The retinoic acid receptor drives neuroinflammation and fine tunes the homeostasis of interleukin-17-producing T cells

The vitamin A metabolite retinoic acid (RA) and its receptor (RAR) are one of the key interactions regulating cellular immunity and neural signaling. Whether endogenous RA-RAR interactions contribute to the development of neuroinflammation and diseases like multiple sclerosis, remains to be elucidated. Herein, we used the murine experimental autoimmune encephalomyelitis (EAE) model and an established genetic RAR silencing approach to decipher its role in pathogenic T cell responses. We show that RAR is necessary for the development of interleukin(IL)-17-driven, cell-mediated immunopathology in the brain and that it fine tunes the homeostasis of IL-17-producing gamma delta ({gamma}{delta}T17) and CD4+ T cells (TH17). At steady-state, RAR was required in the {gamma}{delta}T17 compartment to sustain optimal cell numbers and maintain expression of genes involved in cell cycle progression. In contrast, RAR negatively regulated T helper-17 (TH17) cell homeostasis. Our data show that RAR is required during the early phases of EAE in order to induce a {gamma}{delta}T17 response and that its activity is necessary throughout the course of the disease to allow TH17 and {gamma}{delta}T17 cells to infiltrate the brain. This is correlated with failure of RAR deficient cells to express surface integrin-alpha4, a major brain homing molecule. Collectively, our work demonstrates that endogenous RA-RAR interactions are important for the homeostasis of IL-17-producing T cells and necessary for their pathogenicity during neuroinflammation. One sentence summaryRetinoic acid receptor activity was required on IL-17-producing CD4+ and {gamma}{delta} T cells to induce their neuropathogenicity, and to regulate both positively and negatively their homeostasis.