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. The ability to avoid autoimmunity is a cardinal feature of the immune system. In healthy individuals, this is achieved by several mechanisms of 'immunological tolerance,'where the immune system acquires unresponsiveness to self-antigens, whilst retaining reactivity to foreign microbes. Emerging evidence suggests a critical role for dendritic cells (DCs) in maintaining this delicate balance between immunity and tolerance. However, the nature of the intracellular signaling networks and transcription factors that program DCs to induce tolerogenic responses are poorly understood. In this context our work, performed during the previous cycle of this grant, has identified two novel and convergent signaling mechanisms in DCs that induce T regulatory responses: + TLR2 mediated activation of ERL AP kinase, which mediates the production of anti-inflammatory mediators such as IL-10 and the retinoic acid metabolizing enzymes (RALDH2), thus programming the DCs to induce T regulatory cells + TLR-mediated induction of the wnt-b-catenin signaling axis in DCs, which also facilitates induction of IL-10 and RALDH2, again programming a tolerogenic state in DCs. Strikingly, our preliminary study showed the wnt-b-catenin signaling axis and TLR-b-catenin signaling axis are constitutively active in the lamina propria antigen-presenting cells (APCs) and might play an important role in mucosal tolerance.
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