The genes that encode diverse antigen receptors of B and T lymphocytes are generated by the rearrangement in individual lymphocytes of different variable (V) region gene segments with diversity (D) and joining (J) gene segments. A novel rearranged exon for each antigen receptor gene is generated by fusing a specific distant upstream V gene segment to a downstream segment on the same chromosome. This specialized process of site-specific gene rearrangement is called V(D)J recombination. (The terms recombination and rearrangement are used interchangeably.) Elucidation of the mechanisms of antigen receptor gene rearrangement, and therefore of the underlying basis for the generation of immune diversity, represents one of the landmark achievements of modern immunology.
The first insights into how millions of different antigen receptors could be generated from a limited amount of coding DNA in the genome came from analyses of the amino acid sequences of Ig molecules. These analyses showed that the polypeptide chains of many different antibodies of the same isotype shared identical sequences at their C-terminal ends (corresponding to the constant domains of antibody heavy and light chains) but differed considerably in the sequences at their N-terminal ends that correspond to the variable domains of immunoglobulins (see Chapter 5). Contrary to one of the central tenets of molecular genetics, enunciated as the "one gene-one polypeptide hypothesis" by Beadle and Tatum in 1941, Dreyer and Bennett postulated in 1965 that each antibody chain is actually encoded by at least two genes, one variable and the other constant, and that the two are physically combined at the level of DNA or of messenger RNA (mRNA) to eventually give rise to functional Ig proteins. Formal proof of this hypothesis came more than a decade later when Susumu Tonegawa demonstrated that the structure of Ig genes in the cells of an antibody-producing tumor, called a myeloma or plasmacytoma, is different from that in embryonic tissues or in nonlym-phoid tissues not committed to Ig production. These differences arise because DNA segments within the loci encoding Ig heavy and light chains are specifically ligated together only in developing B cells but not in other tissues or cell types. Similar rearrangements were found to occur during T cell development in the loci encoding the polypeptide chains of TCRs. Antigen receptor gene rearrangement is best understood by first describing the unrearranged, or germline, organization of Ig and TCR genes and then describing their rearrangement during lymphocyte maturation.
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