8536d_ch08_185-199 8/22/02 11: 49 AM Page 185 mac100 mac 100: 12B8_tm: 8536d: Goldsby et al./Immunology 5e chapter8 Antigen processing g and presentation ECOGNITION OF FOREIGN PROTEIN ANTIGENS BY a T cell requires that peptides derived from the antigen be displayed within the cleft of an MHO molecule on the membrane of a cell. The formation of these peptide-MHC complexes requires that a protein antigen be degraded into peptides by a sequence of events called anti- gen processing. The degraded peptides then associate with Antigen Processing for Presentation by Class I MHC MHC molecules within the cell interior, and the peptide MHC complexes are transported to the membrane, where they are displayed (antigen presentation) Self-MHC Restriction of T Cells Class I and class II MHC molecules associate with pep- tides that have been processed in different intracellular com- Role of Antigen-Presenting Cells partments. Class I MHC molecules bind peptides derived from endogenous antigens that have been processed within a Evidence for Two Processing and Presentation Pathways the cytoplasm of the cell(e.g, normal cellular proteins,tu mor proteins, or viral and bacterial proteins produced a Endogenous Antigens: The Cytosolic Pathway within infected cells). Class II MHC molecules bind peptides a Exogenous Antigens: The Endocytic Pathway derived from exogenous antigens that are internalized by phagocytosis or endocytosis and processed within the endo- Presentation of Nonpeptide Antigens cytic pathway. This chapter examines in more detail the mechanism of antigen processing and the means by which processed antigen and MHC molecules are combined. In ad dition, a third pathway for the presentation of nonpeptide The results of these experiments, outlined in Figure8-1 showed that strain-2 antigen-pulsed macrophages activated strain-2 and FI T cells but not strain-13 T cells. Similarly, strain-13 antigen-pulsed macrophages activated strain-13 Self-MHC Restriction of t cells and Fi T cells but not strain-2 T cells. Subsequently, congenic and recombinant congenic strains of mice, which differed Both CD4 and CD8 T cells can recognize antigen only when from each other only in selected regions of the H-2 complex, it is presented by a self-MHC molecule, an attribute called self- were used as the source of macrophages and T cells. These ex- MHC restriction. Beginning in the mid-1970s, experiments periments confirmed that the CD4* TH cell is activated and conducted by a number of researchers demonstrated self- proliferates only in the presence of antigen-pulsed MHC restriction in T-cell recognition. A. Rosenthal and E rophages that share class II MHC alleles. Thus, Shevach, for example, showed that antigen-specific prolifera- recognition by the CD4 TH cell is class II MHC restricted tion of TH cells occurred only in response to antigen presented In 1974 R. Zinkernagel and P. Doherty demonstrated the y macrophages of the same MHC haplotype as the T cells In self-MHC restriction of CD8 T cells. In their experiments, their experimental system, guinea pig macrophages from mice were immunized with lymphocytic choriomeningitis strain 2 were initially incubated with an antigen. After the (LCM) virus; several days later, the animals'spleen cells, antigen-pulsed" macrophages had processed the antigen and which included Tc cells specific for the virus, were isolated presented it on their surface, they were mixed with T cells from and incubated with LCM-infected target cells of the same or the same strain(strain 2), a different strain(strain 13), or different haplotype( Figure 8-2). They found that the Tc cells (2 X 13)FI animals, and the magnitude of T-cell proliferation killed only syngeneic virus-infected target cells. Later studies in response to the antigen-pulsed macrophages was measured. with congenic and recombinant congenic strains showedchapter 8 The results of these experiments, outlined in Figure 8-1, showed that strain-2 antigen-pulsed macrophages activated strain-2 and F1 T cells but not strain-13 T cells. Similarly, strain-13 antigen-pulsed macrophages activated strain-13 and F1 T cells but not strain-2 T cells. Subsequently, congenic and recombinant congenic strains of mice, which differed from each other only in selected regions of the H-2 complex, were used as the source of macrophages and T cells. These ex￾periments confirmed that the CD4 TH cell is activated and proliferates only in the presence of antigen-pulsed macrophages that share class II MHC alleles. Thus, antigen recognition by the CD4 TH cell is class II MHC restricted. In 1974 R. Zinkernagel and P. Doherty demonstrated the self-MHC restriction of CD8 T cells. In their experiments, mice were immunized with lymphocytic choriomeningitis (LCM) virus; several days later, the animals’ spleen cells, which included TC cells specific for the virus, were isolated and incubated with LCM-infected target cells of the same or different haplotype (Figure 8-2). They found that the TC cells killed only syngeneic virus-infected target cells. Later studies with congenic and recombinant congenic strains showed ■ Self-MHC Restriction of T Cells ■ Role of Antigen-Presenting Cells ■ Evidence for Two Processing and Presentation Pathways ■ Endogenous Antigens: The Cytosolic Pathway ■ Exogenous Antigens: The Endocytic Pathway ■ Presentation of Nonpeptide Antigens Antigen Processing and Presentation R      a T cell requires that peptides derived from the antigen be displayed within the cleft of an MHC molecule on the membrane of a cell. The formation of these peptide-MHC complexes requires that a protein antigen be degraded into peptides by a sequence of events called anti￾gen processing. The degraded peptides then associate with MHC molecules within the cell interior, and the peptide￾MHC complexes are transported to the membrane, where they are displayed (antigen presentation). Class I and class II MHC molecules associate with pep￾tides that have been processed in different intracellular com￾partments. Class I MHC molecules bind peptides derived from endogenous antigens that have been processed within the cytoplasm of the cell (e.g., normal cellular proteins, tu￾mor proteins, or viral and bacterial proteins produced within infected cells). Class II MHC molecules bind peptides derived from exogenous antigens that are internalized by phagocytosis or endocytosis and processed within the endo￾cytic pathway. This chapter examines in more detail the mechanism of antigen processing and the means by which processed antigen and MHC molecules are combined. In ad￾dition, a third pathway for the presentation of nonpeptide antigens derived from bacterial pathogens is described. Self-MHC Restriction of T Cells Both CD4 and CD8 T cells can recognize antigen only when it is presented by a self-MHC molecule, an attribute called self￾MHC restriction. Beginning in the mid-1970s, experiments conducted by a number of researchers demonstrated self￾MHC restriction in T-cell recognition. A. Rosenthal and E. Shevach, for example, showed that antigen-specific prolifera￾tion of TH cells occurred only in response to antigen presented by macrophages of the same MHC haplotype as the T cells. In their experimental system, guinea pig macrophages from strain 2 were initially incubated with an antigen. After the “antigen-pulsed” macrophages had processed the antigen and presented it on their surface, they were mixed with T cells from the same strain (strain 2), a different strain (strain 13), or (2 13) F1 animals, and the magnitude of T-cell proliferation in response to the antigen-pulsed macrophages was measured. Antigen Processing for Presentation by Class I MHC Molecules 8536d_ch08_185-199 8/22/02 11:49 AM Page 185 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-: