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 showed
chapter 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 experiments 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 antigen processing. The degraded peptides then associate with MHC molecules within the cell interior, and the peptideMHC complexes are transported to the membrane, where they are displayed (antigen presentation). Class I and class II MHC molecules associate with peptides that have been processed in different intracellular compartments. 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, tumor 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 endocytic 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 addition, 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 selfMHC restriction. Beginning in the mid-1970s, experiments conducted by a number of researchers demonstrated selfMHC restriction in T-cell recognition. A. Rosenthal and E. Shevach, for example, showed that antigen-specific proliferation 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-:
8536d_ch08_185-199 8/2/02 10:08 AM Page 186 mac79 Mac 79: 45_Bwppldsby et al./ Immunology Se 186 PART 11 Generation of B-Cell and T-Cell Response y LCM virus Strain 2 or 13 Strain 2 or 13 orC2×13)F1 orC2×13)F1 Peritoneal exudate cells Lymph node cells (containing Tc cells) (retains Peritoneal macrophages H-2k target cells H-2 LCM-infected H-2b LCM-infected target cells arget cells Antigen-pulsed Antigen-primed T-cells ⊙⊙⊙ B!:8 51Cr release +51Cr release 51 Cr release (no lysis) lysis) (no lysis) FICURE8-2 Classic experiment of Zinkernagel and Doherty demonstrating that antigen recognition by Tc cells exhibits MHC re- strictionH-2 mice were primed with the lymphocytic choriomeni gitis(LCM)virus to induce cytotoxic T lymphocytes(CTLs) specific Measure t-cell for the virus Spleen cells from this LCM-primed mouse were then added to target cells of different H-2 haplotypes that were intracellu- larly labeled withCr(black dots)and either infected or not with the LCM virus CTL-mediated killing of the target cells, as measured by Antigen-primed Antigen-pulsed macrophages the release of Cr into the culture supernatant, occurred only if the Strain 2 Strain 13(2x 13)F, target cells were infected with LCM and had the same MHC haplo- ype as the CTLs. ADapted from P C. Doherty and R. M. Zinkemagel, Strain 13 1975,.Exp.Med.141:502 (2×13)F1 restricted. In 1996, Doherty and Zinkernagel were awarded FIGURE8-1Experimental demonstration of self-MHC restriction of the Nobel prize for their major contribution to the under TH cells. Peritoneal exudate cells from strain 2, strain 13, or(2 X 13)F1 standing of cell-mediated immunity. guinea pigs were incubated in plastic Petri dishes, allowing enrichment of macrophages, which are adherent cells. The peritoneal macro- phages were then incubated with antigen. These "antigen-pulse macrophages were incubated in vitro with T cells from strain 2, strain Role of Antigen-Presenting Cells 13, or(2X 13)F1 guinea pigs, and the degree of T-cell proliferation As early as 1959, immunologists were confronted with data was assessed. The results indicated that TH cells could proliferate only suggesting that T cells and B cells recognized antigen by dif- in response to antigen presented by macrophages that shared MHC al- ferent mechanisms. The dogma of the time, which persisted leles.(Adapted from A Rosenthal and E Shevach, 1974, J. Exp. Med. until the 1980s, was that cells of the immune system recog- 138: 1194, by copyright permission of the Rockefeller University Press. I nize the entire protein in its native conformation. However, experiments by P G H. Gell and B Benacerraf demonstrated that, while a primary antibody response and cell-mediated that the Tc cell and the virus-infected target cell must share response were induced by a protein in its native conforma class I molecules encoded by the K or D regions of the MHC. tion, a secondary antibody response(mediated by B cells) Thus, antigen recognition by CD8 Tc cells is class I MHc could be induced only by native antigen, whereas a secondary
restricted. In 1996, Doherty and Zinkernagel were awarded the Nobel prize for their major contribution to the understanding of cell-mediated immunity. Role of Antigen-Presenting Cells As early as 1959, immunologists were confronted with data suggesting that T cells and B cells recognized antigen by different mechanisms. The dogma of the time, which persisted until the 1980s, was that cells of the immune system recognize the entire protein in its native conformation. However, experiments by P. G. H. Gell and B. Benacerraf demonstrated that, while a primary antibody response and cell-mediated response were induced by a protein in its native conformation, a secondary antibody response (mediated by B cells) could be induced only by native antigen, whereas a secondary 186 PART II Generation of B-Cell and T-Cell Responses Antigen-pulsed macrophages Antigen-primed T cell Strain 2 Strain 13 (2 × 13)F1 Strain 2 Strain 13 (2 × 13)F1 + + − + − + + + + Strain 2 or 13 or (2 × 13)F1 Strain 2 or 13 or (2 × 13)F1 Antigen Peritoneal exudate cells Peritoneal macrophages Adherent cells Antigen Antigen-pulsed macrophages Measure T-cell proliferation Lymph node cells Antigen-primed T-cells Adherence column (retains macrophages) 7 days FIGURE 8-1 Experimental demonstration of self-MHC restriction of TH cells. Peritoneal exudate cells from strain 2, strain 13, or (2 13) F1 guinea pigs were incubated in plastic Petri dishes, allowing enrichment of macrophages, which are adherent cells. The peritoneal macrophages were then incubated with antigen. These “antigen-pulsed” macrophages were incubated in vitro with T cells from strain 2, strain 13, or (2 13) F1 guinea pigs, and the degree of T-cell proliferation was assessed. The results indicated that TH cells could proliferate only in response to antigen presented by macrophages that shared MHC alleles. [Adapted from A. Rosenthal and E. Shevach, 1974, J. Exp. Med. 138:1194, by copyright permission of the Rockefeller University Press.] that the TC cell and the virus-infected target cell must share class I molecules encoded by the K or D regions of the MHC. Thus, antigen recognition by CD8 TC cells is class I MHC Spleen cells (containing Tc cells) H–2k target cells H–2k LCM-infected target cells H–2b LCM-infected target cells –51Cr release (no lysis) –51Cr release (no lysis) +51Cr release (lysis) H–2k LCM virus 51Cr FIGURE 8-2 Classic experiment of Zinkernagel and Doherty demonstrating that antigen recognition by TC cells exhibits MHC restriction. H-2k mice were primed with the lymphocytic choriomeningitis (LCM) virus to induce cytotoxic T lymphocytes (CTLs) specific for the virus. Spleen cells from this LCM-primed mouse were then added to target cells of different H-2 haplotypes that were intracellularly labeled with 51Cr (black dots) and either infected or not with the LCM virus. CTL-mediated killing of the target cells, as measured by the release of 51Cr into the culture supernatant, occurred only if the target cells were infected with LCM and had the same MHC haplotype as the CTLs. [Adapted from P. C. Doherty and R. M. Zinkernagel, 1975, J. Exp. Med. 141:502.] 8536d_ch08_185-199 8/2/02 10:08 AM Page 186 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch08_185-199 8/2/02 10:08 AM Page 187 mac79 Mac 79: 45_Bwppldsby et al./ Immunology Se Antigen Processing and Presentation CHAPTER 8 187 cell-mediated response could be induced by either the native 8-3a, b). During that interval of 1-3 h, the antigen-presenting or the denatured antigen(see Table 3-5). These findings were cells had processed the antigen and had displayed it on the viewed as an interesting enigma, but implications for antigen membrane in a form able to activate T presentation were completely overlooked until the early Subsequent experiments by R. P. Shimonkevitz showed that internalization and processing could be bypassed if anti- gen-presenting cells were exposed to peptide digests of an Processing of Antigen Is Required antigen instead of the native antigen(Figure 8-3c). In these for Recognition by T Cells experiments, antigen-presenting cells were treated with glu taraldehyde(this chemical, like paraformaldehyde, fixes the The results obtained by K. Ziegler and E. R. Unanue were cell, making the membrane impermeable)and then incu among those that contradicted the prevailing dogma that bated with native ovalbumin or with ovalbumin that had ntigen recognition by B and T cells was basically similar. been subjected to partial enzymatic digestion. The digested These researchers observed that TH-cell activation by bacter- ovalbumin was able to interact with the glutaraldehyde-fixed ial protein antigens was prevented by treating the antigen- antigen-presenting cells, thereby activating ovalbumin presenting cells with paraformaldehyde prior to antigen specific TH cells, whereas the native ovalbumin failed to do posure. However, if the antigen-presenting cells were first so. These results suggest that antigen processing involves the allowed to ingest the antigen and were fixed with paraform- digestion of the protein into peptides that are recognized by ldehyde 1-3 h later, TH-cell activation still occurred( Figure the ovalbumin-specific TH cell EXPERIMENTAL CONDITIONS T-CELL ACTIVA THell APO APC Fixation TH cell APC APC FIGURE8-3Experimental demonstration that antigen process. before antigen exposure and incubated with peptide digests of the ing is necessary for TH-cell activation.(a)When antigen-presenting antigen(rather than native antigen), they also can activate TH cells cells(APCs)are fixed before exposure to antigen, they are unable TH-cell activation is determined by measuring a specific TH-cell to activate TH cells.(b) In contrast, APCs fixed at least 1 h after response(e. g, cytokine secretion antigen exposure can activate TH cells. (c) When APCs are fixed
