: Chemokines and their receptors have emerged as important mediators of hematopoietic cell development, homeostasis, and function. However, relatively little is understood about how these molecules influence B cell development and immune response. The long-term goal of this application is to molecularly define how chemokines and their receptors participate in the selection of B cells and their response to foreign antigens as mature lymphocytes. This objective has been partially motivated by our preliminary analyses of a mouse line engineered to be deficient for a signaling molecule that regulates heptahelical receptor signaling within B lineage cells. Using these mutants in combination with wild-type, novel, and established mouse models of B cell development and function we test our central hypothesis that chemokine receptor signaling is regulated in vivo for selecting newly-generated B cells and orchestrating appropriate B cell movements during an immune response. We address this hypothesis in three specific aims the first of which examines whether chemokine receptor responsiveness is regulated during B cell development as a mechanism that aids in the selection of immature B cells.
Specific Aim 2 will investigate how distinct chemokines guide mature B cells upon antigen activation during the early phase of an immune response. Successful execution of the above two Aims will illustrate how regulating chemokine responses may influence B cell biology although will provide limited insight into the molecular details of how chemokine receptor signaling is regulated within the cell. Ultimately, chemokine responses involve receptor signaling and subsequent reorganization of the actin cytoskeleton as cells migrate through a chemoattractant gradient.
Specific Aim 3 investigates the molecular nature of how chemokine receptor signaling is regulated within B cells and the basis of its coupling to the actin cytoskeleton. By accomplishing the goals of this proposal, these studies will not only further our understanding of how chemokines orchestrate immune system function, but will also enhance our basic knowledge on the mechanisms leading to B cell tolerance and effective humoral responses.
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