Essential Role for Retinoic Acid in the Promotion of CD4+ T Cell Effector Responses via Retinoic Acid Receptor Alpha

Abstract

SUMMARY Vitamin A and its metabolite, retinoic acid (RA), have recently been implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells. Here we show that RA is also required to elicit proinflammatory CD4+ helper T cell responses to infection and mucosal vaccination. Retinoic acid receptor alpha (RARα) is the critical mediator of these effects. Strikingly, antagonism of RAR signaling and deficiency in RARα(Rara−/−) results in a cell autonomous CD4+ T cell activation defect. Altogether, these findings reveal a fundamental role for the RA/RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses.

Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

“…In line with previously published data using RAR␣ antagonist, both our lab (68,69,151) and Hall et al (70) showed that intrinsic RA signaling is required for gut-imprinting of T cells. Downregultion of RA-induced ␣4␤7 and CCR9 expression was observed in both dnRAR␣-expressing and RAR␣-deficient CD8 ϩ T cells and illustrated the requirement of RAR␣-RXR for CCR9 upregulation (68).…”

“…To more accurately assess the role of RA in Th17 differentiation fate, new insights should be gained through the analysis of Th17 response via genetic blockade of RA signaling. In this regard, Hall et al (70) and our group reported deficient Th17 cell differentiation in RAR␣-deficient CD4 ϩ T cells. In the study of Hall et al (70), defective TCR signaling was observed in the RAR␣-deficient CD4 ϩ T cells, too.…”

“…In this regard, Hall et al (70) and our group reported deficient Th17 cell differentiation in RAR␣-deficient CD4 ϩ T cells. In the study of Hall et al (70), defective TCR signaling was observed in the RAR␣-deficient CD4 ϩ T cells, too. It remains unknown whether RAR␣ deficiency has any impact on ROR␥T expression per se.…”

“…Hall et al (70) have discovered that RA is essential for TCR signaling in early CD4 ϩ T-cell activation and controls CD4 ϩ T-cell proliferation and differentiation into Th1 and Th17 cells in vitro. In this study, the authors used T cells from RAR␣ knockout (KO) mice and showed that RAR␣-deficient CD4 ϩ T cells are defective in calcium influx and ERK phosphorylation and displayed insufficient activation.…”

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…22 Previous studies have shown that mice raised on a diet lacking vitamin A (VAD diet) have defects in T H -cell activation and intestinal migration, resulting in an overall impairment in T-cell-driven immune responses in the intestine. [23][24][25] To test whether RA influenced HIC1 expression in intestinal T H cells, we raised Hic1 Citrine mice on a VAD diet. We found that LP T H cells from VAD mice failed to express HIC1 (Figure 4a), suggesting that HIC1 expression in T H cells in the LP is dependent on the presence of RA.…”