V(D)J recombination drives normal B and T cell development, but deregulation of recombination can lead to genomic instability and cancer. The vast majority of B cells in the body are bone marrow B-2 cells whereas B-1 cells represent a smaller pool of the B cell compartment. B-1 cells can be divided into B-1a and B-1b that have many unique and overlapping characteristics. In contrast to B-2 cells, B-1a cells are long-lived cells that accumulate in peritoneal/pleural cavities, have a biased gene segment usage conferring autoreactive BCRs, and are preferentially generated from early embryonic/fetal tissues. The origin of B-1a cells has been a hotly debated subject and the field has had difficulty reconciling the balance between distinct B-1a progenitor cells and positive selection of the BCRs on B-1a cells. We find that fetal liver pro-B cells have low levels of IL-7R/STAT5 signaling that enable Igk recombination, such that both Igh and Igk recombination occur at the same cell stage. Productive heavy- and light-chain at the pro-B cell stage can assemble a mature B cell receptor without surrogate light chain (SLC) pairing/pre-BCR signaling. We propose that bypassing pairing with SLC and pre-BCR signaling can explain the origin of B-1a cells. Finally, we have created novel mouse models that can contribute to better understanding RAG DNA binding activity and feedback control of RAG-cleavage. Rag1D600A mice express RAG1 that can bind to DNA but cannot cleave it. Rag2S365A mice can lead to an increase in biallelic cleavage events, a defect that can be rescued in Rag2S365E mice. The novel mouse models described here will provide a resource for future investigations dissecting aspects of controlling RAG cleavage.
|Advisor:||Skok, Jane A.|
|Commitee:||Koralov, Sergei, Littman, Dan, Reizis, Boris, Chiorazzi, Nicholas|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 81/5(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Oncology, Developmental biology|
|Keywords:||Autoreactive BCRs, B-1a cell development, IL-7R/STAT5 siangling, Pre-BCR signaling, PtC, Surrogate light chain|
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