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

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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.