Retinoic acid (RA) in the steady state enhances induction of Foxp3(+) regulatory T (Treg) cells and inhibits differentiation of Th1 and Th17 cells, thereby maintaining tolerance, but can in inflammatory conditions promote effector Th1 and Th17 cells that mediate inflammation. IL-17-producing γδ T cells have recently been shown to have a major pathogenic role in autoimmune diseases. Here, we examined the immunomodulatory effects of RA on γδ T cells. We found that RA had a dramatic suppressive effect on IL-17A and IL-17F production by γδ T cells stimulated with IL-1β and IL-23. RA suppressed RORγt, IL-1R and IL-23R expression in γδ T cells. Treatment of mice with RA suppressed IL-17 production by γδ T cells in vivo. Furthermore, treatment of T cells with RA attenuated their ability to induce disease in experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis. This was associated with a reduction in the number of central nervous system-infiltrating γδ T cells, but also CD4(+) T cells that produced IL-17A, IL-17F or GM-CSF. Interestingly, treatment of γδ T cells with RA or removal of γδ T cells from a bulk population of T cells significantly reduced their capacity to induce EAE, demonstrating a critical role for γδ T cells in promoting pathogenic Th17 cells. Our findings demonstrate that the anti-inflammatory properties of RA are mediated in part by suppressing STAT3-mediated activation of cytokine production and cytokine receptor expression in γδ T cells, which suppresses their ability to activate Th17 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoimmunity
  • Central Nervous System / drug effects
  • Central Nervous System / immunology*
  • Central Nervous System / pathology
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Immunologic Factors / pharmacology
  • Interleukin-17 / biosynthesis*
  • Interleukin-1beta / metabolism
  • Interleukin-23 / metabolism
  • Mice, Inbred C57BL
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Tretinoin / pharmacology*

Substances

  • Immunologic Factors
  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-23
  • Myelin-Oligodendrocyte Glycoprotein
  • Receptors, Antigen, T-Cell, gamma-delta
  • Tretinoin