BLC AND BLR1 AND IMMUNE FUNCTION AND DYSFUNCTION

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Chemokines are well characterized as small chemotactic cytokines that recruit cells from the blood to sites of infection. Recent studies have uncovered a role for chemokines in cell trafficking through lymphoid tissues. In mice deficient in Burkitt's Lymphoma Receptor 1 (BLR1/CXC- R5), B cell follicles fail to form in spleen and Peyer's patches and inguinal lymph nodes do not develop. B-Lymphocyte Chemoattractant (BLC/BCA1), the only known ligand for BLR1, is expressed by follicular stromal cells in these tissues. How BLR1 and BLC function to organize cells in follicles is not understood. The long-term objective of this propose is to define the contribution of BLR1/BLC to cell migration and organization in both lymphoid and non-lymphoid tissues. The first of three aims seeks to determine if changes in BLR1 expression or BLC responsiveness contribute to the changes in B cell tropism that occur upon activation and differentiation. Similar studies will also be performed on T cells since T cell migration into follicles is essential for germinal center reactions and may also permit access to antigen trapped on follicular dendritic cells such as HIV in patients with AIDS. Aim 1 will also test if a splice variant of BLR1 in human macrophages is expressed in the mouse and will determine the BLC responsiveness of macrophage subsets. In Aim 2 the mouse BLC gene will be inactivated by gene targeting. BLC-deficient mice are important for reestablishing the role of BLC in follicular compartmentalization of B cells, for determining whether BLC is the only ligand for BLR1 and for characterizing whether BLC has functions in addition to a role in cell homing to follicles. The targeting construct will also introduce the green fluorescent protein gene (GFP) into the BLC locus to permit characterization of BLC expressing cells. In patients suffering chronic inflammatory diseases such as rheumatoid arthritis and diabetes, there are often large accumulations of B cells in the affected tissue. The third aim will explore whether BLC is expressed at sites of chronic inflammation in mouse models and, using the gene targeted mice, test to what extent BLC contributes to the inflammation. This aim will also test the effect of BLC expression to an ectopic site (the pancreatic islets) using a transgenic approach both to determine whether BLC is sufficient to promote follicle formation and to establish a system where the relationship between B cell accumulation and pathology can be studied.