B-1 (CD5 B) cells represent a developmentally and functionally distinct lineage of B cells in both mouse and man. Clinically, elevated levels of B-1 cells have been associated with a number of autoimmune diseases and they routinely develop neoplasias in mice and B-CLL in humans. Three major characteristics distinguish B-1 cells from the majority of B cells referred to as conventional B cells: 1) they are generated from fetal tissue but poorly from adult bone marrow; 2) in the adult they are long- lived and/or self-replenishing; and 3) they have a restricted, distinctive repertoire which is skewed towards anti-bacterial specificities. The studies in this proposal are designed to define the role B-1 cells play in the immune system of an individual. We have recently discovered two fundamental differences in B cell development in fetal/neonatal liver and spleen, where most B-1 cells are generated, and adult bone marrow, where most conventional B cells are generated. First, B cells generated up to 10 days after birth, express surface Ig in the absence of class II for up to three days. The implications of this are quite profound with respect to both the question of B-1 and conventional B cell development and more importantly with respect to the differences in their respective repertoires. In contrast to B cells generated in adult bone marrow which express class II before the expression of Ig, newly generated Ig+ B cells in the neonate cannot present exogenous antigens to T cells via class II or perhaps more importantly may not respond to T cell interaction. Thus in the neonate Ig+ B cells do not express class II at a time when they are exquisitely sensitive to positive selection and/or clonal deletion. It is possible that this lack of class II expression plays an important role in determining the selection of the neonatal (and therefore the B-1) B cell repertoire. Second, we have identified an """"""""I-A-like"""""""" which is expressed during fetal but not adult B cell development. In light of this new information, it is possible that both the """"""""lineage"""""""" and the """"""""selection"""""""" model of B-1 cell development may be in essence correct, that is, B-1 cells do represent a separate lineage of B cells which develop from distinct progenitors in which class II is not expressed until after Ig, however, this difference may result in different triggering signals which induce the classic B-1 cell phenotype and are responsible for the selected repertorie. The goal of the research outlined in this proposal is to extend our initial observation on the differences in fetal and adult B cell development and to determine the extent to which these differences play a role in the development of B-1 and conventional B cells and more importantly in their unique repertoires. These studies will be carried out in normal mice and mice with known defects in B cell development; in particular in mu transgenic mice where we have documented a preferential defect in conventional B cell development. In addition, we will characterize the potentially new """"""""I-A-like"""""""" antigen which we have identified. We will determine whether this antigen, which is expressed during fetal but not adult B cell development, is identical to the recently described class II H-20 molecule or is a new, undefined antigen.
