Abstract
SAMP1/YP mice develop a spontaneous chronic inflammation specifically in the ileum. Using these mice, we investigated the gut chemokine network involved in specific migration of T-cell subsets to the inflamed lesion of the intestine. The expression of homeostatic chemokine axis (CCL25-CCR9) is largely unchanged; however, an additional chemokine axis (CCL5-CCR5) is up-regulated in the inflamed intestine of SAMP1/YP mice compared to control mice. CCR5+ T cells preferentially migrate to the inflamed lesion. Interestingly, many more FoxP3+, than FoxP3−, T cells of the inflamed lesion of SAMP1/YP mice expresses CCR5. CCR5 blockade suppresses the migration of FoxP3+ T cells into inflamed intestine and significantly exacerbates the intestinal inflammation. The inflammation-related CCL5-CCR5 chemokine network is involved in recruitment of FoxP3+ T cells and is, actually, beneficial. CCR9 is important chemokine receptor in FoxP3+ T-cell migration into small intestine. Recently, it has been reported that all-trans retinoic acid stimulates T cells to express gut homing receptors, CCR9 and a4b7. We found that all-trans retinoic acid not only regulates gut homing receptor expression on FoxP3+ T cells, but also induces FoxP3+ T cells from naïve CD4+ T cells in the presence of TGF-b. Retinoid-induced FoxP3+ T cells can efficiently suppress target cells and, have a regulatory function typical for FoxP3+ T cells. Therefore, we hypothesized that increased vitamin A intake (Hi-A) would alleviate tissue inflammation by increasing the numbers of FoxP3+ T cells in the intestine, while limited vitamin A intake (low-A) would exacerbate the inflammation by decreasing the numbers of the CCR9+ a4b7+ subset of FoxP3+ T cells. Hi-A ameliorates the intestinal inflammation as expected. Strikingly, we found also that limiting vitamin A intake induces specialized regulatory FoxP3+ T cells that are even more efficient than control FoxP3+ T cells in suppressing intestinal inflammation. The FoxP3+ T cells induced in limited vitamin A availability have distinct homing capacity and phenotype compared to the FoxP3+ T cells induced in the presence of retinoic acid. These results provide new insight into the roles of the vitamin A-dependent and independent pathways in regulation of immune responses and inflammation in the intestine.