The antigen-driven activation of B lymphocytes is regulated by multiple interactions with helper T cells, mediated by specific cell surface receptors. Helper T cells provide at least two regulatory functions for B cells namely to activate mature B cells to proliferate and differentiate into antibody secreting cells and to overt the tolerization of immature or developing B cells. For T cells to be activated to provide such regulatory functions antigen must be processed by antigen presenting cells (APC). This involves a number of poorly delineated steps beginning with the uptake of the antigen into an acidic compartment where proteolysis occurs. The resulting peptide fragments containing the T cell antigenic determinants are associated with Ia and displayed on the APC surface. Antigen-specific B cells are extraordinarily efficient APC as they are able to bind native antigen through surface Ig and internalize it for subsequent processing. Recent studies show that the APC function is a late acquisition of developing neonatal splenic B cells closely paralleling a phase during which they are extraordinarily sensitive to tolerance induction, which may be significant in shaping the mature B cell repertoire. This proposal represents an approach to elucidating the molecular mechanisms by which antigen is processed by mature B cells and to understanding the deficit in immature B cell populations. Advantage will be taken of recently developed radiolabeled conjugates of antigen covalently coupled to antibodies directed toward surface Ig which allows the antigen to be efficiently endocytosed by all B cells. Using such conjugates several key questions will be addressed concerning the individual steps involved in antigen processing and how these are developmentally regulated. These include reconstitution of functional peptide-Ia complexes in collaboration with Dr. R. MacDonald and analysis of the factors which effect the acquisition of the APC function in developing B cells, with Dr. Patel. It is hoped that the studies proposed here will lend valuable insight into the mechanisms underlying the developmental acquisition of an essential cell interaction complex in lymphocytes.
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