Elisa K. Boden

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

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.

Sa1755 Peripheral Blood E. coli Outer Membrane Protein C (OmpC)-Specific T-Cells Display a Distinct Immunophenotype

Interleukin-6 Drives Production of Pathogenic Cytokines by Innate Lymphoid Cells in Patients and Mice With Chronic Intestinal Inflammation Nick Powell, Jonathan W. Lo, Paolo Biancheri, Anna Vossenkamper, Eirini D. Pantazi, Emilie Stolarczyk, Alan Walker, Paul Scott, James B. Canavan, Esperanza Perucha, Natividad Garrido-Mesa, Ian Jackson, Francesca Ammoscato, Peter M. Irving, Jeremy D. Sanderson, Bu Hayee, Julian Parkhill, MacDonald Thomas, Graham M. Lord

Tu1968 Increased Sensitivity to TGF Results in Defects in T Cell Proliferation and Regulatory T Cell Induction in the Absence of Wiskott-Aldrich Syndrome Protein (WASp)

with reduced TNF release after TLR2 activation. Conclusions: In conclusion, we have developed a successful strategy to identify abnormal expression of genes in individual CD patients relevant to diminished macrophage function. In a wider context, this approach may be equally applicable in delineating the molecular pathogenesis of other complex disorders. 1. A. Franke et al., Nat. Genet. 42, 1118 (2010) 2. A. M. Smith et al., J. Exp. Med. 206, 1883 (2009)

703 Aberrant Antigen Presenting Cells Activate Effector T Cells and Inhibit Regulatory T Cell Function

3 d). TNBS caused an increase c-fos positive neurons (37.2±5.1 vs 16.8±1.5; p<0.05) and visceral hyperalgesia (mV*sec 0.3±0.07 vs 0.14±0.02; p<0.05) in TRPA1+/+ mice, but not in TRPA1-/mice (c-fos 17.5±2.5 vs 16.7±1.3; hyperalgesia mV*sec 0.13±0.03). Thus, TRPA1 deletion ameliorates pain in an IBD-model, suggesting TRPA1 has a major role in visceral hyperalgesia and might provide a novel therapeutic target. Supported by NIH DK043207, CCFA1730.