Regulation of antigen receptor gene assembly in lymphocytes.
Somatic alterations affecting the mammalian genome occur exclusively in B and T cells. Developing lymphocytes employ a series of DNA recombination events (V(D)J recombination) to assemble a diverse repertoire of immunoglobulin (Ig) and T cell receptor (TCR) variable regions from a large array of germline gene segments. V(D)J recombination is required not only for receptor diversification but also for lymphocyte development. At a molecular level, these recombination events are directed by conserved DNA sequences flanking all antigen receptor gene segments that function as recognition signals for a single recombinase activity. Despite these shared features, recombination events are controlled at the levels of stage- and tissue-specificity. Our primary research focus is to dissect the mechanisms that regulate assembly of antigen receptor loci by rendering certain gene segments accessible to a common V(D)J recombinase. This article discusses recent discoveries from the author's laboratory that address this long-standing issue. We have found that transcriptional promoters are critical cis-acting regulatory elements for targeting efficient recombination of chromosomal gene segments. We have also demonstrated that activation of NF-kappaB signaling in precursor B cells is required for global regulation of Ig light chain gene assembly. Together, these findings provide key insights into the genetic mechanisms that regulate antigen receptor diversity and the developmental pathways leading to the acquisition of lymphocyte effector function.
Oltz
E M
EM
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. oltzem@ctrvax.vanderbilt.edu
D000818:Animals; D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000378:metabolism*; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D015322:Gene Rearrangement, B-Lymphocyte; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D015329:Gene Rearrangement, T-Lymphocyte; D005803:Genes, Immunoglobulin; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D008322:Mammals / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D018448:Models, Immunological; D016328:NF-kappa B / Q000502:physiology; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic; D045567:VDJ Recombinases
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases