The RAG1 Ubiquitin Ligase Domain Stimulates Recombination of TCRβ and TCRα Genes and Influences Development of αβ T Cell Lineages.
Thomas N BurnCharline MiotScott M GordonErica J CulbersonTamir DiamondPortia A KreigerKatharina E HayerAnamika BhattacharyyaJessica M JonesCraig H BassingEdward M BehrensPublished in: Journal of immunology (Baltimore, Md. : 1950) (2022)
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 TCRβ and TCRα genes in thymocytes and impaired thymocyte developmental transitions that require the assembly and selection of functional TCRβ and/or TCRα genes. These Rag1 mutant mice present diminished positive selection and superantigen-mediated negative selection of conventional αβ T cells, decreased genesis of invariant NK T lineage αβ T cells, and mature CD4 + αβ T cells with elevated autoimmune potential. Our findings reveal that the Rag1 ubiquitin ligase domain functions in vivo to stimulate TCRβ and TCRα gene recombination and influence differentiation of αβ T lineage cells, thereby establishing replete diversity of αβ TCRs and populations of αβ T cells while restraining generation of potentially autoreactive conventional αβ T cells.
Keyphrases
- regulatory t cells
- genome wide
- dna repair
- genome wide identification
- dna damage
- bioinformatics analysis
- single cell
- induced apoptosis
- oxidative stress
- genome wide analysis
- immune response
- metabolic syndrome
- risk assessment
- quantum dots
- gene expression
- high fat diet induced
- transcription factor
- type diabetes
- cell proliferation
- signaling pathway
- copy number
- pi k akt
- drug induced
- visible light