THE ROLE OF MUCOSAL ANTIGEN-PRESENTING CELLS IN REGULATING IMMUNE RESPONSES

Emory University, Atlanta GA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A major focus in the past year has been on defining a signaling pathway within intestinal DCs, which program them to stimulate T regulatory cells. Our data demonstrates that Wnt-beta-catenin signaling in intestinal DCs regulates balance between inflammatory vs regulatory responses in the gut. Beta-catenin in intestinal DCs was required for expression of anti-inflammatory mediators such as retinoic acid-metabolizing enzymes, interleukin-10, transforming growth factor-beta and stimulation of regulatory T-cell induction while suppressing inflammatory effector T-cells. Furthermore, ablation of beta-catenin expression in DCs enhanced inflammatory responses and diseases in a mouse model of inflammatory bowel disease. Thus beta-catenin signaling programs DCs to a tolerogenic state, limiting inflammatory response. These data highlight an unappreciated role for beta-catenin in antigen-presenting cell in regulating Th17-T regulatory balance. A second major focus of our research has been to understand mechanisms by which innate response stimulates Th2 responses. We have demonstrated that cysteine protease-induced T(H)2 responses occur via 'cooperation'between migratory dermal DCs and basophils positive for IL-4. Subcutaneous immunization with papain plus antigen induced ROS in LN DCs and in dermal DCs and epithelial cells of skin. ROS orchestrated T(H)2 responses by inducing oxidized lipids that triggered the induction of TSLP by epithelial cells mediated by TLR4 and the adaptor protein TRIF;by suppressing production of the T(H)1-inducing molecules IL-12 and CD70 in LN DCs;and by inducing the DC-derived chemokine CC7, which mediated recruitment of IL-4(+) basophils to the lymph node. The T(H)2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.