Abstract
BACKGROUND & AIMS: Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich syndrome protein (WASP), a hematopoietic cell-specific intracellular signaling molecule that regulates the actin cytoskeleton. Development of colitis in WASP-deficient mice requires lymphocytes; transfer of T cells is sufficient to induce colitis in immunodeficient mice. We investigated the interactions between innate and adaptive immune cells in mucosal regulation during development of T cellmediated colitis in mice with WASP-deficient cells of the innate immune system. METHODS: Naidie;ve and/or regulatory CD4+ T cells were transferred from 129 SvEv mice into RAG-2deficient (RAG-2 KO) mice or mice lacking WASP and RAG-2 (WRDKO). Animals were observed for the development of colitis; effector and regulatory functions of innate immune and T cells were analyzed with in vivo and in vitro assays. RESULTS: Transfer of unfractionated CD4+ T cells induced severe colitis in WRDKO, but not RAG-2 KO, mice. Nave wild-type T cells had higher levels of effector activity and regulatory T cells had reduced suppressive function when transferred into WRDKO mice compared with RAG-2 KO mice. Regulatory T-cell proliferation, generation, and maintenance of FoxP3 expression were reduced in WRDKO recipients and associated with reduced numbers of CD103+ tolerogenic dendritic cells and levels of interleukin-10. Administration of interleukin-10 prevented induction of colitis following transfer of T cells into WRDKO mice. CONCLUSIONS: Defective interactions between WASP-deficient innate immune cells and normal T cells disrupt mucosal regulation, potentially by altering the functions of tolerogenic dendritic cells, production of interleukin-10, and homeostasis of regulatory T cells.
Original language | English (US) |
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Pages (from-to) | 719-729.e2 |
Journal | Gastroenterology |
Volume | 143 |
Issue number | 3 |
DOIs | |
State | Published - Sep 2012 |
Externally published | Yes |
Keywords
- Antigen-Presenting Cells
- Immunodeficiency
- Inflammatory Bowel Disease
- Mouse Model
ASJC Scopus subject areas
- Hepatology
- Gastroenterology