Regulation of Th2 differentiation by skin-resident dendritic cells

点击翻译按钮获取中文摘要

Project Summary T helper type 2 (Th2) cells play a crucial role in allergies, humoral immunity and host protection against parasitic infections, but our understanding of the mechanism of their differentiation remains incomplete. Upon encountering a cognate antigen presented by dendritic cells (DCs), naive CD4T cells make a fate decision to become one of the effector cell types such as Th1, Th2, and Th17 cells. However, unlike their differentiation into Th1 or Th17 cells, in which IL-12 and IL-23 play a crucial role, respectively, the DC-derived fate instruction signal universally required for Th2 differentiation has not been identified. CD301b (Mgl2) and its human homolog CLEC10A are selectively expressed by a major subset of type 2 conventional DCs in the dermis and other peripheral organs. We previously developed mouse models in which CD301b+ DCs are depleted, enriched or genetically manipulated and demonstrated that CD301b+DCs are both necessary and sufficient for the Th2 cell differentiation upon exposure to a protease allergen papain in the skin as well as after infection with a hookworm Nippostrongylus brasiliensis. Interestingly, the depletion of CD301b+DCs results in a shift of the effector CD4T cell phonotype from Th2 to Th1 and Th17 phenotype, suggesting that CD301b+ DCs regulate the effector cell fate at the clonal level. The molecular mechanism for the Th2 fate instruction by CD301b+DCs still remains unclear, but our data indicate the requirement of cognate interactions between CD301b+DCs and antigen-specific CD4T cells. Thus, we hypothesize that CD301b+ DCs imprint the Th2 fate on CD4T cells mainly through a contact-dependent, rather than soluble, mechanisms. In this application, we aim to address the following two questions by vigorously characterizing the CD4T cell differentiation kinetics in our unique mouse models: (1) What is the CD4T cell-intrinsic, Th2-skewing signal(s) imprinted by CD301b+ DCs?; and (2) How do CD301b+ DCs instruct antigen-specific CD4T cells to become Th2 cells? Answering these questions will deepen our basic understanding of the in vivo mechanism of the initiation of a Th2 response and help us to develop a unified model that comprehensively explains the role of DC subsets in CD4T cell differentiation. Understanding such mechanism would help us to improve our strategies for treating allergic diseases and developing effective vaccines for infectious diseases.