T helper type 2 (Th2) immunity regulates humoral responses and underlies allergic and autoimmune diseasesas well as host protection against parasitic infections. Thus, understanding how development, maintenanceand 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 severaldifferentiation paths to effector cells such as Th1, Th2, and Th17 cells, but how they decide on the path toTh2 differentiation over the other in vivo is incompletely understood. DCs in vivo consist of highlyheterogeneous subsets and provide two important cues for differentiation of CD4T cells – stimulation throughthe T cell receptor and cytokines. We have shown previously that CD301b (Mgl2) is specifically expressed bya majority of CD11b+DCs in the dermis of the skin as well as in other organs, and that depletion ofCD301b+DCs results in a severe and selective defect in developing Th2 cells upon immunization with type 2adjuvants 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 playa role in maintaining Th2 cells in the peripheral organ are unclear. We recently generated Mgl2-Cre mouseand confirmed Cre recombinase activity in CD11b+DCs. By using the Mgl2-Cre mouse and the Mgl2-DTRmouse that we previously made (in which diphtheria toxin receptor expression in CD301b+DCs allows theirspecific ablation by injecting diphtheria toxin), in this proposal, we will examine (1) if direct antigenpresentation and cytokine production by CD301b+DCs are required for priming Th2 differentiation, (2) ifCD301b+DCs are sufficient for inducing Th2 cells, and (3) if and how CD301b+DCs are required for themaintenance of effector and memory Th2 cells in the skin. These approaches will not only deepen our basicunderstanding of the in vivo mechanism of Th2 regulation, but also help us to improve our strategies fortreating allergic diseases or developing effective vaccines.
|Effective start/end date||8/1/17 → 7/31/22|
- National Institutes of Health (NIH)