The RAG1 Ubiquitin Ligase Domain Enhances T Cell Receptor Gene Assembly and Thymic Selection

RAG1/RAG2 (RAG) endonuclease-mediated assembly of diverse lymphocyte antigen receptor genes by V(D)J recombination is critical for the development and immune function of T and B cells. However, this process creates highly self-reactive cells that must be negatively selected to suppress autoimmunity. The RAG1 protein contains a ubiquitin ligase domain that stabilizes RAG1 and stimulates RAG endonuclease activity. We report here that mice lacking RAG1 ubiquitin ligase activity exhibit diminished recombination of T cell receptor (TCR) b and a loci, and impaired thymocyte developmental transitions that require the assembly of these genes and signaling by their proteins. The mice also have reduced expression of TCR signaling proteins within thymocytes, less efficient negative selection of highly self-reactive thymocytes, and mature ab T cells of elevated autoimmune potential. Thus, we propose that the RAG1 ubiquitin ligase domain provides ab T cell developmental stage-specific means to augment TCR signaling and thereby enhance selection for beneficial TCR genes and against ab TCRs possessing high autoimmune potential.