The RAG1 Ubiquitin Ligase Domain Stimulates Recombination of TCR beta and TCR alpha Genes and Influences Development of alpha beta T Cell Lineages

RAG1/RAG2 (RAG) endonuclease-mediated assembly of diverse lymphocyte Ag receptor genes by V(D)J recombination is critical for the development and immune function of T and B cells. The RAG1 protein contains a ubiquitin ligase domain that stabilizes RAG1 and stimulates RAG endonuclease activity in vitro. We report in this study that mice with a mutation that inactivates the Rag1 ubiquitin ligase in vitro exhibit decreased rearrangements and altered repertoires of TCR beta and TCR alpha genes in thymocytes and impaired thymocyte developmental transitions that require the assembly and selection of functional TCR beta and/or TCR alpha genes. These Rag1 mutant mice present diminished positive selection and superantigen-mediated negative selection of conventional alpha beta T cells, decreased genesis of invariant NK T lineage alpha beta T cells, and mature CD4(+)alpha beta T cells with elevated autoimmune potential. Our findings reveal that the Rag1 ubiquitin ligase domain functions in vivo to stimulate TCR beta and TCRa gene recombination and influence differentiation of alpha beta T lineage cells, thereby establishing replete diversity of alpha beta TCRs and populations of alpha beta T cells while restraining generation of potentially autoreactive conventional alpha beta T cells.