IMMUNOLOGY - Roit A. - Mir 2000

Chapter 9. Antigen Recognition

ANTIGEN PROCESSING AND PRESENTATION

Antigen presentation to T Cells is preceded by Processing

Circulating Antibodies and Cell-mediated immune responses are typically specific for different determinants of the same antigen. For example, in mice, B cells recognize the amino-terminal epitopes of Glucagon, whereas T cells recognize its carboxy-terminal determinants (Fig. 9.18). This occurs because intact antigen molecules are not presented directly; instead, their fragments (the products of Cleavage, or processing) are presented in association with MHC products on The Cell surface. The cells that process Antigens for presentation are either specialized antigen-presenting cells (APCs) capable of stimulating T-cell proliferation, or virus-infected host cells, which subsequently become targets for cytotoxic T cells.

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Fig. 9.18. Different forms of the Immune Response upon immunization with two Peptides comprising the glucagon molecule. Antibodies (B-cell response) are directed primarily against the epitopes of the N-terminal peptide, whereas the C-terminal peptide (positions 18-29) stimulates a T-cell response, specifically in vitro lymphocyte blastogenesis and in vivo delayed-type hypersensitivity (DTH).

Antigen processing consists of its cleavage into peptide fragments. The vast majority of epitopes recognized by T cells are fragments of the peptide chain that are often inaccessible to immune recognition within intact protein molecules. Only a small fraction of the peptide fragments from a protein antigen are capable of binding to a corresponding MHC molecule. Moreover, different MHC molecules bind different sets of peptides. For example, helper T cells from mice of different haplotypes (i.e., bearing different MHC molecules) recognize distinct peptides of a viral antigen (Fig. 9.19). These differences in recognition are primarily due to the ability of a given peptide to bind to a specific class II MHC molecule.

Fig. 9.19. Differences between peptide fragments of the same protein antigen recognized by T cells from mice of different haplotypes (i.e., bearers of different class II MHC molecules). Animals were immunized with the bacteriophage X repressor protein, T-cell hybridomas were generated, and their ability to recognize a set of overlapping peptide fragments of this protein was determined. Antigenic peptide positions are highlighted in dark blue. One of the peptides is always immunodominant, although multiple peptides were antigenic for certain mouse strains. (After Roy S. et al., 1989).

Before binding to MHC molecules, protein antigens are cleaved into peptides. Antigen processing, which generates peptides capable of binding to MHC molecules, occurs within intracellular Organelles of antigen-presenting cells (Fig. 9.20). For research purposes, antigen cleavage can be bypassed by using synthetic peptides as antigens. The Use of such easily synthesized peptides with known Amino acid sequences has made it possible to identify epitopes recognized by T cells of varying specificities (Fig. 9.21). Amino Acid Substitutions at various positions have made it possible to determine the relative importance of specific amino acid residues within particular epitopes. Furthermore, experiments with peptides of known Structure have proven the ability of class I and class II MHC molecules to bind antigen fragments directly. By comparing the effects of amino acid substitutions—specifically, their impact on MHC binding and T-cell reactivity—it has been possible to establish which exact amino acid residues contact the MHC molecule and the T-cell receptor. For instance, the fragment consisting of residues 52–61 of the hen egg-white Lysozyme polypeptide chain is recognized by H-2-IA^k-restricted T cells. This peptide binds to IA^k molecules, and three amino acid residues have been shown to participate in its interaction with class II MHC products, while three other residues make contact with the TCR.

Fig. 9.20. Exogenous antigens are captured by antigen-presenting cells and subsequently cleaved by Proteolytic Enzymes within specialized intracellular compartments. Antigenic peptides form complexes with class II MHC molecules in vesicles that travel toward the cell surface, moving in the direction opposite to endocytic vesicles.

Fig. 9.21. The table presents T-cell-recognized peptides from A number of Proteins. Synthetic peptides reproducing the complete Amino Acid Sequence of the corresponding protein can be used to activate T cells, though activation is often achieved by exposure to just one or a few individual fragments of its chain.