Abstract
Abstract Antigen receptor genes are assembled by V(D)J recombination, which is mediated by two lymphoid cell-specific proteins called RAG1 and RAG2. In B cells, primary V(D)J rearrangements yield B cell receptors displaying diverse antigenic specificity. Recent evidence suggests that certain populations of peripheral CD5+ B cells may express the RAG proteins in order to initiate secondary V(D)J rearrangements to “edit” receptor specificity away from autoreactivity or “revise” receptor specificity to further expand an antigen-specific B cell repertoire. In principle, if a means were identified to block this process, B cell maturation and/or function may be impaired. To explore this idea, we generated transgenic mice overexpressing catalytically inactive full-length RAG1 in the periphery. In two founder lines, transgenic mice exhibit a polyclonal expansion of B1-like B cells (B220loCD19+CD5+), pronounced hypogammaglobulinemia, and an impaired humoral immune response. Interestingly, B1-like B cells fail to accumulate in mice expressing both catalytically inactive RAG1 and a heavy chain transgene specific for dsDNA (3H9H56R.KI), but bi-transgenic mice still exhibit hypogammaglobulinemia and may also be susceptible to bacterial infection. This work was supported by the Health Future Foundation, and the State of Nebraska LB506 and LB692 Research Programs.