The role of SWAP-70 in Dendritic Cell Activation, Antigen Presentation and Migration

树突状细胞（dc）是诱导适应性免疫反应的核心。幼稚dc通过包括toll样受体在内的各种信号被激活成熟。通常，dc内吞抗原，从外周迁移到淋巴结和其他部位，并将加工后的抗原在MHCII受体上呈递给T淋巴细胞。DC的活化、内吞作用和迁移已经得到了深入的研究，但尚未得到充分的了解。我们最近报道了在DC中表达的SWAP-70在DC激活和MHCII在DC表面的定位中起重要作用。我们发现SWAP-70不仅与Rac相互作用，还与RhoA相互作用，RhoA在没有SWAP-70的情况下出人意料地具有组成活性。Swap- 70-/- dc向淋巴器官的迁移也受到损害。因此，很明显SWAP-70在DC生物学中起着关键作用。需要研究这些功能。本提案的具体目的是：(1)了解SWAP-70与Rac， Rho和Cdc42之间的分子关系；(2)确定SWAP-70调控dc中Rac、Rho和Cdc42的生物学功能；(3)破译SWAP-70在特定膜结构域的形成和功能中的作用。要研究的潜在生物学过程包括DC内吞作用、形态发生、迁移和粘附。所提出的实验应产生的关键信息，新被描述的途径，调节DC功能。

Dendritic cells (DCs) are central to induction of the adaptive immune response. Naive DCs are activated to mature through various signals including those from Toll-like receptors. Typically, DCs endocytose antigen, migrate from the periphery to lymph nodes and other sites and present the processed antigen on their MHCII receptor to T lymphocytes. DC activation, endocytosis, and migration are intensely researched but not sufficiently understood. We recently documented SWAP-70, which is expressed in DCs, plays an important role in DC activation and the localization of the MHCII on their surface. We showed SWAP-70 interacts not only with Rac, but also with RhoA, which unexpectedly is constitutive active in absence of SWAP-70. Swap- 70-/- DCs are also impaired in migration to lymphoid organs. Thus, it became clear that SWAP-70 contributes key functions to DC biology. These functions need to be investigated. The specific aims of this proposal are: (1) to understand the molecular relationship between SWAP-70 and Rac, Rho, and Cdc42; (2) to determine the biological functions of SWAP-70 control of Rac, Rho and Cdc42 in DCs; and (3) to decipher the role of SWAP-70 in formation and function of specific membrane domains. The underlying biological processes to be studied include DC endocytosis, morphogenesis, migration, and adhesion. The proposed experiments should yield key information on newly to be described pathways that regulate DC functions.