Activation and inactivation of VH gene recombination

National Institute On Aging

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Abstract

Diversity of B and T cell antigen receptor repertoires underlies the ability of adaptive immunity to respond with high specificity to pathogen challenge. The main source of diversity is generated during lymphocyte development via the process of VDJ recombination. As a consequence, each B or T cell expresses one out of many variable (V) gene segments present in the germline. The goals of this project are to understand how B lymphocytes efficiently utilize the entire repertoire of close to one hundred VH gene segments of the immunoglobulin heavy chain (IgH) gene locus. During FY21 we accomplished the following: - demonstrated that 3D chromosome organization by the intergenic control region 1 (IGCR1) prevents aberrant rearrangements. We obtained evidence for VDV rearrangements on IgH alleles that lack IGCR1. Structures of rearrangement products were confirmed by cloning and sequencing. - such rearrangements were also easily detectable in human B cells from peripheral blood. One possibility is that the human IgH locus lacks an IGCR1-like regulatory element. Further studies are ongoing. - standardized VDJ repertoire analysis by HT-GTS in our laboratory. we used this to study VH usage in pro- and pre-B cells from young and old mice. We found that the ratio of proximal to distal VH usage was different in old pro-B cells. The difference was less distinct at the pre-B cell stage suggesting equilibration by selection via the pre-BCR. Mechanistic studies are ongoing.