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The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4⁺ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease¹

Masayuki Fukata^*, Keith Breglio^*, Anli Chen^*, Arunan S. Vamadevan^*, Tyralee Goo^*, David Hsu^*, Daisy Conduah^*, Ruliang Xu and Maria T. Abreu^2,*

^* Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, and Department of Pathology, Mount Sinai School of Medicine, New York, NY 10029

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^lowCD25⁺ 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 [³H]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-. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI052266 (to M.T.A.) and DK069594 (to M.T.A.), and a Uehara Memorial Foundation Research Fellowship (to M.F.).

² Address correspondence and reprint requests to Dr. Maria T. Abreu, Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1069, New York, NY 10029. E-mail address: maria.abreu{at}mssm.edu

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; PAMP, pathogen-associated molecular pattern; Treg, regulatory T cell; DC, dendritic cell; LP, lamina propria; MLN, mesenteric lymph node.

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