The cells that are responsible for specific recognition of foreign antigens (i.e., adaptive immunity) are B and T lymphocytes (see Box 10-3). These cells have surface proteins that bind to (recognize) antigens with high specificity and affinity: each particular surface protein can bind effectively to one and only one antigen. These surface recognition proteins are called antigen receptors, and it is the precision of these receptors (they will bind to only one epitope out of all possible epitopes) that is responsible for the amazing specificity of the immune system. (Box 10-4). For T cells, the epitope is usually a small peptide; for B cells, it is frequently more than a small peptide that is recognized. When the antigen receptor binds its antigen, the B or T cell becomes activated and the immune response is initiated.

Both B and T cells can recognize any antigen that might possibly be encountered, including synthetic antigens that do not exist in nature. How such a vast array of receptors could exist was a puzzle to immunologists during the many years when it was believed that each unique antibody molecule was encoded by its own gene, because there is not enough DNA in the entire body to code for one gene for each possible antibody. The key to this diversity was determined first for B cells (Figure 10-1), and subsequently shown to apply to T cells (Figure 10-2) as well. One section of the receptor protein consists of relatively constant amino acid sequences that are shared by many receptors and coded for by a small number of genes. The second section is a highly variable part of the receptor
that recognizes the vast diversity of antigens which is created by allowing rearrangement of gene segments to generate a huge number of permutations (Box 10-5). The genes coding for the constant and variable segments are assembled within a given B or T cell into a single DNA sequence that codes for the final receptor molecule that will be expressed by that cell (see Box 10-7 for a more detailed description of this process).

Although generated by similar mechanisms, Band T-cell antigen receptors work in different ways. The B-cell receptor recognizes antigens in their native form—that is, as they exist in nature. As a consequence, the antigen does not need to be manipulated in any way, and the B cell can recognize the antigen by itself. This is true whether the B-cell receptor, which is an antibody molecule, is attached to the surface membrane of the B cell, or has been secreted from the cell and is free of the B cell entirely.

The T-cell antigen receptor differs from the B cell antigen receptor in two ways. First, it cannot recognize native antigens. Instead, it recognizes only antigens that have been broken down into short, epitope-sized peptide fragments. This process, which is referred to as antigen processing, can occur within the cytoplasm of many types of cells, called antigen-presenting cells. The processed antigen is then carried to the surface of the antigen-presenting cell by major histocompatibility(MHC) proteins. (Box 10-6) This leads to the second major difference between B- and T-cell recognition of antigens: the T-cell receptor binds not only to the processed peptide, but also to the carrier (MHC) protein on the surface of the antigen-presenting cell. This process of re-expressing the processed antigen on the surface of the antigen-presenting cell is called antigen presentation. In other words, the T-cell antigen receptor, even though it is specific for one peptide, is also specific for one MHC protein, and T-cells recognize an antigen only if it is bound to the correct MHC protein. (Figure 10-3). For this reason, antigen recognition by T cells is said to be MHC-restricted, and antigen-presenting cells and T cells must be histocompatible for T-cell activation to occur. Because of MHCrestriction, one person’s T cells will not recognize any antigens unless they are presented by that person’s own antigen-presenting cells (or antigen-presenting cells from another person who happens to have some of the same particular MHC proteins). In summary, T-cell responses require the processing and presentation of antigens by an antigen-presenting cell to a histocompatible T cell.

MHC proteins are highly variable from person to person, and, in fact, are among the most variable proteins known (Box 10-7). It is this enormous variability from person to person that allows the immune system to distinguish self from non-self—that is, to differentiate between one’s own cells and antigens and someone else’s. Two broad classes of MHC molecules exist: Class I molecules, which are expressed on all nucleated cells in the body, and Class II molecules, which are primarily expressed by cells of the immune system (monocytes/macrophages, dendritic cells, B cells, and activated T cells). In humans, MHC proteins are also called human leukocyte antigens (HLA), and we refer to a person’s “HLA type.” MHC Class I proteins are the primary antigens responsible for graft rejection and must be expressed by a target cell for this cell to be killed by an antigen-specific CD8 T cell.¹ MHC Class II must be the same on the antigen-presenting cell and the CD4 T cells for the latter to be triggered.² In fact, all of the cells listed previously as expressing Class II MHC molecules are important antigen-presenting cells, even B cells. Of note, activated B cells can use their antigen-specific surface receptor to facilitate antigen uptake as the first step in antigen processing. For this reason, B cells can process antigens that are present in very low concentrations, and they are important cells for presentation of antigens to T cells during mature immune responses.³ However, B cells specific for a given antigen are much less numerous than other antigenpresenting cells, which explains why the non-specific antigen-presenting cells are essential.

Because they vary so widely among individuals, the MHC proteins from different people will interact differently with the foreign proteins or peptides encountered by those individuals. Most of the antigens
associated with pathogens are complex molecules that can be degraded by antigen-processing cells into many different peptides. Among individuals with different MHC proteins (i.e., different HLA types), therefore, different peptides may bind most efficiently to a given individual’s repertoire of MHC proteins. For example, if a protein contains epitopes A and B, and individuals X and Y have different HLA types, then only epitope A may be presented by antigen-presenting cells in individual X and only epitope B may be presented by the corresponding cells in individual Y. Some individuals may have an MHC type that will not bind either of these epitopes; these individuals will not recognize this protein at all. This point means that immunizing a human population against a T-cell epitope (i.e., eliciting a cellular immune response at a population level) is much more difficult than eliciting a B-cell response, because B cells recognize native antigens, which are the same for everybody. Given the huge diversity of MHC proteins in the human population, development of vaccines that will induce general T-cell immunity represents an extremely formidable challenge. It is not a coincidence that almost all successful vaccines generated to date have depended largely on B-cell responses (i.e., antibodies) rather than T-cell responses.

A third type of lymphocyte, termed natural killer (NK) cells, plays a key role in triggering innate immunity (Box 10-8).

The mechanism by which NK cells are triggered to kill has only recently been elucidated. Although they do not have antigen receptors, NK cells have surface receptors that inhibit their killing function. These inhibitory receptors, termed killer inhibitory receptors (KIRs), recognize abnormal levels of MHC Class I molecules on all other nucleated cells in the body. Thus, if the target cell expresses MHC Class I to a normal degree, the NK cell is not triggered and the target cell is not killed. Conversely, down-regulation of MHC Class I molecule expression (which is common in some virally-infected cells and some tumor cells) removes the inhibition of the NK cell, so that the target cell is killed.

This mechanism appears to be an important component of host defense against certain viral infections.⁴, ⁵ Many viruses interfere with expression of MHC molecules by the host cell (possibly as a means of evading cytotoxic CD8⁺ T-cells, which require MHC Class I molecules to be expressed on the target cell, as discussed previously). Thus, NK cells help prevent the virus from getting away with this trick. This mechanism elegantly explains the function of NK cells.

After this understanding was reached, in somewhat of a surprise, stimulatory NK receptors were discovered by researchers. The function of NK cells is regulated by the balance of signals coming from the KIR and the stimulatory receptors. It has been hypothesized that stimulatory receptors on NK cells may be important in situations in which MHC proteins are over-expressed, which is uncommon in infectious diseases but may occur in neoplastic or pre-neoplastic conditions.

Macrophages and dendritic cells have been described in Box 10-2. How do they recognize antigens? In contrast to the specific recognition of particular antigens by T-cells, as described previously, macrophages and dendritic cells recognize molecules common to multiple pathogens, or structures derived from such antigens. For this reason, antigen receptors on these cells are referred to as pattern recognition receptors (Box 10-9).⁶