Chapter 18 - Generation of Diversity in the Adaptive Immune Response

Abstract

The adaptive immune system responds specifically to a large number of different antigenic determinants. F. Macfarlane Burnet proposed the clonal selection theory of antibody formation in 1959. One postulate of this theory is that antibody-forming lymphocytes (and by extension T lymphocytes) respond to a single antigen and that the specificity of these lymphocytes is determined during development prior to interaction with antigen. The mechanism by which lymphocytes generate this extensive repertoire of specificities remained an enigma until amino acid sequences and the molecular genetics of the formation of B and T lymphocyte receptors were determined. In the mid-1960s, William Dreyer and J. Claude Bennett hypothesized that immunoglobulin chains are coded for by two separate genes. Amino acid data confirmed that heavy and light chains had variable (V) and constant (C) regions. By 1976, Susumu Tonegawa and colleagues demonstrated that gene rearrangement involving separate genes coding for the V, diversity (D), joining (J), and C regions occurs during B lymphocyte development. Once the mechanism of gene rearrangement was understood for B lymphocytes, a similar mechanism in T lymphocytes was described. This process of gene rearrangement provides the lymphocyte with a unique set of specificities that are randomly determined and that allow the host to interact with virtually any antigen found in its environment.