Abstract
BackgroundThe 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.Methodology/Principal FindingsWe 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/SignificanceOur 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.
Highlights
The vitamin A metabolite, retinoic acid (RA), plays critical roles in many life processes including immune responses
RA induces Cyp26b1 expression in T cells upon activation As RA is consistently provided by dendritic cells (DCs) and some other cells in the gut-related lymphoid organs [1,21], we examined if RA induced Cyp26b1 expression in T cells
We found that Cyp26b1 is expressed in antigen-experienced T cells from gut-related lymphoid organs, and that RA induced Cyp26b1 expression in naıve T cells upon activation (Fig. 1 & 2)
Summary
The vitamin A metabolite, retinoic acid (RA), plays critical roles in many life processes including immune responses. It has been found that these DCs enhance the transforming growth factor (TGF)- b-dependent differentiation of naıve CD4+ T cells to Foxp3+ inducible regulatory T cells (iTreg) and suppress the TGFb/IL-6-dependent differentiation of proinflammatory Th17 cells [6,7,8,9,10,11]. It remains unclear how RA is catabolized in T cells to prevent excessive RA stimulation. Dendritic cells in gut-related lymphoid organs can produce RA, thereby imprinting gut-homing specificity on T cells and enhancing transforming growth factor (TGF)-b-dependent induction of Foxp3+ regulatory T cells upon antigen presentation. It remained unclear if T cells could actively catabolize RA
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