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The Generation of Lymphocyte Antigen Receptors
A lymphocyte expresses many exact copies of a single antigen receptor that has a unique antigen-binding site (see Section 1-12). The clonal expression of antigen receptors means that each lymphocyte is unique among the billions of lymphocytes that each person possesses. Chapter 4 described the structural features of immunoglobulins and T-cell receptors, the antigen receptors on B cells and T cells, respectively. We saw that the vast repertoire of antigen receptors results from variations in the amino acid sequence at the antigen-binding site, which is composed of the two variable regions from the two chains of the receptor. In immunoglobulins, these are the heavy-chain variable region (VH) and the light-chain variable region (VL), and in T-cell receptors, the Vα and Vβ regions. The immunoglobulin domains of these regions contain three loops that comprise three hypervariable regions, or complementarity-determining regions (CDRs) (see Section 4-6) that determine the receptor’s antigen binding site and allow for seemingly limitless diversity in specificity.
In the 1960s and 1970s, immunologists recognized that the limited size of the genome (at roughly 3 billion nucleotides) meant that the genome could not directly encode a sufficient number of genes to account for the observed diversity of antigen receptors. For example, encoding each distinct antibody by its own gene could easily fill the genome with nothing but antibody genes. As we will see, variable regions of the receptor chains are not directly encoded as a complete immunoglobulin domain by a single DNA segment. Instead, the variable regions are initially specified by so-called gene segments that encode only a part of the immunoglobulin domain. During the development of each lymphocyte, these gene segments are rearranged by a process of somatic DNA recombination to form a complete and unique variable-region coding sequence. This process is known generally as gene rearrangement. A fully assembled variable region sequence is produced by combining two or three types of gene segments, each of which is present in multiple copies in the germline genome. The final diversity of the receptor repertoire is the result of assembling complete antigen receptors from the many different gene segments of each type during the development of each individual lymphocyte. This process gives each new lymphocyte only one of many possible combinations of antigen receptors, providing the repertoire of diverse antigen specificities of naive B cells and T cells.
The first and second parts of this chapter describe the gene rearrangements that generate the primary repertoire of immunoglobulins and T-cell receptors. The mechanism of gene rearrangement is common to both B cells and T cells, and its evolution was probably critical to the evolution of the vertebrate adaptive immune system. The third part of the chapter explains how the transition from production of transmembrane immunoglobulins by activated B cells results in the production of secreted antibodies by plasma cells. Immunoglobulins can be synthesized as either transmembrane receptors or secreted antibodies, unlike T-cell receptors, which exist only as trans-membrane receptors. Antibodies can also be produced with different types of constant regions, or isotypes (see Section 4-1). Here, we describe how the
Primary immunoglobulin gene rearrangement.
T-cell receptor gene rearrangement.