To silence autoimmune disease, we seek a means to expand in mice CD25+ CD4+ foxp3+ regulatory T cells (Treg) that are specific for disease producing autoantigens. We will pursue three themes that have begun through synergisms with Drs. Nussenzweig and Ravetch in this program: 1) The efficiency of antigen presentation in vivo can be greatly increased by targeted delivery of antigen within monoclonal antibodies to uptake receptors on dendritic cell (DCs). 2) A pivotal feature to the outcome of antigen presentation is the state of differentiation or maturation of the DC;this can be enhanced or blocked through selective ligation of activating and inhibitory FcyR respectively. 3) DCs are specialized antigen presenting cells for CD25+ foxp3+ Treg, being able to drive their expansion with maintenance of foxp3 expression and function (5) and to convert CD25- foxp3- T cells into CD25+ foxp3+ T reg (preliminary data). Therefore we will identify DC receptors, subsets and maturation states that are required to control the development and maintenance of antigen-specific T reg in the peripheral tissues of mice.
Aim 1 will determine the DC requirements for the expansion of CD25+ CD4+ foxp3+ antigen-specific Treg in vivo, pursuing initial evidence that the 33D1 receptor on CDS- DCs is an effective pathway.
Aim 2 will determine the DC requirements for the differentiation of CD25+ CD4+ foxp3+ antigen-specific Treg in vivo from CD25- CD4+ foxpS- progenitors, pursuing initial evidence that the DEC-205 receptor on CD8+ DCs is an effective pathway and that TGFp works in concert with antigen presenting DCs to generate typical antigen-specific foxp3+ T reg.
Aim 3 will induce, expand and maintain antigen-specific Tregs from a naive polyclonal T cell repertoire, including capacity of DC-targeting antibodies to ligate activating and inhibitory Feyreceptors. By harnessing the biology of DCs in vivo, particularly by targeting antigens within monoclonal antibodies to uptake receptors expressed on DCs, and by controlling the state of differentiation or maturation of DCs, we will be able to define the priniciples for generating large numbers of disease specific regulatory T cells in intact mice. This should in turn translate into new targeted therapies and products required to control autoimmunity in patients in a much more disease specific manner than has previously been feasible.
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