As one of the most effective weapons in our anti- pathogen artillery, antibodies need to be made and released fast. To accomplish this, antigen-engaged B cells must interact rapidly with antigen-specific helper T cells. At the same time, autoantibody producing B cells must be kept tightly in check. When B cells encounter antigen in the periphery, whether foreign or self, instead of migrating into B cell areas of secondary lymphoid organs, they move to the outer T cell zones. This relocalization is likely to be critical for favoring encounters with helper T cells and, in the case of autoantigen binding cells, may contribute to their rapid elimination. This study has two long-term goals: to define the mechanism of B cell exclusion from lymphoid follicles following encounter with antigen; and to determine the basis for the rapid elimination of autoantigen binding B cells in the periphery. These goals will be pursued by following three specific aims. First, the molecular cues directing antigen- and autoantigen-binding B cells to the outer T zone will be determined. Recent findings have established that the CXC chemokine, BLC, is important in guiding B cells to follicles, whereas the CC chemokines, ELC and SLC, guide T cells to the T zone. The possibility that increased responsiveness to ELC and SLC directs antigen-engaged B cells to the T zone will be explored by genetic approaches.
The second aim will characterize the intracellular signaling pathways downstream of the BCR that promote B cell migration to the outer T zone. A retroviral gene- transduction protocol will be used to introduce molecules that activate or inhibit specific branches of the BCR signaling pathway, such as dominant negative Ras, MEK or PI3-kinase, to hen egg lysozyme (HEL) specific Ig-transgenic B cells. The genetically modified cells will be returned to mice that contain or lack HEL antigen and the effect of the modification on B cell positioning will be determined. Finally, the third aim is to determine the relationship between B cell positioning and B cell survival. B cells that lack chemokine receptors needed for migration to follicles or T cell areas will be used to test the contribution these compartments make to promoting B cell survival. The involvement of BAFF, a TNF family member, in enhancing the survival of autoreactive B cells will be explored. As well as improving our understanding of factors regulating the efficiency of B cell antibody production to foreign pathogens, these studies are likely to provide insight into how defects in B cell trafficking and homeostasis contribute to autoimmunity or immunodeficiency.
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