Wiskott-aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice

Deanna D. Nguyen, Marc Andre Wurbel, Jeremy A. Goettel, Michelle A. Eston, Osub S. Ahmed, Romela Marin, Elisa K. Boden, Eduardo J. Villablanca, Helena Paidassi, Vineet Ahuja, Hans Christian Reinecker, Edda Fiebiger, Adam Lacyhulbert, Bruce H. Horwitz, J. Rodrigo Mora, Scott B. Snapper

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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 languageEnglish (US)
Pages (from-to)719-729.e2
JournalGastroenterology
Volume143
Issue number3
DOIs
StatePublished - Sep 2012

Keywords

  • Antigen-Presenting Cells
  • Immunodeficiency
  • Inflammatory Bowel Disease
  • Mouse Model

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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