title: The myeloid differentiation factor 88 (MyD88) is required for CD4+ T cell effector function in a murine model of inflammatory bowel disease.
abstract: Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease. MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4(+)CD45Rb(high) T cells and/or CD4(+)CD45Rb(low)CD25(+) regulatory T cells were isolated and adoptively transferred to RAG1(-/-) mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [(3)H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4(+)CD45Rb(high) T cells expressed TLR2, TLR4, TLR9, and TLR3, and TLR ligands could act as costimulatory molecules. MyD88(-/-) CD4(+) T cells showed decreased proliferation compared with WT CD4(+) T cells both in vivo and in vitro. CD4(+)CD45Rb(high) T cells from MyD88(-/-) mice did not induce wasting disease when transferred into RAG1(-/-) recipients. Lamina propria CD4(+) T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88(-/-) cells than mice receiving WT cells. In vitro, MyD88(-/-) T cells were blunted in their ability to secrete IL-17 but not IFN-gamma. Absence of MyD88 in CD4(+)CD45Rb(high) cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of inflammatory bowel disease.
authors.affiliation: Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukata
authors.forename: Keith
authors.initials: K
authors.lastname: Breglio
authors.forename: Anli
authors.initials: A
authors.lastname: Chen
authors.forename: Arunan S
authors.initials: AS
authors.lastname: Vamadevan
authors.forename: Tyralee
authors.initials: T
authors.lastname: Goo
authors.forename: David
authors.initials: D
authors.lastname: Hsu
authors.forename: Daisy
authors.initials: D
authors.lastname: Conduah
authors.forename: Ruliang
authors.initials: R
authors.lastname: Xu
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018398:Homeodomain Proteins / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D018398:Homeodomain Proteins; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D053594:Myeloid Differentiation Factor 88; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; C064658:RAG-1 protein; D017493:Leukocyte Common Antigens