Author:
Burn Thomas N.,Miot Charline,Gordon Scott,Culberson Erica J.,Diamond Tamir,Kreiger Portia,Hayer Katharina E.,Bhattacharyya Anamika,Jones Jessica M.,Bassing Craig H.,Behrens Edward M.
Abstract
AbstractRAG1/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 properly selected to suppress autoimmunity. The RAG1 protein contains a ubiquitin ligase domain that stabilizes RAG1 and stimulates RAG endonuclease activity in vitro. We report that mice with a mutation that inactivates the RAG1 ubiquitin ligase in vitro exhibit modestly decreased assembly and altered repertoires of T cell receptor (TCR) β and α genes in thymocytes and impaired thymocyte developmental transitions that require assembly of these genes and signaling by their proteins. The mice also exhibit a combined phenotype of: 1) decreased expression of TCR signaling proteins in thymocytes, 2) less efficient positive selection of conventional αβ T cells and agonist selection of iNKT cells, 3) impaired superantigen-mediated negative selection of highly self-reactive thymocytes, and 4) CD4+ αβ T cells with elevated autoimmune potential. Our findings demonstrate that the RAG1 ubiquitin ligase domain functions in vivo to stimulate TCRβ and TCRα gene assembly and αβ TCR selection, thereby establishing replete αβ TCR diversity and αβ T cell lineages while restraining the inherent autoimmune hazard of creating diverse antigen specificities.Key PointsThe RAG1 ubiquitin ligase domain stimulates TCR α and β gene assembly in vivo.The RAG1 ubiquitin ligase domain enhances αβ TCR selection of thymocytes.The RAG1 ubiquitin ligase domain limits autoimmune potential of αβ T cells.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献