USE OF ISOLATED IMMATURE-STAGE B-CELLS TO UNDERSTAND NEGATIVE SELECTION AND TOLERANCE INDUCTION AT THE MOLECULAR-LEVEL

Encounter with antigen by newly developing antigen receptor-positive B cells leads to negative selection. This process positions the B cell antigen receptor (BCR) in a central role for initiating the process of negative selection and suggests developmental regulation of its signa ling. The observation that immature B cells are more susceptible to ne gative selection than are mature B cells has been demonstrated in a nu mber of in vitro and in vivo model systems and support the idea of dev elopmental regulation of BCR-initiated responses. Since identical anti gen receptors are expressed on immature and mature B cells, the critic al fate-determining distinction between these developmental stages mus t lie downstream of the receptor-ligand interaction itself, in the for m of different BCR-linked signaling processes or with different second ary events occurring subsequent to BCR cross-linking. To address the f irst possibility, our laboratory and others have sought to define the differences in BCR-mediated signal transduction in immature and mature B lymphocytes. In this review article we will discuss current in vitr o systems to study this question in primary, nontransformed murine B l ymphocytes. In addition, we will discuss our previously published work in order to illustrate how these model systems have been useful in be ginning to unravel the molecular basis for immune B cell negative sele ction and tolerance.