Regulation of antigen receptor gene assembly in lymphocytes

Somatic alterations affecting the mammalian genome occur exclusively in B a nd T cells. Developing lymphocytes employ a series of DNA recombination eve nts (V(D)J recombination) to assemble a diverse repertoire of immunoglobuli n (Ig) and T cell receptor (TCR) variable regions from a large array of ger mline 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 fo r a single recombinase activity. Despite these shared features, recombinati on events are controlled at the levels of stage- and tissue-specificity. Ou r primary research focus is to dissect the mechanisms that regulate assembl y 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 fou nd that transcriptional promoters are critical cis-acting regulatory elemen ts for targeting efficient recombination of chromosomal gene segments. Wt: 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 t hat regulate antigen receptor diversity and the developmental pathways lead ing to the acquisition of lymphocyte effector function.