bacteria by creating pores in the bacterial membranes. The infected host cell then processes the degraded bacteria into antigens.
Antigen Presentation to the Immune System
Processing of Protein Antigens by Dendritic Cells
When microbes or their products first enter the body, professional phagocytes called antigen-presenting cells (APCs) engulf, process, and present antigens on their surfaces, which then direct other cells in the adaptive immune system to develop into cells with specific antibacterial activity. There are three types of APCs: dendritic cells (DCs), macrophages, and B cells. As described in chapter 3, macrophages and DCs are important players in the innate immune system, but they also serve as links to the adaptive immune system. Macrophages, as part of the innate immune system, are produced in an immature form (monocytes) and migrate through the bloodstream before moving into tissue where an infection is taking place. They help clear debris from dead human cells that may be circulating in blood or deposited in tissue. Macrophages also play a critical role in initiating and organizing the adaptive immune response.
DCs, like macrophages, initiate and organize the adaptive immune response, but because they are found mainly in localized areas of the dermis, the mucosal lining of the intestinal tract, and lymphoid tissue, they are the first APCs on the scene to process microbial antigens and stimulate the adaptive immune response. B cells can also function as APCs, albeit not as efficiently as macrophages or DCs. In addition to producing and secreting soluble antibodies, B cells also produce membrane immunoglobulins (mIg) that they display on their surfaces. When the mIg captures an antigen, the mIg-antigen complex is internalized and the antigen is processed and presented to the T helper cells.
Peptide Antigens. Figure 4-6 shows an overview of how APCs process protein antigens and display the resulting peptide epitopes on their surfaces bound to a protein complex called the major histocompatibility complex (MHC). Two main classes of MHC molecules, MHC I and MHC II, form complexes with peptide epitopes (Figure 4-7). MHC I molecules are produced by all nucleated cells in the body, while only professional phagocytic APCs, such as DCs, macrophages, B cells, and certain activated epithelial cells, produce MHC II molecules in addition to MHC I molecules. In the case of peptide antigens, the type of MHC used to display the epitope determines the type of immune response that will be elicited (more on this later).
Figure 4-6. MHC I, MHC II, and CD1 pathways of antigen processing by APCs and presentation to T cells leads to activation and increased proliferation of T cells. (A) In the MHC I pathway, protein antigens present in the cytosol are processed by the proteasome, and the resulting peptides are transported to the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP). In the endosome, the peptide antigens are further processed by an endosomal protease into smaller peptide epitopes, which then bind to MHC I, and the complex traffics to the cell surface, where it binds to the T cell receptor (TCR) and CD8 on the surface of CD8+ T cells. (B) In the class II MHC pathway, extracellular protein antigens are endocytosed into late endosomal and lysosomal vesicles, where they are processed into peptides that displace the invariant chain of the MHC II molecule. An accessory protein, called H-2M in mice (HLA-DM in humans), facilitates the displacement of the invariant chain with the peptide epitope. The peptide epitope-MHC II complex is then transported to the cell surface, where the complex binds to the T cell receptor (TCR) and CD4 on the surface of CD4+ T cells. (C) The CD1 antigen presentation pathway. Uptake of foreign glycolipid or lipid antigens occurs through multiple pathways. Glycolipid antigens bind to APCs via pattern recognition molecules such as CD14 and the mannose receptor. The low-density lipoprotein receptor (LDLR) can bind to the lipoprotein transporter ApoE. The mannose receptor can also mediate the uptake and trafficking of such lipid or glycolipid antigens through the endosomal pathway where, at acidic pH, the lipid portions of the glycolipid antigens are released and displace the self-lipids at the binding cleft of the CD1 molecule. Accessory proteins, called saposins, and possibly CD1e help process the lipid antigen and displace the self-lipid on the CD1 with the lipid antigen. An ER protein, called microsomal triglyceride transfer protein (MTP), facilitates the loading of the self-lipids onto CD1. The antigen-CD1 complex then traffics to the cell surface, where it is recognized by the CD1-specific T cell receptor. CD1-mediated antigen presentation occurs through TCRs in both αβ T cells and γδ T cells.
Figure 4-7. Major histocompatibility complexes I and II. Shown are the structures of major histocompatibility complex I (MHC I) and II (MHC II) proteins, which bind to peptide antigens and present them to T cell receptors (TCRs) on the surface of Th1 and Th2 cells, respectively. NOTE: In humans, the corresponding MHC molecules are called human leukocyte antigens (HLA).
How does an APC decide whether to display an epitope on MHC I or MHC II? This question has received a great deal of attention because understanding what leads to each type of presentation is critical for developing effective vaccines. From cumulative data so far, some basic rules have emerged. Intracellular pathogens such as viruses and some bacteria, particularly those that can enter the cytoplasm or nucleus of an APC, are most likely to elicit an MHC I display of the epitopes (Figure 4-6A). Additionally, large particulate or aggregated antigens that do not escape the phagocytic or pinocytic vesicle seem to elicit primarily an MHC I-linked display. By contrast, epitopes processed from soluble antigens, such as peptides or proteins secreted from bacteria or those exposed on the surface of extracellular pathogens, are displayed almost exclusively by MHC II (Figure 4-6B). Thus, if one wishes to use peptides to elicit a CTL response, it is necessary to present these peptides in particulate form (e.g., bound up in a large immune complex, or to deliver them directly into the cytosol to ensure their processing will occur via the MHC I pathway). Alternatively, these peptides could be expressed intracellularly using mammalian expression vectors (more on this in chapter 17).
Differences in immunogenicity have important practical consequences. For example, it is now possible to produce epitope-sized peptides synthetically. Peptides are not only much cheaper to produce than full-length proteins, which must be purified through time-consuming biochemical procedures, but they also make it possible to target a specific antibody or CTL response toward one or more defined regions of an antigen. Epitopes differ in the way they are recognized by the immune system, and only a small subset of the potential epitopes present in any given antigen will elicit an immune response. Epitopes that are processed and presented on the surface of APCs bound as MHC complexes, which are then recognized by T cell receptors on Th cells, are referred to as T cell epitopes. T cell epitopes that bind to MHC I complexes are typically 8 to 11 amino acid residues in length, whereas T cell epitopes that bind to MHC II complexes are 13 to 17 amino acid residues in length. Epitopes that are recognized by antibodies expressed on the surface of the B cells are called B cell epitopes. B cell epitopes vary from 5 to 10 amino acids in length and are found on the exposed surface of the native conformation of the antigen (i.e., they are not processed by APCs). B cell epitopes can elicit strong antibody responses, while T cell epitopes can also elicit strong cell-mediated CTL responses.
Directing the adaptive immune response toward particular epitopes is important because not all immunogenic epitopes elicit protective responses. Some immunogenic epitopes, for example, are buried within a folded protein and are therefore inaccessible to the antibody or are expressed inside a microbe and are thus not exposed to circulating antibodies. Eliciting an antibody response to such an epitope is useless because the antibody will not be able to bind and neutralize the antigen or enhance its
