Major Histocompatibility Complex

The major histocompatibility complex (MHC), also designated HLA for "human leukocyte antigen," is expressed on the surfaces of a large variety of cells and is translated from a region of highly polymorphic genes.1-3 A number of very elegant studies in mice led to the MHC's being recognized as responsible for immune responses, and the region to which these genes mapped was called the Ir region for immune response genes.35 These genes were subsequently shown to be necessary for activation of helper T lymphocytes, which are necessary for the production of T-dependent antibody. Later it was recognized that T cells do not recognize free or soluble antigens, but rather peptides of antigens that are bound to MHC. The MHC has two types of gene products: class I and class II. Class I consists of a transmembrane heavy chain, which is complexed to soluble P2-microglobulin. All cells, with the sole exception of erythrocytes, express class I. Class II is composed of an a and P transmembrane chain and is predominantly expressed on antigen-presenting cells. Both classes of MHC contain a "groove" in which processed peptide binds.36

MHC and Antigen Presentation

The manner in which MHC class I and II molecules are synthesized and assembled determines which types of pathogenic peptides can be bound by them (Fig. 11-4). Some of the

Cross-presentation pathway

Apoptotic bleb with microbial antigen

Class I endogenous pathway

Class II exogenous pathway

Cross-presentation pathway

Apoptotic bleb with microbial antigen

Class I endogenous pathway

Class II exogenous pathway

1. Viral proteins

FIGURE 11-4 The pathways for processing antigens for presentation with major histocompatibility complex (MHC) molecules. Intracellular antigens (left), such as those derived from viruses, are degraded in the proteosome (1); complexed with TAP (transporter associated with antigen processing) (2); exported from the Golgi as an MHC class I antigen pep-tide complex (3), which are then expressed on the outer plasma membrane (4). Extracellular antigens (right) are phagocytosed or endocytosed (1), and degraded in lysosomes (2). Class II MHC molecules are synthesized and leave the Golgi in vesicles

(3) that fuse with late endosomes containing antigenic peptides allowing the peptides to complex with MHC class II proteins (4); and the peptide-MHC class II complexes move to the plasma membrane (5). Cross-presentation (center) occurs when exogenous antigens, usually in a complex with apoptotic debris, are internalized by phagocytosis or endocytosis (1); move through a lysosomal compartment (2) to the proteosome (3). Thereafter, the degraded peptides are bound to TAP

(4) for movement into the endoplasmic reticulum (ER) and Golgi for complex-ing with MHC class I proteins for transport and expression at the plasma membrane (5).

1. Viral proteins proteins synthesized endogenously by the host cell's ribosomes, as is the case for viral proteins, are normally degraded in the constitutive proteosome, an organelle designed to break down denatured or nonessential proteins to peptides. In the case of an intracellular infection, "immunoproteosomes" are induced by IFNy and replace some of the constitutive proteosomes. The two types of proteosomes have distinctive proteolytic specificities and thereby enhance the repertoire of available peptides being presented to T cells.37 Some of these peptides are transported into the endoplasmic reticulum (ER) by the TAPs (transporters of antigen presentation), where peptides usually of 8 to 9 amino acids in length are loaded into the groove of nascently synthesized class I molecules. Finally, the MHC class I-peptide complex is transported through the Golgi complex and exocy-tosed to the cell surface.38 Nonself peptides (foreign, e.g., viral, peptides) complexed with the MHC will be recognized. The T cells that recognize foreign peptides complexed to class I MHC activate cytotoxic CD8+ T cells, which specifically lyse the virus-infected cell (Fig. 11-5). Because, potentially, any nucleated cell could be infected with a virus, all cells in the body, except erythrocytes, express class I MHC and are thereby scrutinized by T cells for evidence of a foreign peptide. Host peptides are also presented by class I MHC, but are generally not recognized, since self-recognizing T cells are eliminated in the thymus and never circulate. Those T cells reacting with host peptides with low affinity can be removed in the periphery.

A different pathway of antigen presentation is followed for molecules synthesized outside the cell, such as those from the extracellular pathogen Streptococcus pneumoniae. In this case, antigen-presenting cells, which are primarily monocytes, macrophages, dendritic cells, and B lymphocytes, sample the extracellular milieu. This sampling might take the form of phagocytosis of particles, such as bacteria, by monocytes or macrophages, or endocytosis and pinocytosis of soluble samples by any of the antigen-presenting cells. The larger antigens are proteolytically degraded, and eventually the derived pep-tides end up in an endocytic vesicle, which contains class II MHC. The class II MHC was previously synthesized in the ER and then packaged in an endosomal compartment by the Golgi complex of the antigen-presenting cell. In an elegant process, antigenic peptides bind to the class II MHC and then are expressed on the surface of the antigen-presenting cell.39

Es330 Wiring

FIGURE 11-5 Responses of T-lymphocyte subsets to infectious agents. CD8+ T cells respond to antigens from intracellular pathogens, such as viruses, presented with class I major histocompatibility complex (MHC) molecules. These cytolytic CD8+ T cells lyse infected target cells by release of toxic proteins (perforin, granzyme) and by induction of apoptosis (programmed cell death) by engagement of Fas. CD4+ T cells can be directed to develop into T helper 1 (Th1) cells that stimulate macrophage killing of intracellular pathogens (cell-mediated immunity) or T helper 2 (Th2) cells that produce antibody or enhance eosinophil- and mast cell-mediated responses to helminthic parasites. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-y, interferon-y; IL-4, etc., interleukins; TNF-a, tumor necrosis factor-a.

FIGURE 11-5 Responses of T-lymphocyte subsets to infectious agents. CD8+ T cells respond to antigens from intracellular pathogens, such as viruses, presented with class I major histocompatibility complex (MHC) molecules. These cytolytic CD8+ T cells lyse infected target cells by release of toxic proteins (perforin, granzyme) and by induction of apoptosis (programmed cell death) by engagement of Fas. CD4+ T cells can be directed to develop into T helper 1 (Th1) cells that stimulate macrophage killing of intracellular pathogens (cell-mediated immunity) or T helper 2 (Th2) cells that produce antibody or enhance eosinophil- and mast cell-mediated responses to helminthic parasites. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-y, interferon-y; IL-4, etc., interleukins; TNF-a, tumor necrosis factor-a.

It is the CD4+ helper T cells that recognize antigens bound to class II MHC. Again, as in the case of peptides expressed with class I MHC, the majority of peptides bound to class II MHC will be host-derived, but there will no T cells to react with the host peptides because those T cells will have been previously eliminated in the thymus by negative selection.

Two addenda to the classic distinction of class I and class II pathways of antigen presentation are necessary. First, although class I and class II MHC are efficient at presenting peptide antigens, lipid and glycolipid antigens, such as those derived from Mycobacterium species, are presented by CD1 proteins. Distinguishing features of the CD1 proteins are that they have limited diversity and their cytoplasmic tails target them to distinct endosomal compartments for the potential loading of lipids from different intracellular pathogens.40 The second addendum to the class I/class II paradigm is the concept of "cross presentation." Cross presentation occurs when an antigen made outside the antigen-presenting cell is internalized by endocytosis or phagocytosis and instead of com-plexing with class II MHC, it is routed to a compartment containing class I MHC (see Fig. 11-4).41,42 At least one pathway involves digestion in the proteosome and complexing of the peptide with class I in the ER in the usual manner. Antigenic material that is from apoptotic infected cells or complexed with heat shock proteins from stressed or necrotic cells is favored for cross presentation.43,44

Reason for MHC Diversity

In humans, the MHC, or HLA, genes are located on chromosome 6. There are three major polymorphic genes for class I (A, B, and C).1-3 Because these genes are codominant, a cell will commonly express six different MHC class I molecules (three from each parent). The class II polymorphic genes are DR, DP, and DQ, all composed of a and P chains. Many individuals also have a gene for an extra DR P chain, either of which can combine with the DR a chain. Thus, class II MHC heterozygous individuals can express eight different polymorphic alleles (four from each parent). The reason an individual needs so many possible MHC proteins is to be able to generate a diverse array of grooves in the MHC molecules, such that there would be a groove to fit at least some antigens from each potential pathogen. Although this strategy works most of the time, there are some MHC types that have been linked to susceptibility to certain pathogens (see Tables 8-2 and 8-3), or to an increased frequency of certain immunologic diseases. The reason the human species maintains such a large and diverse MHC repertoire likely relates to the capacity to respond to numerous and diverse pathogens. Although an evolving pathogen might find a susceptible MHC-"deficient" type in a few individuals, others in the population will have different and functional MHC types and therefore will not be susceptible to the altered pathogen.

Costimulation

Activation of T cells is not accomplished solely by the TCR complex binding to antigen in the cleft of the MHC. If this were so, then self-reacting T cells that escape negative selection in the thymus could induce autoimmune responses. Control of T-cell activation is in part regulated by a number of accessory molecules that must be engaged in order for the T cell to respond. These regulatory molecules are called "costimulatory" molecules.45 While the presence of CD28 on T cells is constitutive, its ligands on the antigen-presenting cell, CD80 and CD86 (previously known as B7.1 and B7.2), are induced when innate immunity recognizes the PAMPs.46 Ligation of lymphocyte CD40 ligand (CD154) by CD40 on the antigen-presenting cell stimulates the production of cytokines and allows for activation of integrins, which provide stable adhesion between the two cells and thereby enhances the possibility of stimulating an immune response.47

Complement C3 fragment C3dg can effect another type of costimulation. Antigens can directly interact with a B cell's immunoglobulin receptor and trigger a proliferative response. If, however, the antigen is first recognized as foreign by the complement system and tagged with C3b, which is processed to C3dg, the threshold amount of antigen needed to evoke a B-cell response is lowered by a factor of 10,000.31 One reason C3dg-tagged antigen is efficient is that the CD21/CD19 signaling complex is costimulated with the antigen receptor. CD21 is the receptor for C3dg, while CD19 gives positive signaling to B cells.

The ability of the innate immune system to appropriately recognize pathogens and upregulate costimulatory molecules on antigen-presenting cells provides an important control over the immune system: Interaction between a peripheral lymphocyte that binds a self-antigen on an antigen-presenting cell that lacks costimulatory molecules leads to functional paralysis of the lymphocyte, or tolerance (vide infra).48

Anergy and Tolerance

Anergy is a state of global immunologic unresponsiveness, which can be remedied by removal or addition of one or more factors.1-3 For instance, an abundance of IL-10 leads to down-regulation of molecules on antigen-presenting cells such that they are unable to activate T cells to respond in the presence of specific antigen. Removal of IL-10 from the system leads to restoration of responsiveness.

Tolerance is different from a state of anergy and occurs when the immune system is unable to respond to specific antigens.1-3 Therefore, all other immune responses would occur normally except for the response to the specific antigen to which the organism has been made tolerant. There are multiple steps in the immune response that are susceptible to tolerance, and these steps are used as a safeguard to prevent the immune system from reacting against itself, so-called auto-immunity. During development, most T cells in the periphery are tolerant to self-antigens because those cells avidly reacting with self-antigens are eliminated in the thymus during "negative selection." Immature B cells that react with multivalent self-antigens are destroyed by programmed cell death, or apop-tosis, a process referred to as "clonal deletion." Immature B cells that react with soluble self-antigens are rendered inactive by the downregulation of their surface IgM and their signaling potential. Finally, when CD4+ T cells bind an antigen-presenting cell expressing antigen-MHC but no costimulatory molecules, these T cells will be rendered tolerant. Tolerance can be induced experimentally in animals and has been shown to be partially dependent on the form and the route of administration of the antigen. High doses of antigen, orally administered antigen, or repetitive doses of low concentrations of antigen may all lead to tolerance. Successful vaccine strategies must avoid inducing tolerance.

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