S

Endocytic vesicle

Endosome

Lysosome

Endosome

Lysosome

FIGURE 6-17 The class II MHC pathway of antigen presentation. The stages in the processing of extracellular antigens are described in the text. CLIP, class Il-associated invariant chain peptide; ER, endoplasmic reticulum; Ij, invariant chain.

includes calnexin, calreticulin, and the oxidoreductase Erp57, all of which contribute to class I assembly and loading. Peptides that enter the ER through TAP and peptides produced in the ER, such as signal peptides, are often trimmed to the appropriate size for MHC binding by the ER-resident aminopeptidase ERAP. The peptide is then able to bind to the cleft of the adjacent class I molecule. Once class I MHC molecules are loaded with peptide, they no longer have an affinity for tapasin, so the peptide-class I complex is released from tapasin, and it is able to exit the ER and be transported to the cell surface. In the absence of bound peptide, many of the newly formed a chain-P2-microglobulin dimers are unstable and cannot be transported efficiently from the ER to the Golgi. These misfolded empty class I MHC complexes are transported into the cytosol and are degraded in proteasomes.

Peptides transported into the ER preferentially bind to class I but not class II MHC molecules, for two reasons. First, newly synthesized class I molecules are attached to the luminal aspect of the TAP complex, and they capture peptides rapidly as the peptides are transported into the ER by the TAP. Second, as discussed later, in the ER, the peptide-binding clefts of newly synthesized class II molecules are blocked by the associated Ii.

Surface Expression of Peptide-Class I MHC Complexes

Class I MHC molecules with bound peptides are structurally stable and are expressed on the cell surface. Stable peptide-class I MHC complexes that were produced in the ER move through the Golgi complex and are transported to the cell surface by exocytic vesicles. Once expressed on the cell surface, the peptide-class I complexes may be recognized by peptide antigen-specific CD8+ T cells, with the CD8 coreceptor playing an essential role by binding to nonpolymorphic regions of the class I molecule. In later chapters, we will return to a discussion of the role of class I-restricted CTLs in protective immunity. Several viruses have evolved mechanisms that interfere with class I assembly and peptide loading, emphasizing the importance of this pathway for antiviral immunity (see Chapter 15).

The Class II MHC Pathway for Processing and Presentation of Vesicular Proteins

The generation of class II MHC-associated peptides from endocytosed antigens involves the proteolytic degradation of internalized proteins in endocytic vesicles and the binding of peptides to class II MHC molecules in these vesicles. This sequence of events is illustrated in Figure 6-17, and the individual steps are described next.

Generation of Vesicular Proteins

Most class II-associated peptides are derived from protein antigens that are captured from the extracellular environment and internalized into endosomes by specialized APCs. The initial steps in the presentation of an extracellular protein antigen are the binding of the native antigen to an APC and the internalization of the antigen. Different APCs can bind protein antigens in several ways and with varying efficiencies and specificities. Dendritic cells and macrophages express a variety of surface receptors that recognize structures shared by many microbes (see Chapter 4). These APCs use the receptors to bind and internalize microbes efficiently. Macrophages also express receptors for the Fc portions of antibodies and receptors for the complement protein C3b, which bind antigens with attached antibodies or complement proteins and enhance their internalization. Another example of specific receptors on APCs is the surface immunoglobulin on B cells, which, because of its high affinity for antigens, can effectively mediate the internalization of proteins present at very low concentrations in the extracellular fluid (see Chapter 11).

After their internalization, protein antigens become localized in intracellular membrane-bound vesicles called endosomes. The endosomal pathway of intracellular protein traffic communicates with lysosomes, which are more dense membrane-bound enzyme-containing vesicles. A subset of class II MHC-rich late endosomes plays a special role in antigen processing and presentation by the class II pathway; this is described later. Particulate microbes are internalized into vesicles called phago-somes, which may fuse with lysosomes, producing vesicles called phagolysosomes or secondary lysosomes. Some microbes, such as mycobacteria and Leishmania, may survive and even replicate within phagosomes or endosomes, providing a persistent source of antigens in vesicular compartments.

