Cyp26b1 regulates retinoic acid-dependent signals in T cells and its expression is inhibited by transforming growth factor-β

• Published in: PloS one Vol. 6; no. 1; p. e16089
• Main Authors: Takeuchi, Hajime, Yokota, Aya, Ohoka, Yoshiharu, Iwata, Makoto
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.01.2011; Public Library of Science (PLoS)
• Subjects: Aberration; Acids; Animals; Antigen presentation; Biology; CCR9 protein; CD44 antigen; Cell activation; Cell Differentiation; Cell migration; Chemokines; Crohns disease; Cytochrome; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - physiology; Cytochrome P450; Dendritic cells; Differentiation; Drainage; Enzymatic activity; Enzymes; Foxp3 protein; Gastroenterology; Gene Expression; Genomic imprinting; Growth factors; Homing; Immunoglobulins; Immunology; Immunoregulation; Imprinting; Intestines; Laboratories; Lymph Nodes; Lymphatic system; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Lymphoid tissue; Medicine; Metabolism; Metabolites; Mice; Morphogenesis; Organs; Pathogenesis; Pharmaceutical sciences; Retinoic acid; Retinoic Acid 4-Hydroxylase; Ribonucleic acid; RNA; Rodents; Signal transduction; Signal Transduction - drug effects; siRNA; Skin; Spleen; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes, Regulatory; Tissues; Transforming Growth Factor beta - physiology; Transforming growth factor-b; Tretinoin - pharmacology; Vitamin A; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0016089

The vitamin A metabolite, retinoic acid (RA), plays important roles in the regulation of lymphocyte properties. Dendritic cells in gut-related lymphoid organs can produce RA, thereby imprinting gut-homing specificity on T cells and enhancing transforming growth factor (TGF)-β-dependent induction of Foxp3+ regulatory T cells upon antigen presentation. In general, RA concentrations in cells and tissues are regulated by its degradation as well. However, it remained unclear if T cells could actively catabolize RA. We assessed the expression of known RA-catabolizing enzymes in T cells from mouse lymphoid tissues. Antigen-experienced CD44+ T cells in gut-related lymphoid organs selectively expressed Cyp26b1, a member of the cytochrome P450 family 26. However, T cells in the spleen or skin-draining lymph nodes did not significantly express Cyp26b1. Accordingly, physiological levels of RA (1-10 nM) could induce Cyp26b1 expression in naïve T cells upon activation in vitro, but could not do so in the presence of TGF-β. Overexpression of Cyp26b1 significantly suppressed the RA effect to induce expression of the gut-homing receptor CCR9 on T cells. On the other hand, knocking down Cyp26b1 gene expression with small interfering RNA or inhibiting CYP26 enzymatic activity led to enhancement of the RA-induced CCR9 expression. Our data demonstrate a role for CYP26B1 in regulating RA-dependent signals in activated T cells but not during TGF-β-dependent differentiation to Foxp3+ regulatory T cells. Aberrant expression of CYP26B1 may disturb T cell trafficking and differentiation in the gut and its related lymphoid organs.