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 section, we will 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 Effector T-Cell Responses
The presentation of cytosolic versus vesicular proteins by the MHC-I or MHC-II pathway determines which subset of T cells will recognize antigens found in these two pools of proteins and is intimately linked to the functions of the T cells (Fig.1). In the case of viruses that establish infection in the cytosol of cells, or tumor cells that produce mutated proteins also in the cytosol, the foreign antigens are recognized by MHC-I-restricted CD8+ CTLs, which kill the cells producing these antigens. The anti gens of microbes in vesicles, such as bacteria (e.g., mycobacteria and Salmonella) and fungi, activate MHC-II-restricted CD4+ T cells because proteins processed in late endosomes or lysosomes are loaded onto MHC-II molecules. CD4+ T cells activate macrophages to enhance their phagocytic functions, which serves to eliminate microbes in vesicles. CD4+ helper T cells also recognize internalized vesicular antigens in B lymphocytes and stimulate antibody responses.
Fig1. Presentation of extracellular and cytosolic antigens to different subsets of effector T cells. (A) Cytosolic antigens are presented by nucleated cells to CD8+ cytotoxic T lymphocytes (CTLs), which kill 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 anti gens. MHC, Major histocompatibility complex.
Thus, by segregating peptides derived from microbes residing in different cellular compartments, the MHC molecules guide CD4+ and CD8+ subsets of T cells to respond to the microbes that each subset can effectively combat. This is especially important because the antigen receptors of CTLs and helper T cells cannot distinguish between microbes in different cellular compartments.
Immunogenicity of Protein Antigens
MHC molecules determine the immunogenicity of protein anti gens in two related ways.
• The epitopes of complex proteins that elicit the strongest T-cell responses are in 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 an individual and are thus immunodominant (Fig.2). Defining immunodominant epitopes of antigens may be useful in the design of vaccines. For example, a viral protein could be analyzed for the presence of amino acid sequences that would form epi topes capable of binding to an individual’s MHC molecules with high affinity. Such analyses can be done experimentally or in silico. Synthetic peptides containing these epitopes may be effective vaccines for eliciting T-cell responses against the viral peptides expressed in an infected cell. Similarly, peptides produced by mutated genes in cancers are analyzed for their ability to bind to the MHC-I molecules in each patient with cancer. The ones that bind are most likely to stimulate antitumor immunity in that patient.
• The expression of particular MHC-II alleles in an individual determines the ability of that individual to respond to particular antigens. As discussed earlier, the Ir genes that control antibody responses are MHC-II genes. They influence immune responsiveness because various MHC-II molecules produced by different alleles differ in their ability to bind different antigenic peptides and therefore to stimulate specific helper T cells. The consequences of inheriting a given MHC allele depend on the nature of the peptide anti gens that can bind the MHC molecule encoded by that allele. For example, if the antigen is a peptide from ragweed pollen, the individual who expresses MHC-II molecules capable of binding the peptide would be genetically prone to allergic reactions against pollen. Conversely, some individuals do not respond to vaccines (such as hepatitis B virus surface antigen vaccine), perhaps because their HLA molecules cannot bind and display the major peptides of the vaccine antigen.
Fig2. Immunodominance of peptides. Protein antigens are processed to generate multiple peptides; immunodominant peptides are the ones that bind best to the available major histocompatibility complex (MHC) class I and MHC-II 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 MHC-I molecules. APC, Antigen-presenting cell.
