ABSTRACT
Intraepithelial lymphocytes (IELs) are T cells important for the maintenance of barrier integrity in the intestine. Colon IELs are significantly reduced in both MyD88-deficient mice and those lacking an intact microbiota, suggesting that MyD88-mediated detection of bacterial products is important for the recruitment and/or retention of these cells. Here, using conditionally deficient MyD88 mice, we show that myeloid cells are the key mediators of TCRαß+ IEL recruitment to the colon. Upon exposure to luminal bacteria, myeloid cells produce sphingosine-1-phosphate (S1P) in a MyD88-dependent fashion. TCRαß+ IEL recruitment may be blocked using the S1P receptor antagonist FTY720, confirming the importance of S1P in the recruitment of TCRαß+ IELs to the colon epithelium. Finally, using the TNFΔARE/+ model of Crohn's-like bowel inflammation, we show that disruption of colon IEL recruitment through myeloid-specific MyD88 deficiency results in reduced pathology. Our results illustrate one mechanism for recruitment of a subset of IELs to the colon.
Subject(s)
Colon , Intestinal Mucosa , Intraepithelial Lymphocytes , Lysophospholipids , Mice, Knockout , Myeloid Cells , Myeloid Differentiation Factor 88 , Receptors, Antigen, T-Cell, alpha-beta , Sphingosine , Animals , Lysophospholipids/metabolism , Mice , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Colon/immunology , Myeloid Differentiation Factor 88/metabolism , Myeloid Cells/immunology , Myeloid Cells/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Antigen, T-Cell, alpha-beta/genetics , Mice, Inbred C57BL , Fingolimod Hydrochloride/pharmacology , Crohn Disease/immunologyABSTRACT
Interleukin-10 mediates regulatory functions of commensal-specific TH17 cells in murine small intestine.