期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 198, 期 9, 页码 1439-1450出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20030627
关键词
antigen receptor; DNA cleavage; RS; hybrid joint; immune deficiency
资金
- NIAID NIH HHS [AI35714, R01 AI020047, AI20047, P01 AI035714, R37 AI020047] Funding Source: Medline
RAG1 and RAG2 are the lymphocyte-specific components of the V(D)J recombinase. In vitro analyses of RAG function have relied on soluble, highly truncated core RAG proteins. To identify potential functions for noncore regions and assess functionality of core RAG1 in vivo, we generated core RAG1 knockin (RAG1(c/c)) mice. Significant B and T cell numbers are generated in RAG1(c/c) mice, showing that core RAG1, despite missing similar to40% of the RAG1 sequence, retains significant in vivo function. However, lymphocyte development and the overall level of V(D)J recombination are impaired at the progenitor stage in RAG1(c/c) mice. Correspondingly, there are reduced numbers of peripheral RAG1(c/c) B and T lymphocytes. Whereas normal B lymphocytes undergo rearrangement of both J(H) loci, substantial levels of germline J(H) loci persist in mature B cells of RAG1(c/c) mice, demonstrating that DJ(H) rearrangement on both IgH alleles is not required for developmental progression to the stage of V-H to DJ(H), recombination. Whereas V-H to DJ(H) rearrangements occur, albeit at reduced levels, on the nonselected alleles of RAG1(c/c) B cells that have undergone D to J(H) rearrangements, we do not detect V-H to D-H rearrangenients in RAG(c/c) B cells that retain germline J(H) alleles. We discuss the potential implications of these findings for noncore RAG1 functions and for the ordered assembly of V-H, D-H, and J(H) segments.
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