cell-mediated response could be induced by either the native or the denatured antigen (see Table 3-5). These findings were viewed as an interesting enigma, but implications for antigen presentation were completely overlooked until the early 1980s. Processing of Antigen Is Required for Recognition by T Cells The results obtained by K. Ziegler and E. R. Unanue were among those that contradicted the prevailing dogma that antigen recognition by B and T cells was basically similar. These researchers observed that TH-cell activation by bacterial protein antigens was prevented by treating the antigenpresenting cells with paraformaldehyde prior to antigen exposure. However, if the antigen-presenting cells were first allowed to ingest the antigen and were fixed with paraformaldehyde 1–3 h later, TH-cell activation still occurred (Figure 8-3a,b). During that interval of 1–3 h, the antigen-presenting cells had processed the antigen and had displayed it on the membrane in a form able to activate T cells. Subsequent experiments by R. P. Shimonkevitz showed that internalization and processing could be bypassed if antigen-presenting cells were exposed to peptide digests of an antigen instead of the native antigen (Figure 8-3c). In these experiments, antigen-presenting cells were treated with glutaraldehyde (this chemical, like paraformaldehyde, fixes the cell, making the membrane impermeable) and then incubated with native ovalbumin or with ovalbumin that had been subjected to partial enzymatic digestion. The digested ovalbumin was able to interact with the glutaraldehyde-fixed antigen-presenting cells, thereby activating ovalbuminspecific TH cells, whereas the native ovalbumin failed to do so. These results suggest that antigen processing involves the digestion of the protein into peptides that are recognized by the ovalbumin-specific TH cells. Antigen Processing and Presentation CHAPTER 8 187 FIGURE 8-3 Experimental demonstration that antigen processing is necessary for TH-cell activation. (a) When antigen-presenting cells (APCs) are fixed before exposure to antigen, they are unable to activate TH cells. (b) In contrast, APCs fixed at least 1 h after antigen exposure can activate TH cells. (c) When APCs are fixed before antigen exposure and incubated with peptide digests of the antigen (rather than native antigen), they also can activate TH cells. TH-cell activation is determined by measuring a specific TH-cell response (e.g., cytokine secretion). T-CELL ACTIVATION EXPERIMENTAL CONDITIONS + Antigen peptides Fixation APC Fixation – APC APC Antigen 1h Antigen 1h APC APC TH cell APC + Fixation APC TH cell (a) (b) (c) 8536d_ch08_185-199 8/2/02 10:08 AM Page 187 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch08_185-199 8/22/02 11: 49 AM Page 188 mac100 mac 100: 128_tm: 8536d: Goldsby et al./ Immunology 5e- 188 PART I1 Generation of B-Cell and T-Cell Response TABLE8-1 Antigen-presenting cells Professional antigen-presenting cells Nonprofessional antigen-presenting cells Dendritic cells(several types) Fibroblasts(skin) Thymic epithelial cells Glial cells(brain) Thyroid epithelial cells Pancreatic beta cells Vascular endothelial cells At about the same time, A. Townsend and his colleagues Macrophages must be activated by phagocytosis of began to identify the proteins of influenza virus that were particulate antigens before they express class II mHC ecognized by Tc cells. Contrary to their expectations, they molecules or the co-stimulatory B7 membrane found that internal proteins of the virus, such as matrix molecule and nucleocapsid proteins, were often recognized by Tc. b cells constitutively express class II MHC molecules but more Moreover, Townsends work revealed that Tc cells recog must be activated before they express the co-stimulatory B7 molecule nized short linear peptide sequences of the influenza pro- tein. In fact, when noninfected target cells were incubated Several other cell types, classified as nonprofessional in vitro with synthetic peptides corresponding to se- antigen-presenting cells, can be induced to express class ll quences of internal influenza proteins, these cells could be MHC molecules or a co-stimulatory signal (Table 8-1) cognized by Tc cells and subsequently lysed