Wiskott–Aldrich Syndrome Protein Deficiency in Innate Immune Cells Leads to Mucosal Immune Dysregulation and Colitis in Mice

Abstract

Background & Aims Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich Syndrome protein (WASP), a hematopoietic-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 to 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 (IL)-10. Administration of IL-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 IL-10, and homeostasis of regulatory T cells.

Wiskott-Aldrich syndrome protein–mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells

“…Our data suggest that IFN- signaling diverts DCs toward a proinflammatory phenotype, which may directly contribute to development of colitis by inhibiting T reg cell proliferation (Murai et al, 2009). Consistent with this, a recent report showed a role for innate immune cells in inducing colitis in WASp null mice (Nguyen et al, 2012). Type-I IFN may also have direct effects in promoting CpG-B (top) or LPS (bottom).…”

Interleukin-10 Receptor Signaling in Innate Immune Cells Regulates Mucosal Immune Tolerance and Anti-Inflammatory Macrophage Function

“…We have recently reported that aberrant interactions between innate immune cells devoid of the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASP) and WT CD4 + T cells lead to colitis development (Nguyen et al, 2012a). In this model, Was −/− Rag2 −/− mice develop severe intestinal inflammation following WT CD4 + T cell transfer, characterized by reduced production of IL-10; colitis development can be prevented by exogenous administration of IL-10Ig.…”

“…Our work is consistent with studies employing LyzM - cre - or Itgax-cre -mediated deletion of IL-10Rα predominantly in macrophages or DCs, respectively, that were associated with elevated LPS-induced pro-inflammatory cytokines and effector T cell responses in the skin (Girard-Madoux et al, 2012; Pils et al, 2010). Moreover, recent studies have demonstrated that peritoneal monocytes lacking IL-10Rα differentiate into a pro-inflammatory MHCII high macrophages subset (Nguyen et al, 2012b). Finally, IL-10-mediated signaling is known to suppress IL-1β secretion (Guarda et al, 2011), and in turn, IL-1β-dependent signals drive effector T cell responses and colitis development (Coccia et al, 2012).…”

β7 integrins are required to give rise to intestinal mononuclear phagocytes with tolerogenic potential

“…Recombination activating gene 2 deficient (RAG −/− ) mice were adoptively transferred with CD4 + CD25 − CD45RB hi naïve T cells alone (colitogenic) or combined with CD4 + CD25 + CD45RB low T REG cells (protected), as described previously15 16 (figure 1B). We observed that both CD103 + DC and ALDE + DC were decreased in the small intestine propria (SI-LP), but not in the spleen, of colitogenic mice when compared to protected animals (figure 1C).…”