P nucleotides N nucleotides

FIGURE 8-13 Junctional diversity. During the joining of different gene segments, addition or removal of nucleotides may lead to the generation of novel nucleotide and amino acid sequences at the junction. Nucleotides (P sequences) may be added to asymmetrically cleaved hairpins in a templated manner. Other nucleotides (N regions) may be added to the sites of VD, VJ, or DJ junctions in a nontemplated manner by the action of the enzyme TdT. These additions generate new sequences that are not present in the germline.

frameshifts, theoretically generating termination codons in two of every three joining events. These genes cannot produce functional proteins, but such inefficiency is the price that is paid for generating diversity.

Because of junctional diversity, antibody and TCR molecules show the greatest variability at the junctions of V and C regions, which form the third hypervariable region, or CDR3 (see Fig. 8-6). In fact, because of junc-tional diversity, the numbers of different amino acid sequences that are present in the CDR3 regions of Ig and TCR molecules are much greater than the numbers that can be encoded by germline gene segments. The CDR3 regions of Ig and TCR molecules are also the most important portions of these molecules for determining the specificity of antigen binding (see Chapters 5 and 7). Thus, the greatest diversity in antigen receptors is concentrated in the regions of the receptors that are the most important for antigen binding.

Although the theoretical limit of the number of Ig and TCR proteins that can be produced is enormous (see Table 8-1), the actual number of antigen receptors on B or T cells expressed in each individual is probably on the order of only 107. This may reflect the fact that most receptors, which are generated by random DNA recombination, do not pass the selection processes needed for maturation.

A practical application of our knowledge of junctional diversity is the determination of the clonality of lymphoid tumors that have arisen from B or T cells. This laboratory test is commonly used to distinguish monoclonal tumors from polyclonal proliferations of lymphocytes in response to some external stimulus. Because every lymphocyte clone expresses a unique antigen receptor CDR3 region, the sequence of nucleotides at the V(D)J recombination site serves as a specific marker for each clone. Thus, by measuring the length of the junctional regions of Ig or TCR genes in different B or T cell lesions by polymerase chain reaction assays, one can establish whether these lesions arose from a single clone (indicating a tumor) or independently from different clones (implying non-neoplastic proliferation of lymphocytes). The same method may be used to identify small numbers of tumor cells in the blood or tissues.

With this background, we proceed to a discussion of B lymphocyte development and then the maturation of T cells.

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