just as well Many of these cells function in antigen presentation only as target cells that had been infected with live influenza for short periods of time during a sustained inflammator virus. These findings along with those presented in Figure response 8-3 suggest that antigen processing is a metabolic process Because nearly all nucleated cells express class I MHC that digests proteins into peptides, which can then be dis- molecules, virtually any nucleated cell is able to function played on the cell membrane together with a class I or class target cell presenting endogenous antigens to Tc cells. Most II MHC molecule ften, target cells are cells that have been infected by a virus or some other intracellular microorganism. However, altered Most Cells Can Present Antigen with Class I self-cells such as cancer cells, aging body cells, or allogeneic MHC: Presentation with Class ll mhc cells from a graft can also serve as targets Is Restricted to apcs Since all cells expressing either class I or class lI MHC mole. Evidence for Two Processing les can present peptides to T cells, strictly speaking they all could be designated as antigen-presenting cells. However, by and Presentation Pathways convention,cells that display peptides associated with class I MHC molecules to CD8 Tc cells are referred to as target cells, The immune system uses two different pathways to eliminate cells that display peptides associated with class II MHC mole. intracellular and extracellular antigens. Endogenous anti- les to CD4* tH cells are called antigen-presenting cells gens(those generated within the cell) are processed in the cy- (APCs). This convention is followed throughout this text. rosolic pathway and presented on the membrane with class I A variety of cells can function as antigen-presenting cell MHC molecules; exogenous antigens( those taken up by en Their distinguishing feature is their ability to express class l sented on the membrane with class I mhc molecul MHC molecules and to deliver a co-stimulatory signal. Three cell types are classified as professional antigen-presenting (Figure 8-4) cells: dendritic cells, macrophages, and B lymphocytes. These Experiments carried out by L. A. Morrison and T. J. cells differ from each other in their mechanisms of antigen Braciale provided early evidence that the antigenic peptides uptake, in whether they constitutively express class II MHc presented by class I and class II MHC molecules are derived molecules, and in their co-stimulatory activity: from different processing pathways. These researchers based their experimental protocol on the properties of two clones a Dendritic cells are the most effective of the antigen- of Tc cells, one that recognized influenza hemagglutinin a high level of class II MHC molecules and co-k presenting cells. Because these cells constitutively (HA)associated with a class I MHC molecule, and an atypical Tc line that recognized the same antigen associated stimulatory activity, they can activate naive TH cells with a class II MHC molecule.(In this case, and in son
At about the same time, A. Townsend and his colleagues began to identify the proteins of influenza virus that were recognized by TC cells. Contrary to their expectations, they found that internal proteins of the virus, such as matrix and nucleocapsid proteins, were often recognized by TC cells better than the more exposed envelope proteins. Moreover, Townsend’s work revealed that TC cells recognized short linear peptide sequences of the influenza protein. In fact, when noninfected target cells were incubated in vitro with synthetic peptides corresponding to sequences of internal influenza proteins, these cells could be recognized by TC cells and subsequently lysed just as well as target cells that had been infected with live influenza virus. These findings along with those presented in Figure 8-3 suggest that antigen processing is a metabolic process that digests proteins into peptides, which can then be displayed on the cell membrane together with a class I or class II MHC molecule. Most Cells Can Present Antigen with Class I MHC; Presentation with Class II MHC Is Restricted to APCs Since all cells expressing either class I or class II MHC molecules can present peptides to T cells, strictly speaking they all could be designated as antigen-presenting cells. However, by convention, cells that display peptides associated with class I MHC molecules to CD8 TC cells are referred to as target cells; cells that display peptides associated with class II MHC molecules to CD4 TH cells are called antigen-presenting cells (APCs). This convention is followed throughout this text. A variety of cells can function as antigen-presenting cells. Their distinguishing