Lymphocyte migration through secondary lymphoid tissues is an integral part of immune surveillance, acting to bring together rare antigen-specific cells and antigen. Recent studies indicate that migration of lymphocytes to specific compartments within lymphoid tissues also functions in immunological tolerance and B-cell homeostasis. Autoreactive B-cells that have bound self-antigen are excluded from follicular niches by competing B-cells and, instead of surviving more than one week, undergo cell death within three days. This application has three specific aims, with the long-term objective being to understand the mechanism by which B-cells localize in follicular microenvironments and to define how this contributes to B-cell homeostasis.
Specific Aim 1 proposes to define cellular requirements for autoreactive B-cell exclusion from follicles and rapid elimination. Mice deficient in B-cells will be used to test how well mature autoreactive B-cells persist when competitors are lacking, and mice deficient in T-cells to determine whether T-cells play a role in retaining autoreactive B-cells in the T zone or in reducing their lifespan. By blocking lymphotoxin function, the investigator will also test whether marginal zone macrophages regulate B-cell compartmentalization.
Specific Aim 2 proposes to study the intracellular signaling requirements for follicular entry and B-cell survival using three mutant mouse strains. Mice with mutations in the tyrosine phosphatases, PTP1C and CD45, will be crossed with immunoglobulin transgenic mice and the effect on autoantigen mediated exclusion from follicles will be measured. X-linked immunodeficient (xid) mice, which have a deficiency of peripheral B-cells, will be studied to determine whether the deficiency involves a failure of B-cells to migrate into follicles.
Specific Aim 3 proposes to use in vitro splenic and lymph node fragment cultures to test the effect of activators or inhibitors of biochemical pathways, and antibodies to surface molecules, on B-cell migration and survival. As well as improving our understanding of normal B-cell function, these studies are likely to provide important insight into defects in B-cell trafficking and homeostasis that contribute to autoimmunity or immunodeficiency.
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