T Cell-Intrinsic Expression Of Hic1 Links Retinoic Acid To Tissue Residency

Abstract The interaction between micronutrients and the immune system is emerging as a key control point in immune cell function in homeostasis and disease. For example, the vitamin A metabolite all-trans retinoic acid (atRA) has established roles in immune cell migration and effector function. Vitamin A deficiency results in a significant reduction in intestinal immune cells, which is thought to be associated with a lack of intestinal homing receptor expression and reduced migration to the intestine. However, the precise molecular pathways controlling intestinal immune cell homeostasis remains unclear. Here, we show that the atRA-inducible BTB-POZ transcriptional repressor Hypermethylated in cancer 1 (HIC1, ZBTB29) controls intestinal T cell residency. Mice with a T cell-intrinsic deletion of HIC1 (Hic1ΔT mice) have reduced numbers of CD69+ CD103+ tissue resident memory T (TRM) cells in the intestine, demonstrating that the atRA/HIC1 axis is critical for establishing and maintaining TRM cells. Further, following influenza A virus infection, numbers of TRM cells in the lungs are significantly reduced in Hic1ΔT mice, as well as in mice treated with the pan-retinoic acid receptor inhibitor BMS493, or in mice with a T cell-specific deletion of RARa (RaraΔT mice). Consistent with this, activation of naive CD8+ T cells from mice or humans in the presence of IL-2, IL-15, TGFβ and atRA results in the generation of CD69+ CD103+ ‘TRM-like’ cells that share the transcriptional profile of bona fide TRM cells. Taken together, these results identify atRA as a critical regulator of T cell tissue residency, acting by inducing expression of HIC1 and promoting the tissue residency gene program.