feature is their ability to express class II MHC molecules and to deliver a co-stimulatory signal. Three cell types are classified as professional antigen-presenting cells: dendritic cells, macrophages, and B lymphocytes. These cells differ from each other in their mechanisms of antigen uptake, in whether they constitutively express class II MHC molecules, and in their co-stimulatory activity: ■ Dendritic cells are the most effective of the antigenpresenting cells. Because these cells constitutively express a high level of class II MHC molecules and costimulatory activity, they can activate naive TH cells. ■ Macrophages must be activated by phagocytosis of particulate antigens before they express class II MHC molecules or the co-stimulatory B7 membrane molecule. ■ B cells constitutively express class II MHC molecules but must be activated before they express the co-stimulatory B7 molecule. Several other cell types, classified as nonprofessional antigen-presenting cells, can be induced to express class II MHC molecules or a co-stimulatory signal (Table 8-1). Many of these cells function in antigen presentation only for short periods of time during a sustained inflammatory response. Because nearly all nucleated cells express class I MHC molecules, virtually any nucleated cell is able to function as a target cell presenting endogenous antigens to TC cells. Most often, target cells are cells that have been infected by a virus or some other intracellular microorganism. However, altered self-cells such as cancer cells, aging body cells, or allogeneic cells from a graft can also serve as targets. Evidence for Two Processing and Presentation Pathways The immune system uses two different pathways to eliminate intracellular and extracellular antigens. Endogenous antigens (those generated within the cell) are processed in the cytosolic pathway and presented on the membrane with class I MHC molecules; exogenous antigens (those taken up by endocytosis) are processed in the endocytic pathway and presented on the membrane with class II MHC molecules (Figure 8-4). Experiments carried out by L. A. Morrison and T. J. Braciale provided early evidence that the antigenic peptides presented by class I and class II MHC molecules are derived from different processing pathways. These researchers based their experimental protocol on the properties of two clones of TC cells, one that recognized influenza hemagglutinin (HA) associated with a class I MHC molecule, and an atypical TC line that recognized the same antigen associated with a class II MHC molecule. (In this case, and in some 188 PART II Generation of B-Cell and T-Cell Responses TABLE 8-1 Antigen-presenting cells Professional antigen-presenting cells Nonprofessional antigen-presenting cells Dendritic cells (several types) Fibroblasts (skin) Thymic epithelial cells Macrophages Glial cells (brain) Thyroid epithelial cells B cells Pancreatic beta cells Vascular endothelial cells 8536d_ch08_185-199 8/22/02 11:49 AM Page 188 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-:
8536d_ch08_185-199 8/2/02 10: 08 AM Page 189 mac79 Mac 79: 45_BWfpldsby et al./ Immunology 5e Antigen Processing and Presentation CHAPTER 8 189 CYTOSOLIC PATHWAY Endogcnous-ATP-Cytoplasmic--Peptides TAP Endoplasmic--Peptide-cassI proteasome reticulum MHC complex Exopeptidases、 Amino acids ENDOCYTIC PATHWAY Exogen Endocytic compartments Endow phagocytosis FIGURE 8-4 Overview of cytosolic and endocytic pathways for to the cell membrane. TAP(transporter of antigenic peptides) processing antigen. The proteasome complex contains enzymes transports the peptides to the endoplasmic reticulum. It should be that cleave peptide bonds, converting proteins into peptides. The noted that the ultimate fate of most peptides in the cell is neither antigenic peptides from proteasome cleavage and those from of these pathways, but rather to be degraded completely into endocytic compartments associate with class I or class ll MHc amino acids molecules, and the peptide- MHC complexes are then transported others as well, the association of T-cell function with MHc only to target cells treated with infectious virions. Similarly, restriction is not absolute). In one set of experiments, target target cells that had been treated with infectious influenza cells that expressed both class I and class lI MHC molecules irions in the presence of emetine, which inhibits viral pro were incubated with infectious influenza virus or with UV- tein synthesis, stimulated the class II-restricted Tc cells but inactivated influenza virus. (The inactivated virus retained not the class I-restricted Tc cells. Conversely, target cells that its antigenic properties but was no longer capable of replicat- had