Maturation of dendritic cells determines whether an antigenwill elicit a tolerogenic or immunogenicresponse. Endogenous pathways are required to maintain peripheral tolerance to self-antigens by deleting,anergizing or expanding T regulatory cells. Work during the past funding period of this program projectrevealed that IgG immune complexes can promotestrongly immunogenic responses if the normalinhibitoryconstraint is overcome. We will test the hypothesisthat IgG immune complexes, in the steadystate,maintain tolerance through distinct DC subsets by preferentially eliciting inhibitory receptor signaling. Thisendogenous pathwayhas been shown to be perturbed in autoimmune susceptible mouse strains and humanpopulation. This hypothesiswill be tested by 1) Determining the contribution of the inhibitory FcRexpressed on DCsubsets to the autoimmune phenotype; 2) Blocking activation or inhibitory FcRsignaling on DCs in novel FcR humanized mouse models to determine their contribution to developor maintenance of autoimmunity and 3) Dissecting the FcR signaling pathway on DCs that eitherpromotes immunity or tolerance and its potential synergy with TLR signaling pathways. Thesestudies will depend on the reagents and observations developed in the two other projects in this programproject. The results of the studies in this projectwill, in turn, impact on the experimental approachesof theother projects. This synergy will allow us to developapproachesto restore tolerance in autoimmunitythrough the targeting and manipulationof maturationpathways in vivo.
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