Info

Expression of molecules involved in T cell activation: B7, ICAM-1, IL-12

— or low

++

Class II MHC molecules

Half-life

Number of surface molecules

~10 hr ~106

>100 hr ~7 x 106

FIGURE 6-5 Role of dendritic cells in antigen capture and presentation. Immature dendritic cells in the skin (Langerhans cells) or dermis (dermal DCs) capture antigens that enter through the epidermis and transport the antigens to regional lymph nodes. During this migration, the dendritic cells mature and become efficient APCs. The table summarizes some of the changes during dendritic cell maturation that are important in the functions of these cells.

responses to protein antigens requires the presence of DCs to capture and to present the antigens to the T cells. This was first shown for CD4+ T cell responses but is now known to be true for CD8+ T cells as well.

Several properties of DCs make them the most efficient APCs for initiation of primary T cell responses.

• DCs are strategically located at the common sites of entry of microbes and foreign antigens (in epithelia) and in tissues that may be colonized by microbes.

• DCs express receptors that enable them to capture microbes and to respond to microbes.

• These cells migrate from epithelia and tissues preferentially to the T cell zones of lymph nodes, through which naive T lymphocytes circulate, searching for foreign antigens.

• Mature DCs express high levels of peptide-MHC complexes, costimulators, and cytokines, all of which are needed to activate naive T lymphocytes.

DCs can ingest infected cells and present antigens from these cells to CD8+ T lymphocytes. DCs are the best APCs to induce the primary responses of CD8+ T cells, but this poses a special problem because the antigens these lymphocytes recognize may be produced in any cell type infected by a virus, not necessarily DCs. Some specialized DCs have the ability to ingest virus-infected cells or cellular fragments and present antigens from these cells to CD8+ T lymphocytes. This process is called cross-presentation, or cross-priming, and is described later in the chapter.

Functions of Other Antigen-Presenting Cells

Although DCs have a critical role in initiating primary T cell responses, other cell types are also important APCs in different situations (see Fig. 6-2 and Table 6-2).

• In cell-mediated immune responses, macrophages present the antigens of phagocytosed microbes to effector T cells, which respond by activating the macrophages to kill the microbes. This process is central to cell-mediated immunity and delayed-type hypersensitivity (see Chapter 10). Circulating monocytes are able to migrate to any site of infection and inflammation, where they differentiate into macrophages and phagocytose and destroy microbes. CD4+ T cells recognize microbial antigens being presented by the macrophages and provide signals that enhance the microbi-cidal activities of these macrophages.

• In humoral immune responses, B lymphocytes internalize protein antigens and present peptides derived from these proteins to helper T cells. This antigen-presenting function of B cells is essential for helper T cell-dependent antibody production (see Chapter 11).

• All nucleated cells can present peptides, derived from cytosolic protein antigens, to CD8+ T lymphocytes. All nucleated cells are susceptible to viral infections and cancer-causing mutations. Therefore, it is important that the immune system be able to recognize cytosolic antigens, such as viral antigens and mutated proteins, in any cell type. CD8+ CTLs are the cell population that recognize these antigens and eliminate the cells in which the antigens are produced. Phagocytosed microbes may also be recognized by CD8+ CTLs if these microbes or their antigens escape from phagocytic vesicles into the cytosol.

• Vascular endothelial cells in humans express class II MHC molecules and may present antigens to blood T cells that have become adherent to the vessel wall. This may contribute to the recruitment and activation of effector T cells in cell-mediated immune reactions (see Chapter 10). Endothelial cells in grafts are also targets of T cells reacting against graft antigens (see Chapter 16). Various epithelial and mesenchymal cells may express class II MHC molecules in response to the cytokine IFN-y. The physiologic significance of antigen presentation by these cell populations is unclear. Because most of them do not express costimulators and are not efficient at processing proteins into MHC-binding peptides, it is unlikely that they contribute significantly to the majority of T cell responses. Thymic epithelial cells constitutively express MHC molecules and play a critical role in presenting peptide-MHC complexes to maturing T cells in the thymus as part of the selection processes that shape the repertoire of T cell specificities (see Chapter 8).

THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) Discovery of the MHC

The discovery of the fundamental role of the MHC in antigen recognition by CD4+ and CD8+ T cells has revolutionized the field of immunology and paved the way for our current understanding of the activation and functions of lymphocytes.

The Mouse MHC (H-2 Complex)

