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

CCR9 and alpha 4 beta 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 alpha 4 beta 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 alpha 4 beta 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 alpha 4 beta 7 to WT levels in response to RA. Defective binding of RAR alpha and histone acetylation at the regulatory regions of the CCR9 and Itg-alpha 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 alpha 4 beta 7 and for the homeostasis and effector functions of T cell populations in the intestine.