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


RESULTS
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.


CONCLUSIONS
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.
Laboratory of Biodefense Research, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki, Japan. takeuchih@kph.bunri-u.ac.jp
Hajime
H
Takeuchi
Aya
A
Yokota
Yoshiharu
Y
Ohoka
Makoto
M
Iwata
D000818:Animals; D002454:Cell Differentiation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D007422:Intestines; D008198:Lymph Nodes; D008213:Lymphocyte Activation; D051379:Mice; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607081:Cyp26b1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase
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