The MHC was discovered from studies of tissue transplantation, well before the structure and function of MHC molecules were elucidated. It was known that tissues, such as skin, exchanged between nonidentical animals are rejected, whereas the same grafts between identical twins are accepted. This result showed that inherited genes must be involved in the process of tissue rejection. In the 1940s, to analyze the genetic basis of graft rejection, George Snell and colleagues produced inbred mouse strains by repetitive mating of siblings. Inbred mice are homozygous at every genetic locus (i.e., they express only one allele of every gene, even the polymorphic genes), and every mouse of an inbred strain is genetically identical (syngeneic) to every other mouse of the same strain (i.e., they all express the same alleles). Different strains may express different alleles and are said to be allogeneic to one another. By breeding congenic strains of mice that rejected grafts from other strains but were identical for all other genes, these investigators showed that a single genetic region is primarily responsible for rapid rejection of tissue grafts, and this region was called the major histocompatibility locus (histo, tissue). The particular locus that was identified in mice by Snell's group was linked to a gene on chromosome 17 encoding a blood group antigen called antigen II, and therefore this region was named histocompatibility-2, or simply H-2. Initially, this locus was thought to contain a single gene that controlled tissue compatibility. However, occasional recombination events occurred within the H-2 locus during interbreeding of different strains, indicating that it actually contained several different but closely linked genes, many of which were involved in graft rejection. The genetic region that controlled graft rejection and contained several linked genes was named the major histocompatibility complex. Although not known at the time of Snell's experiments, transplant rejection is in large part a T cell-mediated process (see Chapter 16), and therefore it is not surprising that there is a relationship between MHC genes, which encode the peptide-binding MHC molecules that T cells recognize, and graft rejection.

The Human MHC (HA)

The human MHC was discovered by searching for cell surface molecules in one individual that would be recognized as foreign by another individual. This task became feasible when Jean Dausset, Jan van Rood, and their colleagues discovered that individuals who had received multiple blood transfusions and patients who had received kidney transplants contained antibodies that recognized cells from the blood or kidney donors and multiparous women had circulating antibodies that recognized paternal cells. The proteins recognized by these antibodies were called human leukocyte antigens (HLA) (leukocyte because the antibodies were tested by binding to the leukocytes of other individuals, and antigens because the molecules were recognized by antibodies). Subsequent analyses have shown that as in mice, the inheritance of particular HLA alleles is a major determinant of graft acceptance or rejection (see Chapter 16). Biochemical studies gave the satisfying result that the mouse H-2 proteins and the HLA proteins had essentially identical structures. From these results came the conclusion that genes that determine the fate of grafted tissues are present in all mammalian species and are homologous to the H-2 genes first identified in mice; these are called MHC genes. Other polymorphic genes that contribute to graft rejection to a lesser degree are called minor histocompatibility genes; we will return to these in Chapter 16, when we discuss transplantation immunology.

Immune Response Genes

For almost 20 years after the MHC was discovered, its only documented role was in graft rejection. This was a puzzle to immunologists because transplantation is not a natural phenomenon, and there was no reason that a set of genes should be preserved through evolution if the only function of the genes was to control the rejection of foreign tissue grafts. In the 1960s and 1970s, it was discovered that MHC genes are of fundamental importance for all immune responses to protein antigens. Baruj Benacerraf, Hugh McDevitt, and their colleagues found that inbred strains of guinea pigs and mice differed in their ability to make antibodies against some simple synthetic polypeptides, and responsiveness was inherited as a dominant mendelian trait. The relevant genes were called immune response (Ir) genes, and they were all found to map to the MHC. We now know that Ir genes are, in fact, MHC genes that encode MHC molecules that differ in their ability to bind and display peptides derived from various protein antigens. Responder strains, which can mount immune responses to a particular polypeptide antigen, inherit MHC alleles whose products can bind peptides derived from these antigens, forming peptide-MHC complexes that can be recognized by helper T cells. These T cells then help B cells to produce antibodies. Nonresponder strains express MHC molecules that are not capable of binding peptides derived from the poly-peptide antigen, and therefore these strains cannot generate helper T cells or antibodies specific for the antigen. It was also later found that many autoimmune diseases were associated with the inheritance of particular MHC alleles, firmly placing these genes at the center of the mechanisms that control immune responses. Such studies provided the impetus for more detailed analyses of MHC genes and proteins.

The Phenomenon of MHC Restriction

The formal proof that the MHC is involved in antigen recognition by T cells came from the experimental demonstration of MHC restriction by Rolf Zinkernagel and Peter Doherty. In their classic study, reported in 1974, these investigators examined the recognition of virus-infected cells by virus-specific CTLs in inbred mice. If a mouse is infected with a virus, CD8+ CTLs specific for the virus develop in the animal. These CTLs recognize and kill virus-infected cells only if the infected cells express alleles of MHC molecules that are expressed in the animal in which the CTLs were generated (Fig. 6-6). By use of MHC congenic strains of mice (mice that were identical at every genetic locus except the MHC), it was shown that the CTLs and the infected target cell must be derived from mice that share a class I MHC allele. Thus, the recognition of antigens by CD8+ CTLs is restricted by self class I MHC alleles. Subsequent experiments demonstrated that responses of CD4+ helper T lymphocytes to antigens are self class II MHC restricted.

We continue our discussion of the MHC by describing the properties of the genes and then the proteins, and we conclude by describing how these proteins bind and display foreign antigens.

MHC Genes

The MHC locus contains two types of polymorphic MHC genes, the class I and class II MHC genes, which encode two groups of structurally distinct but homologous proteins, and other nonpolymorphic genes whose products are involved in antigen presentation (Fig. 6-7). Class I MHC molecules display peptides to and are recognized by CD8+ T cells, and class II MHC molecules display pep-tides to CD4+ T cells; each of these T cell types serves different functions in protection against microbes.

MHC genes are codominantly expressed in each individual. In other words, for a given MHC gene, each

Infect strain A mouse with lymphocytic choriomeningitis virus (LCMV)

Strain A

Strain B

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