In principle, almost any chemical structure can be recognized as an antigen by the adaptive immune system, but the usual antigens encountered in an infection are the proteins, glycoproteins, and polysaccharides of pathogens. An individual antigen receptor or antibody recognizes a small portion of the antigen’s molecular structure, and the part recognized is known as an antigenic determinant or epitope (Fig. 1.14). Typically, proteins and glycoproteins have many different epitopes that can be recognized by different antigen receptors.
Antibodies and B-cell receptors directly recognize the epitopes of native antigen in the serum or the extracellular spaces. It is possible for different antibodies to simultaneously recognize an antigen by its different epitopes; such simultaneous recognition increases the efficiency of clearing or neutralizing the antigen.
Whereas antibodies can recognize nearly any type of chemical structure, T-cell receptors usually recognize protein antigens and do so very differently from antibodies. The T-cell receptor recognizes a peptide epitope derived from a partially degraded protein, but only if the peptide is bound to specialized cell-surface glycoproteins called MHC molecules (Fig. 1.15). The members of this large family of cell-surface glycoproteins are encoded in a cluster of genes called the major histocompatibility complex (MHC). The antigens recognized by T cells can be derived from proteins arising from intracellular pathogens, such as a virus, or from extracellular pathogens. A further difference from the antibody molecule is that there is no secreted form of the T-cell receptor; the T-cell receptor functions solely to signal to the T cell that it has bound its antigen, and the subsequent immunological effects depend on the actions of the T cells themselves. We will further describe how epitopes from antigens are placed on MHC proteins in Chapter 6 and how T cells carry out their subsequent functions in Chapter 9.
TCRMHCmoleculeMHCmoleculeepitopepeptideThe epitopes recognized by T-cell receptors are often buried The antigen must ÿrst be broken down into peptide fragments The epitope peptide binds to a self molecule, an MHC molecule The T-cell receptor binds to a complex of MHC molecule and epitope peptide
Principles of adaptive immunity.
1-11 Antigen-receptor genes are assembled by somatic gene rearrangements of incomplete receptor gene segments.
The innate immune system detects inflammatory stimuli by means of a relatively limited number of sensors, such as the TLR and NOD proteins, numbering fewer than 100 different types of proteins. Antigen-specific receptors of adaptive immunity provide a seemingly infinite range of specificities, and yet are encoded by a finite number of genes. The basis for this extraordinary range of specificity was discovered in 1976 by Susumu Tonegawa, for which he was awarded the 1987 Nobel Prize. Immunoglobulin variable regions are inherited as sets of gene segments, each encoding a part of the variable region of one of the immunoglobulin polypeptide chains. During B-cell development in the bone marrow, these gene segments are irreversibly joined by a process of DNA recombination to form a stretch of DNA encoding a complete variable region. A similar process of antigen-receptor gene rearrangement takes place for the T-cell receptor genes during development of T cells in the thymus.
Just a few hundred different gene segments can combine in different ways to generate thousands of different receptor chains. This combinatorial diversity allows a small amount of genetic material to encode a truly staggering diversity of receptors. During this recombination process, the random addition or subtraction of nucleotides at the junctions of the gene segments creates additional diversity known as junctional diversity. Diversity is amplified further by the fact that each antigen receptor has two different variable chains, each encoded by distinct sets of gene segments. We will describe the gene rearrangement process that assembles complete antigen receptors from gene segments in Chapter 5.