Invading pathogenic bacteria and viruses use different strategies to survive within infected hosts. Many bacteria, such as the pathogens Staphylococcus, Streptococcus, and various enteric Gram-negative bacilli, survive in the extracellular milieu, whereas viruses and other bacteria, such as Listeria, survive inside host cells. Successful elimination of pathogens in each of these locations requires distinct responses from the host immune system. T cells play a central role in the control of extracellular and intracellular pathogens; however, the responding subset of T cells differs for each type of pathogen, with subsets of T cells expressing the cell surface marker CD4 most important for protection against extracellular pathogens and those expressing the CD8 marker essential for control of intracellular organisms. Stimulated CD4+ T cells act on other cells of the immune system by producing cytokines, soluble mediators that elicit a variety of cellular responses important for clearance of extracellular pathogens, whereas CD8+ T cells function largely by directly lysing host cells that have become infected with an intracellular organism. It is therefore critical for antigens derived from extracellular sources to stimulate CD4+ T cells and for intracellular antigens to stimulate CD8+ T cells. Whether a particular antigenic peptide activates a CD4+ versus a CD8+ T cell is determined by which MHC proteins present the peptide to the TCR.

Class II MHC proteins are found on cells of the innate immune system known as “professional” antigen-presenting cells (APCs) as well as B cells and the thymic epithelium. Professional APCs include dendritic cells (DCs) and various tissue macrophages, which engulf extracellular organisms (often after these are coated with host anti bodies), host cells that have undergone apoptosis (programmed cell death), and cellular debris through an endocytic pathway that brings the ingested material into contact with degradative enzymes. The peptides that are formed in these reactions are bound to the MHC class II proteins for presentation to T cells. The MHC class II com plex is a dimer consisting of a single α chain and a single β chain. Both α and β chains contribute to peptide binding and interaction with the TCR. During synthesis within the cell, MHC class II complexes bind invariant chain (Ii), a protein that directs the newly formed MHC proteins into an acidic vesicle. During this trafficking event, a portion of the Ii occupies the peptide-binding site. Once the MHC class II protein reaches the acidic vesicle, Ii is proteolyzed by cathepsin S, leaving behind a small fragment that remains lodged within the peptide-binding cleft of the MHC class II complex. This fragment is termed the class II–associated invariant chain peptide (CLIP). The MHC class II–containing vesicles then fuse with other vesicles containing the peptide fragments from the endocytosed particles. There, CLIP is replaced with a peptide, thus stabilizing the MHC class II complex and allowing it to be transported to the cell surface, where it interacts with the TCR on CD4+ T cells (Fig. 1).

Fig1. ANTIGEN PROCESSING AND PRESENTATION. Presentation of peptides by major histocompatibility complex (MHC) class I and class II molecules occurs by different mechanisms. Top, In the class I MHC pathway, protein antigens in the cytosol are processed by proteasomes, and peptides are trans ported into the endoplasmic reticulum (ER), where they bind to class I MHC molecules. Bottom, In the class II MHC pathway, protein antigens are endocytosed from the extracellular milieu and degraded in lysosomes. These peptides subsequently bind to class II MHC molecules, displacing the class II-associated invariant chain peptide (CLIP) in the antigen presentation cleft of the class II molecule. ER, Endoplasmic reticulum; TAP, transporter associated with antigen processing. (From Abbas AK, Lichtman AH, Pillai S, Baker DL, Baker A. Cellular and Molecular Immunology. 9th ed. Philadelphia: Elsevier; 2017.)

T cells can respond to antigenic peptides only if these peptides fit into the binding pocket of either MHC class I or MHC class II. Although a large number of peptides are able to bind to a specific MHC complex, the diversity of antigen presentation is enhanced through expression of three different MHC class I alleles (in humans, HLA A, B, and C) and class II alleles (in humans, HLA DR, DP, and DQ). To further increase the spectrum of peptides any particular cell may present, MHC alleles are always codominantly expressed. Thus, any individual expresses a large number of different class II dimers on its APCs and class I dimers on all nucleated cells, providing broad protection against potential pathogenic organisms. It is possible, however, that even with this degree of potential for antigen presentation, pathogens may evolve that do not possess unique proteins with sequences that can be efficiently presented by MHC. To circumvent this problem, the MHC locus has evolved to be highly poly morphic, thus providing enormous diversity within the population for antigen presentation, ensuring that some individuals will express MHC dimers that can present antigens from virtually any pathogen. Interestingly, predominant MHC alleles exist in different parts of the world, suggesting that there is local pressure, perhaps based upon pre vailing microorganisms, that shapes selection of MHC expression.

Neither MHC class I nor MHC class II distinguishes foreign from host peptides as they fill their peptide binding grooves. Because MHC class II are capable of presenting any ingested antigen and MHC class I present peptides produced within the cell, the majority of the MHC complexes are filled with self-peptides. The T cell must distinguish self from non-self to ensure that a response is directed only against peptides generated from foreign peptides. Control over which antigens elicit a T-cell response is accomplished through selection of a population of T cells expressing appropriate TCRs.

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