| First Author | Horowitz JE | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 4 | Pages | 1609-19 |
| PubMed ID | 24415779 | Mgi Jnum | J:209385 |
| Mgi Id | MGI:5567044 | Doi | 10.4049/jimmunol.1301599 |
| Citation | Horowitz JE, et al. (2014) Noncore RAG1 regions promote Vbeta rearrangements and alphabeta T cell development by overcoming inherent inefficiency of Vbeta recombination signal sequences. J Immunol 192(4):1609-19 |
| abstractText | The RAG proteins are comprised of core endonuclease domains and noncore regions that modulate endonuclease activity. Mutation or deletion of noncore RAG regions in humans causes immunodeficiency and altered TCR repertoire, and mice expressing core but not full-length Rag1 (Rag1(C/C)) or Rag2 (Rag2(C/C)) exhibit lymphopenia, reflecting impaired V(D)J recombination and lymphocyte development. Rag1(C/C) mice display reduced D-to-J and V-to-DJ rearrangements of TCRbeta and IgH loci, whereas Rag2(C/C) mice show decreased V-to-DJ rearrangements and altered Vbeta/VH repertoire. Because Vbetas/VHs only recombine to DJ complexes, the Rag1(C/C) phenotype could reflect roles for noncore RAG1 regions in promoting recombination during only the D-to-J step or during both steps. In this study, we demonstrate that a preassembled TCRbeta gene, but not a preassembled DbetaJbeta complex or the prosurvival BCL2 protein, completely rescues alphabeta T cell development in Rag1(C/C) mice. We find that Rag1(C/C) mice exhibit altered Vbeta utilization in Vbeta-to-DJbeta rearrangements, increased usage of 3'Jalpha gene segments in Valpha-to-Jalpha rearrangements, and abnormal changes in Vbeta repertoire during alphabeta TCR selection. Inefficient Vbeta/VH recombination signal sequences (RSSs) have been hypothesized to cause impaired V-to-DJ recombination on the background of a defective recombinase as in core-Rag mice. We show that replacement of the Vbeta14 RSS with a more efficient RSS increases Vbeta14 recombination and rescues alphabeta T cell development in Rag1(C/C) mice. Our data indicate that noncore RAG1 regions establish a diverse TCR repertoire by overcoming Vbeta RSS inefficiency to promote Vbeta recombination and alphabeta T cell development, and by modulating TCRbeta and TCRalpha gene segment utilization. |
