Multi-level orchestration of γδ T cell development and central nervous system inflammation by retinoic acid

The vitamin A metabolite retinoic acid (RA) is critical for the maturation and function of the immune system, however, our knowledge regarding its role in gamma delta ({gamma}{delta}) T cells is limited. By specifically inactivating the RA receptor alpha (RAR) in type 3 lymphocytes and using a combination of fetal thymic organ cultures and single-cell RNA-sequencing we found that RA strengthened TCR signaling to limit the embryonic development of interleukin(IL)-17-producing {gamma}{delta} T cells ({gamma}{delta}T17), while at the same time it promoted their survival after birth. In adult mice, RA imposed a multi-level transcriptional program allowing {gamma}{delta}T17 cells to become activated, survive and sense interferon. Consequently, cells with inactive RAR responded poorly to immunization and produced low level of cytokines leading to near disease resistance in the experimental autoimmune encephalomyelitis model. Finally, RA was required for optimal expression of the 4{beta}1 integrin and {gamma}{delta}T17 cell infiltration to the brain. Collectively, these studies suggest that by acting at various stages during the lifetime of {gamma}{delta} T cells, RA supports their normal development, their survival and their ability to respond to inflammatory stimuli.