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

Gastroenterology. 2012 Sep;143(3):719-729.e2. doi: 10.1053/j.gastro.2012.06.008. Epub 2012 Jun 15.

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 cell-mediated colitis in mice with WASP-deficient cells of the innate immune system.

Methods: Naïve and/or regulatory CD4(+) T cells were transferred from 129 SvEv mice into RAG-2-deficient (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. Naïve 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD / metabolism
  • CD11b Antigen / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / transplantation
  • Cell Proliferation
  • Cells, Cultured
  • Colitis / genetics
  • Colitis / immunology*
  • Colitis / metabolism
  • Colitis / pathology
  • Colon / immunology*
  • Colon / metabolism
  • Colon / pathology
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Forkhead Transcription Factors / metabolism
  • Immune Tolerance
  • Immunity, Innate*
  • Immunity, Mucosal*
  • Integrin alpha Chains / metabolism
  • Interleukin-10 / metabolism
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Lymphocyte Activation
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • T-Lymphocytes, Regulatory / immunology
  • Time Factors
  • Transplantation Chimera
  • Wiskott-Aldrich Syndrome Protein / deficiency*
  • Wiskott-Aldrich Syndrome Protein / genetics

Substances

  • Antigens, CD
  • CD11b Antigen
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IL10 protein, mouse
  • Integrin alpha Chains
  • Rag2 protein, mouse
  • Was protein, mouse
  • Wiskott-Aldrich Syndrome Protein
  • alpha E integrins
  • Interleukin-10