Proteins other than those ingested from the extracellular milieu can also enter the class II MHC pathway. Some protein molecules destined for secretion may end up in the same vesicles as class II MHC molecules and may be processed instead of being secreted. Less often, cytoplasmic and membrane proteins may be processed and displayed by class II molecules. In some cases, this may result from the enzymatic digestion of cytoplasmic contents, referred to as autophagy. In this pathway, cytoplasmic proteins are trapped within membrane-bound vesicles called autophagosomes; these vesicles fuse with lysosomes, and the cytoplasmic proteins are proteo-lytically degraded. The peptides generated by this route may be delivered to the same class II-bearing vesicular compartment as are peptides derived from ingested antigens. Autophagy is primarily a mechanism for degrading cellular proteins and recycling their products as sources of nutrients during times of stress. It also participates in the destruction of intracellular microbes, which are enclosed in vesicles and delivered to lysosomes. It is therefore predictable that peptides generated by autoph-agy will be displayed for T cell recognition. Some peptides that associate with class II molecules are derived from membrane proteins, which may be recycled into the same endocytic pathway as are extracellular proteins. Thus, even viruses, which replicate in the cytoplasm of infected cells, may produce proteins that are degraded into peptides that enter the class II MHC pathway of antigen presentation. This may be a mechanism for the activation of viral antigen-specific CD4+ helper T cells.

FIGURE 6-18 Morphology of class II MHC-rich endosomal vesicles. A, Immunoelectron micrograph of a B lymphocyte that has internalized bovine serum albumin into early endosomes (labeled with 5-nm gold particles, arrow) and contains class II MHC molecules (labeled with 10-nm gold particles, arrowheads) in MIICs. The internalized albumin will reach the MIICs ultimately. (From Kleijmeer MJ, S Morkowski, JM Griffith, AY Rudensky, and HJ Geuze. Major histocompatibility complex class II compartments in human and mouse B lymphoblasts represent conventional endocytic compartments. Reproduced from The Journal of Cell Biology 139:639-649, 1997, by copyright permission of The Rockefeller University Press.) B, Immunoelectron micrograph of a B cell showing location of class II MHC molecules and DM in MIICs (stars) and invariant chain concentrated in the Golgi (G) complex. In this example, there is virtually no invariant chain detected in the MIIC, presumably because it has been cleaved to generate CLIP. (Courtesy of Drs. H. J. Geuze and M. Kleijmeer, Department of Cell Biology, Utrecht University, The Netherlands.)

Proteolytic Digestion of Proteins in Vesicles

Internalized proteins are degraded enzymatically in late endosomes and lysosomes to generate peptides that are able to bind to the peptide-binding clefts of class II MHC molecules. The degradation of protein antigens in vesicles is an active process mediated by proteases that have acidic pH optima. The most abundant proteases of late endosomes are cathepsins, which are thiol and aspartyl proteases with broad substrate specificities. Several cathepsins contribute to the generation of peptides for the class II pathway. Partially degraded or cleaved proteins bind to the open-ended clefts of class II MHC molecules and are then trimmed enzymatically to their final size. Immunoelectron microscopy and subcellular fractionation studies have defined a class II-rich subset of late endosomes that plays an important role in antigen presentation (Fig. 6-18). In macrophages and human B cells, it is called the MHC class II compartment, or MIIC. (In some mouse B cells, a similar organelle containing class II molecules has been identified and named the class II vesicle.) The MIIC has a characteristic multilamellar appearance by electron microscopy. Importantly, it contains all the components required for peptide-class II

Synthesis of class II MHC in ER

Transport of class II MHC and li to vesicle

Binding of processed peptides to class II MHC

Transport of Expression of peptide-Class II peptide-MHC

MHC complex complex on to cell surface cell surface

HLA-DM-catalyzed removal of CLIP

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