Chemokines and Lymphoid Tissue Organization and Function

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DESCRIPTION (provided by applicant): Secondary lymphoid organs promote cell-cell and cell-antigen interactions that are necessary for the initiation of adaptive immune responses. Chemokines have recently been established to have a central role in the development and organization of secondary lymphoid tissues. The long-term objective of this proposal is to define how secondary lymphoid organs become organized and to determine how this organization fosters the cell-cell encounters that are necessary for adaptive immunity. The first of three aims seeks to determine the role of CXCR5 in guiding helper T cells to B cell areas, and to determine the importance of this chemokine receptor for T helper cell function. A second part of this aim will use 2-photon microscopy to study interactions between B cells and T cells within viable lymphoid tissue. B-cell derived chemokine(s) involved in promoting encounters between activated T and B cells will also be characterized. Lymphoid chemokine induction in the spleen is lymphotoxin (LT) dependent and occurs during the first few weeks after birth. In aim 2 the major cell types functioning as sources of LT within the neonatal spleen will be characterized. The role of lymphoid chemokines in organizing the developing white-pulp will be investigated, including an analysis of newly generated ELC knockout mice. In addition, a BLC reporter mouse strain will be generated to permit the appearance of BLC expressing cells to be tracked. Many of the cells within lymphoid organs are in a state of continual motility, a behavior that facilitates their surveillance for antigen. The third aim will explore the role of chemokines and integrins in promoting cell motility within lymphoid organs. By improving our understanding of the factors that promote lymphoid tissue development and organization and by further developing understanding of how B and T lymphocytes interact to mount antibody responses, these studies should lead to approaches to augment immune responses against pathogens and vaccine antigens, and to thwart unwanted responses against allergens or autoantigens.