Regulation of Th2 differentiation by skin-resident dendritic cells

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Project Summary T helper type 2 (Th2) immunity regulates humoral responses and underlies allergic and autoimmune diseases as well as host protection against parasitic infections. Thus, understanding how development, maintenance and function of Th2 cells are regulated would benefit our therapeutic approaches against these diseases. Upon encounter with a cognate antigen presented by dendritic cells (DCs), naive CD4T cells take several differentiation paths to effector cells such as Th1, Th2, and Th17 cells, but how they decide on the path to Th2 differentiation over the other in vivo is incompletely understood. DCs in vivo consist of highly heterogeneous subsets and provide two important cues for differentiation of CD4T cells – stimulation through the T cell receptor and cytokines. We have shown previously that CD301b (Mgl2) is specifically expressed by a majority of CD11b+DCs in the dermis of the skin as well as in other organs, and that depletion of CD301b+DCs results in a severe and selective defect in developing Th2 cells upon immunization with type 2 adjuvants such as papain or alum, or after the infection with a hookworm Nippostrongylus brasiliensis. However, how CD301b+DCs are required and/or sufficient for inducing Th2 differentiation and if they also play a role in maintaining Th2 cells in the peripheral organ are unclear. We recently generated Mgl2-Cre mouse and confirmed Cre recombinase activity in CD11b+DCs. By using the Mgl2-Cre mouse and the Mgl2-DTR mouse that we previously made (in which diphtheria toxin receptor expression in CD301b+DCs allows their specific ablation by injecting diphtheria toxin), in this proposal, we will examine (1) if direct antigen presentation and cytokine production by CD301b+DCs are required for priming Th2 differentiation, (2) if CD301b+DCs are sufficient for inducing Th2 cells, and (3) if and how CD301b+DCs are required for the maintenance of effector and memory Th2 cells in the skin. These approaches will not only deepen our basic understanding of the in vivo mechanism of Th2 regulation, but also help us to improve our strategies for treating allergic diseases or developing effective vaccines.