Efficient Induction of CCR9 on T Cells Requires Coactivation of Retinoic Acid Receptors and Retinoid X Receptors (RXRs): Exaggerated T Cell Homing to the Intestine by RXR Activation with Organotins

Self Cite

Retinoic acid (RA) imprints gut-homing specificity on T cells upon activation by inducing the expression of chemokine receptor CCR9 and integrin α4β7. CCR9 expression seemed to be more highly dependent on RA than was the α4β7 expression, but its molecular mechanism remained unclear. In this article, we show that NFAT isoforms NFATc1 and NFATc2 directly interact with RA receptor (RAR) and retinoid X receptor (RXR) but play differential roles in RA-induced CCR9 expression on murine naive CD4+ T cells. TCR stimulation for 6–24 h was required for the acquisition of responsiveness to RA and induced activation of NFATc1 and NFATc2. However, RA failed to induce CCR9 expression as long as TCR stimulation continued. After terminating TCR stimulation or adding cyclosporin A to the culture, Ccr9 gene transcription was induced, accompanied by inactivation of NFATc1 and sustained activation of NFATc2. Reporter and DNA-affinity precipitation assays demonstrated that the binding of NFATc2 to two NFAT-binding sites and that of the RAR/RXR complex to an RA response element half-site in the 5′-flanking region of the mouse Ccr9 gene were critical for RA-induced promoter activity. NFATc2 directly bound to RARα and RXRα, and it enhanced the binding of RARα to the RA response element half-site. NFATc1 also bound to the NFAT-binding sites and directly to RARα and RXRα, but it inhibited the NFATc2-dependent promoter activity. These results suggest that the cooperativity between NFATc2 and the RAR/RXR complex is essential for CCR9 expression on T cells and that NFATc1 interferes with the action of NFATc2.

Section: Discussionmentioning

confidence: 90%

Retinoic Acid-Induced CCR9 Expression Requires Transient TCR Stimulation and Cooperativity between NFATc2 and the Retinoic Acid Receptor/Retinoid X Receptor Complex

Ohoka

Yokota

Takeuchi

et al. 2011

Self Cite

“…We showed previously that TBT and the RXR agonist PA024 enhance the RAR-dependent expression of CCR9 on naive CD4 + T cells and CD62L + naive-like nTregs, as well as their homing capacity to the small intestine upon activation (37). In the current study, we examined whether RXR agonists could also enhance the RAR-dependent modulation of Foxp3 + iTreg and Th17 differentiation.…”

Section: Ra Enhances Foxp3mentioning

confidence: 84%

“…high T cells were purified from splenocytes and lymph nodes (inguinal, axillary, brachial, and mesenteric), as previously described (1,37). Naive CD4 +…”

Section: Cd62lmentioning

confidence: 99%

“…The mice were sacrificed on day 3, and the transferred cells were recovered from lymphoid organs and the small intestinal lamina propria. The recovery from the small intestinal lamina propria was performed as previously described (37). The recovered cells were stained with allophycocyanin-conjugated anti-CD4 mAb (GK1.5; BioLegend) and PE-conjugated anti-clonotypic mAb (KJ1-26; BD Biosciences) specific for DO11.10 TCR and were analyzed with a FACSCalibur flow cytometer.…”

Section: In Vivo Induction Of Foxp3mentioning

confidence: 99%

See 1 more Smart Citation

Retinoid X Receptor Agonists Modulate Foxp3+ Regulatory T Cell and Th17 Cell Differentiation with Differential Dependence on Retinoic Acid Receptor Activation

Takeuchi

Yokota-Nakatsuma

Ohoka

et al. 2013

Self Cite

Retinoic acid (RA) enhances TGF-β–dependent differentiation of Foxp3+ inducible regulatory T cells (iTregs) and inhibits Th17 differentiation by binding to the RA receptor (RAR)/retinoid X receptor (RXR) heterodimer. The major physiologic RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. It remained unclear whether RXR-mediated stimulation affected the iTregs and Th17 differentiation. We found in this study that the RXR agonists, PA024 and tributyltin, augmented the ability of all-trans-RA or the RAR agonist Am80 to enhance CD4+CD25− T cells to acquire Foxp3 expression and suppressive function. However, they failed to enhance Foxp3 expression in the presence of the RAR antagonist LE540, suggesting that the effect depends on RAR-mediated signals. They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-γ that inhibited Foxp3 expression. Agonists of peroxisome proliferator-activated receptors and liver X receptors (LXRs), permissive partners of RXR, failed to enhance Foxp3 expression. In contrast, RXR agonists and LXR agonists suppressed IL-17 expression. The RXR-mediated suppression was not canceled by blocking RAR stimulation but was likely to involve permissive activation of LXRs. All-trans-RA and an agonist of RXR or LXR additively suppressed IL-17 expression when the all-trans-RA concentration was low. RXR agonists also suppressed Ccr6 expression that is essential for Th17 cells to enter the CNS. Accordingly, tributyltin treatment of mice ameliorated experimental autoimmune encephalomyelitis through regulating Th17 cell activities. These results suggest that RXR stimulation modulates Foxp3+ iTreg and Th17 differentiation with differential dependence on RAR-mediated stimulation.

“…This function is supported by the intestinal RA-producing CD103 + DCs through RARa and RARb but not RARg, whereas the activation of RXR enhances the effect but appears to be dispensable (34,51). In fact, the RA/RARa pathway directly controls the expression of the integrin subunit a4 (52).…”

Section: Ra In Innate Immunity Including Its Influence On Apcsmentioning

confidence: 99%

Modulation of T Cell and Innate Immune Responses by Retinoic Acid

Raverdeau

Mills

2014

186

161

Retinoic acid (RA) is produced by a number of cell types, including macrophages and dendritic cells, which express retinal dehydrogenases that convert vitamin A to its main biologically active metabolite, all-trans RA. All-trans RA binds to its nuclear retinoic acid receptors that are expressed in lymphoid cells and act as transcription factors to regulate cell homing and differentiation. RA production by CD103+ dendritic cells and alveolar macrophages functions with TGF-β to promote conversion of naive T cells into Foxp3+ regulatory T cells and, thereby, maintain mucosal tolerance. Furthermore, RA inhibits the differentiation of naive T cells into Th17 cells. However, Th1 and Th17 responses are constrained during vitamin A deficiency and in nuclear RA receptor α–defective mice. Furthermore, RA promotes effector T cell responses during infection or autoimmune diseases. Thus, RA plays a role in immune homeostasis in the steady-state but activates pathogenic T cells in conditions of inflammation.