| Autor: |
Scott M. Gordon, Charline Miot, Tamir Diamond, Craig H. Bassing, Erica Culberson, Ed Behrens, Thomas N. Burn, Katharina E. Hayer, Portia A. Kreiger, Anamika Bhattacharyya, Jessica M. Jones |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.01.04.425211 |
| Popis: |
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 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 reduced thymic cellularity, decreased assembly and altered repertoires of T cell receptor (TCR) β and α genes in thymocytes, and impaired thymocyte developmental transitions that require the assembly of TCRβ or α genes and signaling by their proteins. These RAG1 mutant mice also exhibit less efficient positive selection and superantigen-mediated negative selection of conventional αβ T cells, 2) impaired differentiation of iNKT lineage αβ T cells, and 3) CD4+ αβ T cells with elevated autoimmune potential. Our findings demonstrate that the RAG1 ubiquitin ligase domain functions in vivo to stimulate the assembly and selection of TCRβ and TCRα genes, thereby establishing replete diversity of αβ TCRs and αβ T cell lineages while restraining the inherent autoimmune hazard of generating diverse antigen specificities. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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