No abstract

To analyze the control of self tolerance to tissue-specific Ag, we have constructed C57BL/6 (H-2b) transgenic mice that express allogeneic class II (I-Ad) molecules exclusively on pancreatic islet cells. By a number of criteria, including I-Ad mRNA, and tissue and cell surface I-Ad protein levels, the islet cells appear to be expressing levels of I-Ad similar to B lymphocytes. Although one of the transgenic lines that expresses only the beta-chain occasionally displays slightly elevated glucose levels, this hyperglycemia is not enhanced when alpha and beta are coexpressed, allowing for cell surface I-Ad expression. None of the mice examined has demonstrated any autoimmune reaction to the I-Ad+ islet cells. Despite this apparent lack of recognition of the I-Ad+ islet cells, these animals demonstrate no reduction in the in vitro MLR generated to the same MHC molecule. Therefore, these mice remain functionally tolerant to the transgene product without inactivating those T cells that can recognize this same MHC molecule in vitro.

The deletion of C kappa is a frequent event in lambda-producing B cells in both mice and humans. Deletions of the murine C kappa gene are mediated by recombination events that involve the RS (recombining segment) element located downstream of the C kappa gene. RS recombinations appear to be mediated by the same mechanisms involved in Ig and TCR gene rearrangement. It has been suggested that RS recombinations might activate a factor that is involved in the initiation of lambda gene rearrangement in maturing pre-B cells. We have identified a unique RNA transcript derived from the recombined RS element present in some pre-B cell lines. However, gene transfer studies indicate that this RS transcript is not sufficient to induce lambda gene recombination in pre-B cell lines. We also find that recombination of the RS element in pre-B cell lines is closely correlated with changes in chromatin structure and transcriptional activation. Thus, recombination of the RS element in pre-B cells appears to be regulated in a manner similar to the regulation of antibody gene VDJ joining.