This is a renewal application of an RO1 grant to study receptor editing in B lymphocytes. Receptor editing is defined as secondary V(D)J recombinations in surface immunoglobulin positive (slg+) cells that eliminate and replace functional L-chain genes, altering B cell antigen specificity. Our data suggest that editing is a major mechanism of central B cell tolerance. Secondary rearrangements can also occur in slg+ cells in the peripheral immune system (known as receptor revision) though there is some debate about the developmental stage of the cells undergoing revision and how recombination is regulated in these cells. Given their potential roles in the prevention of B cell autoreactivity, it is important to understand how receptor editing and revision are regulated, and how editing impacts allelic exclusion of Ig expression. The long term goal of these studies is to determine how B cell receptor signaling regulates recombination. In this proposal we test the hypotheses that the ability of a B cell to undergo receptor editing is developmentally regulated, that cells undergoing editing are similar to small preB cells in their stage of differentiation, that receptor revision is distinct from tolerance-induced editing, though it may involve cells at a similar stage of differentiation, that editing involves destructive rearrangements, including those involving the recombining sequence (RS), that are important in maintaining allelic/isotypic exclusion, and that target genes of BCR regulation that control recombinase can be identified by analysis of RNA expression and transcription factor activity. These hypotheses will be addressed through the following Specific Aims:
Aim l. To test whether or not RS rearrangements promote editing and allelic exclusion.
Aim 2. To test the role of B cell developmental stage on editing.
Aim 3. To determine if tolerance-induce receptor editing occurs in fetal B cells.
Aim 4. To identify functionally relevant changes in gene regulation that promote editing.
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