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BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid.

ABSTRACT: CCR9 and ?4?7 are the major trafficking receptors for lymphocyte migration to the gut, and their expression is induced during lymphocyte activation under the influence of retinoic acid (RA). We report here that BATF (basic leucine zipper transcription factor, ATF-like), an AP-1 protein family factor, is required for optimal expression of CCR9 and ?4?7 by T helper cells. BATF-deficient (knockout [KO]) mice had reduced numbers of effector T and regulatory T cells in the intestine. The intestinal T cells in BATF KO mice expressed CCR9 and ?4?7 at abnormally low levels compared with their wild-type (WT) counterparts, and BATF KO CD4(+) T cells failed to up-regulate the expression of CCR9 and ?4?7 to WT levels in response to RA. Defective binding of RAR? and histone acetylation at the regulatory regions of the CCR9 and Itg-?4 genes were observed in BATF KO T cells. As a result, BATF KO effector and FoxP3(+) T cells failed to populate the intestine, and neither population functioned normally in the induction and regulation of colitis. Our results establish BATF as a cellular factor required for normal expression of CCR9 and ?4?7 and for the homeostasis and effector functions of T cell populations in the intestine.

SUBMITTER: Wang C

PROVIDER: S-EPMC3600908 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid.

Wang Chuanwu C Thangamani Shankar S Kim Myunghoo M Gu Bon-Hee BH Lee Jee H JH Taparowsky Elizabeth J EJ Kim Chang H CH

The Journal of experimental medicine 20130304 3

CCR9 and α4β7 are the major trafficking receptors for lymphocyte migration to the gut, and their expression is induced during lymphocyte activation under the influence of retinoic acid (RA). We report here that BATF (basic leucine zipper transcription factor, ATF-like), an AP-1 protein family factor, is required for optimal expression of CCR9 and α4β7 by T helper cells. BATF-deficient (knockout [KO]) mice had reduced numbers of effector T and regulatory T cells in the intestine. The intestinal T ...[more]

PMID: 23460729

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Project description:All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RAR?, ? and ?) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (; 9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RAR?/? but is well-suited to the larger RAR? binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RAR?, as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described herein can be further applied to the understanding of the molecular basis for the selectivity of different retinoids to RAR?, ? and ?.

Dataset Information

BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid.

Publications

BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid.

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