been treated with infectious virions in the presence of ing within the target cells. ) The target cells were then incu- chloroquine, a drug that blocks the endocytic processing bated with the class I-restricted or the atypical class II- pathway, stimulated class I- but not class II-restricted Tc restricted Tc cells and subsequent lysis of the target cells was cells determined. The results of their experiments, presented in These results support the distinction between the process- Table 8-2, show that the class Il-restricted Tc cells responded ing of exogenous and endogenous antigens, including the to target cells treated with either infectious or noninfectious preferential association of exogenous antigens with class Il influenza virions. The class I-restricted Tc cells responded MHC molecules and of endogenous antigens with class I TABLE Effect of antigen presentation on activation of class I and class ll MHC-restricted Tc cells CTL ACTIVITYt Class I restricted Class il restricte UV-inactivated virus(noninfectious) Infectious virus chloroquine Target cells, which expressed both class I and class ll MHC molecules, were treated with the indicated preparations of influenza virus and other agents. Emetine inhibits viral protein synthesis, and chloroquine inhibits the endocytic processing pathway. DEtermined by lysis(+)and no lysis(-)of the target cells. SOURCE: Adapted from T. ). Braciale et al, 1987, Immunol. Rev. 98: 95
others as well, the association of T-cell function with MHC restriction is not absolute). In one set of experiments, target cells that expressed both class I and class II MHC molecules were incubated with infectious influenza virus or with UVinactivated influenza virus. (The inactivated virus retained its antigenic properties but was no longer capable of replicating within the target cells.) The target cells were then incubated with the class I–restricted or the atypical class II– restricted TC cells and subsequent lysis of the target cells was determined. The results of their experiments, presented in Table 8-2, show that the class II–restricted TC cells responded to target cells treated with either infectious or noninfectious influenza virions. The class I–restricted TC cells responded only to target cells treated with infectious virions. Similarly, target cells that had been treated with infectious influenza virions in the presence of emetine, which inhibits viral protein synthesis, stimulated the class II–restricted TC cells but not the class I–restricted TC cells. Conversely, target cells that had been treated with infectious virions in the presence of chloroquine, a drug that blocks the endocytic processing pathway, stimulated class I– but not class II–restricted TC cells. These results support the distinction between the processing of exogenous and endogenous antigens, including the preferential association of exogenous antigens with class II MHC molecules and of endogenous antigens with class I Antigen Processing and Presentation CHAPTER 8 189 FIGURE 8-4 Overview of cytosolic and endocytic pathways for processing antigen. The proteasome complex contains enzymes that cleave peptide bonds, converting proteins into peptides. The antigenic peptides from proteasome cleavage and those from endocytic compartments associate with class I or class II MHC molecules, and the peptide-MHC complexes are then transported to the cell membrane. TAP (transporter of antigenic peptides) transports the peptides to the endoplasmic reticulum. It should be noted that the ultimate fate of most peptides in the cell is neither of these pathways, but rather to be degraded completely into amino acids. CYTOSOLIC PATHWAY ENDOCYTIC PATHWAY Endogenous antigens ± Ubiquitin ATP Exogenous antigens Cytoplasmic proteasome complex Peptides Peptides TAP Endoplasmic reticulum Peptide–class I MHC complex Peptide–class II MHC complex Exopeptidases Amino acids Endocytosis or phagocytosis Endocytic compartments TABLE 8-2 Effect of antigen presentation on activation of class I and class II MHC-restricted TC cells CTL ACTIVITY† Treatment of target cells* Class I restricted Class II restricted Infectious virus UV-inactivated virus (noninfectious) Infectious virus emetine Infectious virus chloroquine * Target cells, which expressed both class I and class II MHC molecules, were treated with the indicated preparations of influenza virus and other agents. Emetine inhibits viral protein synthesis, and chloroquine inhibits the endocytic processing pathway. † Determined by lysis () and no lysis () of the target cells. SOURCE: Adapted from T. J. Braciale et al., 1987, Immunol. Rev. 98:95. 8536d_ch08_185-199 8/2/02 10:08 AM Page 189 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: