Er

FIGURE 6-19 The functions of class II MHC-associated invariant chain and HLA-DM. Class II molecules with bound invariant chain, or CLIP, are transported into vesicles, where the I is degraded and the remaining CLIP is removed by the action of DM. Antigenic peptides generated in the vesicles are then able to bind to the class II molecules. Another class II-like protein, called HLA-DO, may regulate the DM-catalyzed removal of CLIP. CIIV, class II vesicle.

association, including the enzymes that degrade protein antigens, the class II molecules, and two molecules involved in peptide loading of class II molecules, the invariant chain and HLA-DM, whose functions are described later.

Biosynthesis and Transport of Class II MHC Molecules to Endosomes

Class II MHC molecules are synthesized in the ER and transported to endosomes with an associated protein, the invariant chain (I), which occupies the peptide-binding clefts of the newly synthesized class II molecules (Fig. 6-19). The a and P chains of class II MHC molecules are coordinately synthesized and associate with each other in the ER. Nascent class II dimers are structurally unstable, and their folding and assembly are aided by ER-resident chaperones, such as calnexin. A protein called the invariant chain (Ii) promotes folding and assembly of class II molecules and directs newly formed class II molecules to the late endosomes and lysosomes where internalized proteins have been proteolytically degraded into peptides. The Ii is a trimer composed of three 30-kD subunits, three of which bind one newly synthesized class II aP heterodimer in a way that blocks the peptide-binding cleft and prevents it from accepting peptides. As a result, class II MHC molecules cannot bind and present peptides they encounter in the ER, leaving such peptides to associate with class I molecules (described before). The class II MHC molecules are transported in exocytic vesicles toward the cell surface. During this passage, the vesicles taking class II molecules out of the ER meet and fuse with the endocytic vesicles containing internalized and processed antigens. Thus, class II

molecules encounter antigenic peptides that have been generated by proteolysis of endocytosed proteins, and the peptide-MHC association occurs in the vesicles.

Association of Processed Peptides with Class II MHC Molecules in Vesicles

Within the endosomal vesicles, the Ii dissociates from class II MHC molecules by the combined action of proteolytic enzymes and the HLA-DM molecule, and antigenic pep-tides are then able to bind to the available peptide-binding clefts of the class II molecules (see Fig. 6-19). Because the Ii blocks access to the peptide-binding cleft of a class II MHC molecule, it must be removed before complexes of peptide and class II molecules can form. The same proteolytic enzymes, such as cathepsins, that generate peptides from internalized proteins also act on the Ii, degrading it and leaving only a 24-amino acid remnant called class II-associated invariant chain peptide (CLIP), which sits in the peptide-binding cleft in the same way that other peptides bind to class II MHC molecules. Next, CLIP has to be removed so that the cleft becomes accessible to antigenic peptides produced from extracellular proteins. This removal is accomplished by the action of a molecule called HLA-DM (or H-2M in the mouse), which is encoded within the MHC, has a structure similar to that of class II MHC molecules, and colocalizes with class II molecules in the MIIC endosomal compartment. HLA-DM molecules differ from class II MHC molecules in several respects; they are not polymorphic, and they are not expressed on the cell surface. HLA-DM acts as a peptide exchanger, facilitating the removal of CLIP and the addition of other peptides to class II MHC molecules.

Antigen Cross- T cell capture presentation response

FIGURE 6-20 Cross-presentation of antigens to CD8+ T cells. Cells infected with intracellular microbes, such as viruses, are ingested by dendritic cells, and the antigens of the infectious microbes are processed and presented in association with class I MHC molecules to CD8+ T cells. Thus, dendritic cells are able to present endocytosed vesicular antigens by the class I pathway. Note that the same cross-presenting APCs may display class II MHC-associated antigens from the microbe for recognition by CD4+ helper T cells.

FIGURE 6-20 Cross-presentation of antigens to CD8+ T cells. Cells infected with intracellular microbes, such as viruses, are ingested by dendritic cells, and the antigens of the infectious microbes are processed and presented in association with class I MHC molecules to CD8+ T cells. Thus, dendritic cells are able to present endocytosed vesicular antigens by the class I pathway. Note that the same cross-presenting APCs may display class II MHC-associated antigens from the microbe for recognition by CD4+ helper T cells.

Once CLIP is removed, peptides generated by proteolysis of internalized protein antigens are able to bind to class II MHC molecules. The HLA-DM molecule may accelerate the rate of peptide binding to class II molecules. Because the ends of the class II MHC peptide-binding cleft are open, large peptides may bind and are then "trimmed" by proteolytic enzymes to the appropriate size for T cell recognition. As a result, the peptides that are actually presented attached to cell surface class II MHC molecules are usually 10 to 30 amino acids long and typically have been generated by this trimming step.

Expression of Peptide-Class II MHC Complexes on the Cell Surface

Class II MHC molecules are stabilized by the bound peptides, and the stable peptide-class II complexes are delivered to the surface of the APC, where they are displayed for recognition by CD4+ T cells. The transport of class II MHC-peptide complexes to the cell surface is believed to occur by fusion of vesiculotubular extensions from the lysosome with the plasma membrane, resulting in delivery of the loaded class II MHC complexes to the cell surface. Once expressed on the APC surface, the peptide-class II complexes are recognized by peptide antigen-specific CD4+ T cells, with the CD4 coreceptor playing an essential role by binding to nonpolymorphic regions of the class II molecule. Interestingly, whereas peptide-loaded class II molecules traffic from the late endosomes and lysosomes to the cell surface, other molecules involved in antigen presentation, such as DM, stay in the vesicles and are not expressed in the plasma membrane. The mechanism of this selective traffic is unknown.

Cross-Presentation

Some dendritic cells have the ability to capture and to ingest virus-infected cells or tumor cells and present the viral or tumor antigens to naive CD8+ T lymphocytes (Fig. 6-20). In this pathway, the ingested antigens are transported from vesicles to the cytosol, from where peptides enter the class I pathway. As we discussed before, most ingested proteins do not enter the cytosolic class I pathway of antigen presentation. This permissiveness for protein traffic from endosomal vesicles to the cytosol is unique to dendritic cells. (At the same time, the dendritic cells can present class II MHC-associated peptides generated in the vesicles to CD4+ helper T cells, which are often required to induce full responses of CD8+ cells [see Chapter 9].) This process is called cross-presentation, or cross-priming, to indicate that one cell type (the dendritic cell) can present antigens from another cell (the virus-infected or tumor cell) and prime, or activate, T cells specific for these antigens. The process of cross-presentation seems to violate the rule that vesicular antigens are presented bound to class II MHC molecules and cytosolic antigens with class I. However, it is a normal function of dendritic cells, because of which dendritic cells can activate naive CD8+ T cells even if the antigens are produced in cells incapable of presenting the antigen, as long as the antigen-containing cells can be internalized by dendritic cells into vesicles.

Cross-presentation involves the fusion of phagosomes containing the ingested antigens with the ER. Ingested proteins are then translocated from the ER to the cytosol by poorly defined pathways that are reminiscent of ER-associated degradation. The proteins that were initially internalized in the phagosome are therefore delivered to the compartment (the cytosol) where proteolysis for the class I pathway normally occurs. These phagocy-tosed proteins thus undergo proteasomal degradation, and peptides derived from them are transported by TAP back into the ER, where they are assembled with newly synthesized class I MHC molecules as described for the conventional class I pathway.

Physiologic Significance of MHC-Associated Antigen Presentation

So far, we have discussed the specificity of CD4+ and CD8+ T lymphocytes for MHC-associated foreign protein antigens and the mechanisms by which complexes of peptides and MHC molecules are produced. In this

Antigen uptake or synthesis

Antigen presentation

T cell effector functions

Class I MHC-associated presentation of cytosolic antigen to cytotoxic T lymphocytes

Class I MHC-associated presentation of cytosolic antigen to cytotoxic T lymphocytes

FIGURE 6-21 Presentation of extracellular and cytosolic antigens to different subsets of T cells. A, Cytosolic antigens are presented by nucleated cells to CD8+ CTLs, which kill (lyse) the antigen-expressing cells. B, Extracellular antigens are presented by macrophages or B lymphocytes to CD4+ helper T lymphocytes, which activate the macrophages or B cells and eliminate the extracellular antigens.

Antigen specific B cell

FIGURE 6-21 Presentation of extracellular and cytosolic antigens to different subsets of T cells. A, Cytosolic antigens are presented by nucleated cells to CD8+ CTLs, which kill (lyse) the antigen-expressing cells. B, Extracellular antigens are presented by macrophages or B lymphocytes to CD4+ helper T lymphocytes, which activate the macrophages or B cells and eliminate the extracellular antigens.

section, we consider how the central role of the MHC in antigen presentation influences the nature of T cell responses to different antigens and the types of antigens that T cells recognize.

Nature of T Cell Responses

The presentation of cytosolic versus vesicular proteins by the class I or class II MHC pathways, respectively, determines which subsets of T cells will respond to antigens found in these two pools of proteins and is intimately linked to the functions of these T cells (Fig. 6-21). Endog-enously synthesized antigens, such as viral and tumor proteins, are located in the cytoplasm and are recognized by class I-restricted CD8+ CTLs, which kill the cells producing the intracellular antigens. Conversely, extracellular antigens usually end up in endosomal vesicles and activate class II-restricted CD4+ T cells because vesicular proteins are processed into class II-binding peptides. CD4+ T cells function as helpers to stimulate B cells to produce antibodies and macrophages to enhance their phagocytic activity, both mechanisms that serve to eliminate extracellular antigens. Thus, antigens from microbes that reside in different cellular locations selectively stimulate the T cell responses that are most effective at eliminating that type of microbe. This is especially important because the antigen receptors of CTLs and helper T cells cannot distinguish between extracellular and intracellu-lar microbes. By segregating peptides derived from these types of microbes, the MHC molecules guide CD4+ and CD8+ subsets of T cells to respond to the microbes that each subset can best combat.

Immunogenicity of Protein Antigens

MHC molecules determine the immunogenicity of protein antigens in two related ways.

• The epitopes of complex proteins that elicit the strongest T cell responses are the peptides that are generated by proteolysis in APCs and bind most avidly to MHC molecules. If an individual is immunized with a protein antigen, in many instances the majority of the responding T cells are specific for only one or a few linear amino acid sequences of the antigen. These are called the immunodominant epitopes or determinants. The proteases involved in antigen processing produce a variety of peptides from natural proteins, and only some of these peptides possess the characteristics that enable them to bind to the MHC molecules present in each individual (Fig. 6-22). It is important to define the structural basis of immunodominance because this may permit the efficient manipulation of the immune system with synthetic peptides. An application of such

Internalization of antigen into APC

Multiple possible epitopes

Antigen processing

Processing generates multiple peptides, one of which can bind to class II allele

T cells respond to immunodominant peptide epitope

Multiple possible epitopes

Immunodominant ^epitope

FIGURE 6-22 Immunodominance of peptides. Protein antigens are processed to generate multiple peptides; immunodominant peptides are the ones that bind best to the available class I and class II MHC molecules. The illustration shows an extracellular antigen generating a class II-binding peptide, but this also applies to peptides of cytosolic antigens that are presented by class I MHC molecules.

CD4 T cell

FIGURE 6-22 Immunodominance of peptides. Protein antigens are processed to generate multiple peptides; immunodominant peptides are the ones that bind best to the available class I and class II MHC molecules. The illustration shows an extracellular antigen generating a class II-binding peptide, but this also applies to peptides of cytosolic antigens that are presented by class I MHC molecules.

knowledge is the design of vaccines. For example, a viral protein could be analyzed for the presence of amino acid sequences that would form typical immu-nodominant epitopes capable of binding to MHC molecules with high affinity. Synthetic peptides containing these epitopes may be effective vaccines for eliciting T cell responses against the viral peptide expressed on an infected cell. Conversely, some individuals do not respond to vaccines (such as hepatitis B virus surface antigen vaccine), presumably because their HLA molecules cannot bind and display the major peptides of the antigen.

• The expression of particular class II MHC alleles in an individual determines the ability of that individual to respond to particular antigens. As discussed earlier, the immune response (Ir) genes that control antibody responses are the class II MHC genes. They influence immune responsiveness because various allelic class II MHC molecules differ in their ability to bind different antigenic peptides and therefore to stimulate specific helper T cells.

synthesized CD1 molecules pick up cellular lipids and carry these to the cell surface. From here, the CDl-lipid complexes are endocytosed into endosomes or lysosomes, where lipids that have been ingested from the external environment are captured and the new CDl-lipid complexes are returned to the cell surface. Thus, CD1 molecules acquire endocytosed lipid antigens during recycling and present these antigens without apparent processing. The NKT cells that recognize the lipid antigens may play a role in defense against microbes, especially mycobacte-ria (which are rich in lipid components).

y8 T cells are a small population of T cells that express antigen receptor proteins that are similar but not identical to those of CD4+ and CD8+ T cells (see Chapter 10). y8 T cells recognize many different types of antigens, including some proteins and lipids, as well as small phos-phorylated molecules and alkyl amines. These antigens are not displayed by MHC molecules, and y8 cells are not MHC restricted. It is not known if a particular cell type or antigen display system is required for presenting antigens to these cells.

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