In addition, the infiltration of mast cells, effector cells in the development of food allergy, into the colon was also prevented in the FYT720-treated mice [49]. (e.g., ICAM-1 and VCAM-1) on stromal cells and the expression is regulated by NFB-inducing kinase (NIK). Therefore, NIK-mutant aly/aly mice show decreased sensitivity to FTY720 in the regulation of peritoneal B-cell trafficking due to the impaired expression of adhesion molecules although peritoneal B1 cells in aly/aly mice expressed comparable levels of S1P1. 5. Distinct S1P Dependency of Trafficking of Intraepithelial T-Lymphocytes in the Gut Large numbers of lymphocytes are also present in the intestinal epithelium and called as intraepithelial lymphocytes (IELs) [42]. IELs are mostly T cells, but unlike in conventional T cells observed in the systemic compartments (e.g., spleen) which predominantly express the T-cell receptor (TCR), in the IEL subset presently there is an abundance of T cells expressing the T cell receptor (TCR) in addition to TCR+ T cells [42]. TCR recognizes peptide antigen presented via major histocompatibility complex (MHC) molecules, whereas TCR recognizes nonclassical MHC molecules such as MHC class I chain-related proteins (MIC) A and B (MICA/B) in human and Rae-1 in mouse [43]. Unlike p-Coumaric acid MHC molecules that act as ligand by presenting peptide antigen, non-classical MHC molecules act as a ligand by itself and the expression was induced by stress (e.g., infection, tumors, or chemical treatment) [44]. Thus, it is considered that TCR is involved in acquired immunity through the activation by specific presentation of antigenic peptides, whereas TCR is involved in innate immunity by the ligation of non-classical MHC molecules [42]. A distinctive pattern of CD8 expression has also been noted in IELs. Conventional TCR+ T cells express CD8 as a heterodimer of and (CD8). In contrast, some IELs uniquely express CD8 as a homodimer (CD8) [42]. A previous study identified a unique precursor of CD8 IELs in the thymus [45]. In the thymus, CD4? CD8? double-negative thymocytes differentiate into CD4+ CD8+ double-positive thymocytes and then further differentiate into single-positive thymocytes expressing either CD4 or CD8. CD8+ IELs are derived mainly from CD8+ single-positive thymocytes expressing TCR. CD8+ IELs, however, originate from double-negative thymocytes expressing either TCR or TCR that have themselves differentiated from unique CD4+ CD8+ CD8+ triple-positive thymocytes (Figure 3) [45]. S1P has been involved in the regulation of cell trafficking of different subsets of IELs originated from thymus. We found that each type of IEL shows a different dependency on p-Coumaric acid S1P in its Rabbit polyclonal to GNRH trafficking from the thymus to the intestine, especially in the colon (Figure 3) [46]. When mice were treated with FTY720, decreased numbers of CD8+ IELs were observed. In contrast, the numbers of CD8+ IELs were barely p-Coumaric acid affected. These data suggest that, in the colonic epithelium, CD8+ IELs are S1P dependent and CD8+ IELs are S1P independent. Consistent with this finding, CD8+ single-positive thymocytesthe precursors of CD8+ IELsexpress high levels of S1P1 [8], whereas no S1P1 expression has been noted on double-negative p-Coumaric acid thymocytes, the precursors of CD8+ IELs [46]. These findings suggest that S1P1 expression was different in different subsets of thymic precursors of IELs and provide versatile immunological pathways in the intestine. Figure 3 Open in a separate window Distinct dependency on S1P in T-cell trafficking into the colonic epithelium. In the thymus, CD4? CD8? double-negative (DN) thymocytes differentiate into CD4+ CD8+ double-positive (DP) thymocytes and then p-Coumaric acid into single-positive (SP) thymocytes expressing either CD4 or CD8 and TCR. These SP thymocytes express high levels of S1P1 and migrate out from the thymus and into the colon in an S1P-dependent manner. DN thymocytes express TCR or TCR. DN thymocytes expressing TCR are derived from CD4+ CD8+ CD8+ triple-positive (TP) thymocytes differentiated from DN or DP thymocytes. Little or no S1P1 expression is noted in the DN thymocytes expressing TCR or TCR, so traffic to the colonic epithelium proceeds in an S1P-independent manner. 6. S1P-Mediated Regulation in the Development of Intestinal Immune Diseases Accumulating evidence has revealed the pivotal role of S1P in the development of inflammatory diseases such as autoimmune type 1 diabetes, rheumatoid arthritis, and multiple sclerosis [5]. FTY720 prevents the egress of autoreactive lymphocytes from the lymph nodes into the peripheral circulation and subsequent across the bloodCbrain barrier into the central nerve system and thus has recently been approved as an oral therapy for multiple sclerosis [47]. In addition to being involved in these immune diseases at the systemic immune compartments, S1P is involved in the development of intestinal immune diseases including food allergies.