In this study, we report a novel biological function of vitamin A metabolites in conversion of naive FoxP3⁻ CD4⁺ T cells into a unique FoxP3⁺ regulatory T cell subset (termed “retinoid-induced FoxP3⁺ T cells”) in both human and mouse T cells. We found that the major vitamin A metabolite all-trans-retinoic acid induces histone acetylation at the FoxP3 gene promoter and expression of the FoxP3 protein in CD4⁺ T cells. The induction of retinoid-induced FoxP3⁺ T cells is mediated by the nuclear retinoic acid receptor α and involves T cell activation driven by mucosal dendritic cells and costimulation through CD28. Retinoic acid can promote TGF-β1-dependent generation of FoxP3⁺ regulatory T cells but decrease the TGF-β1- and IL-6-dependent generation of inflammatory Th17 cells in mouse T cells. Retinoid-induced FoxP3⁺ T cells can efficiently suppress target cells and, thus, have a regulatory function typical for FoxP3⁺ T cells. A unique cellular feature of these regulatory T cells is their high expression of gut-homing receptors that are important for migration to the mucosal tissues particularly the small intestine. Taken together, these results identify retinoids as positive regulatory factors for generation of gut-homing FoxP3⁺ T cells.

Migration and trafficking receptors of Th17 cells to mucosal tissues have been unclear. We report that Th17 cells preferentially migrate to the intestine and associated lymphoid tissues, and CCR6 is the homing receptor important for Th17 cell migration to certain tissue microenvironments of the intestine such as Peyer's patches and other sites where its ligand CCL20 is expressed. We found the cytokine transforming growth factor-β1 is required for CCR6 expression whereas IL-2 suppresses it. CCR6-deficient Th17 cells aberrantly migrate to different compartments of the intestine. Surprisingly, administration of CCR6-deficient Th17 cells into severe combined immunodeficiency (SCID) mice led to excessive intestinal inflammation with increased Th1 but decreased Th17 cells and FoxP3⁺ T cells. In addition, CCR6 deficiency led to aberrantly widespread effector T cells in the inflamed intestine of the SCID mice. We conclude that CCR6 regulates Th17 cell migration to the gut and effector T-cell balance/distribution in inflamed intestine.

Batf belongs to the activator protein 1 superfamily of basic leucine zipper transcription factors that includes Fos, Jun, and Atf proteins. Batf is expressed in mouse T and B lymphocytes, although the importance of Batf to the function of these lineages has not been fully investigated. We generated mice (Batf^ΔZ/ΔZ) in which Batf protein is not produced. Batf^ΔZ/ΔZ mice contain normal numbers of B cells but show reduced numbers of peripheral CD4⁺ T cells. Analysis of CD4⁺ T helper (Th) cell subsets in Batf^ΔZ/ΔZ mice demonstrated that Batf is required for the development of functional Th type 17 (Th17), Th2, and follicular Th (Tfh) cells. In response to antigen immunization, germinal centers were absent in Batf^ΔZ/ΔZ mice and the maturation of Ig-secreting B cells was impaired. Although adoptive transfer experiments confirmed that this B cell phenotype can be driven by defects in the Batf^ΔZ/ΔZ CD4⁺ T cell compartment, stimulation of Batf^ΔZ/ΔZ B cells in vitro, or by a T cell–independent antigen in vivo, resulted in proliferation but not class-switch recombination. We conclude that loss of Batf disrupts multiple components of the lymphocyte communication network that are required for a robust immune response.

Follicular helper T cells (T_FH cells) provide critical help to B cells during humoral immune responses. Here we report that mice with T cell–specific deletion of the miR-17 ∼ 92 family of microRNAs (miRNAs) had substantially compromised T_FH differentiation, germinal-center formation and antibody responses and failed to control chronic viral infection. Conversely, mice with T cell–specific expression of a transgene encoding miR-17 ∼ 92 spontaneously accumulated T_FH cells and developed a fatal immunopathology. Mechanistically, the miR-17 ∼ 92 family controlled the migration of CD4⁺ T cells into B cell follicles by regulating signaling intensity from the inducible costimulator ICOS and kinase PI(3)K by suppressing expression of the phosphatase PHLPP2. Our findings demonstrate an essential role for the miR-17 ∼ 92 family in T_FH differentiation and establish PHLPP2 as an important mediator of their function in this process.