Abstract
The immune system has evolved to recognize and destroy pathogens. Invasion by extracellular microorganisms is mainly controlled by B lymphocytes which, using surface immunoglobulins (Ig) as receptors, recognize antigens in their native conformation either free in solution or on the surface of cells. Invasion by intracellular parasites is mainly controlled by cytotoxic T lymphocytes (CTL), which recognize foreign protein antigens on the surface of infected cells by a highly specific receptor and lyse the cells. Both CTL and B lymphocyte responses are specifically enhanced by lymphokines released by antigen-specific T helper cells. Unlike Ig, the T-cell receptor of both CTL and T helper cells does not recognize native proteins but it recognizes a binary complex formed by the association of peptides, derived from degradation of target proteins, with class I and class II molecules encoded in the major histocompatibility complex (MHC). Processing of target proteins occurs through two distinct pathways. Exogenous proteins are degraded in an endolysosome compartment, which intersects the biosynthetic pathway of MHC class II molecules (Neefjes et al., 1990). Thus, peptides derived from degradation of endocytosed proteins bind to MHC class II molecules. Newly synthesized proteins are degraded in the cytosol, and peptides generated from them are transported into the endoplasmic reticulum (ER) where they associate with MHC class I molecules. This review focuses on the latter pathway dealing with processing and presentation of intracellular proteins.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Anderson, K., Cresswell, P., Gammon, M., Hermes, J., Williamson, A., and Zweerink, H., 1991, Endogenously synthesized peptide with an endoplasmic reticulum signal sequence sensitizes antigen processing mutant cells to class I-restricted cell-mediated lysis, J. Exp. Med. 174:489–492.
Attaya, M., Jameson, S., Martinez, C., Hermel, E., Aldrich, C., Forman, J., Fischer Lindahl, K., Bevan, M., and Monaco, J., 1992, HAM-2 corrects the class I antigen-processing defect in RMA-S cells, Nature 355:647–649.
Bell, A., Buckel, J., Groarke, J., Hope, J., Kingsley, D., and Hermodson, M., 1986, The nucleotide sequences of the rbsD, rbsA and rbsC genes of Escherichia coli Kl2, J. Biol. Chem. 261:7652–7658.
Bennink, J., Yewdell, J., and Gerard, W., 1982, A viral polymerase involved in recognition of influenza-infected cells by a cytotoxic T cell clone, Nature 296:75–76.
Bjorkman, P., Saper, M., Samraoui, B., Bennett, W., Strominger, J., and Wiley, D., 1987a, Structure of the human class I histocompatibility antigen HLA-A2, Nature 329:506–512.
Bjorkman, P., Saper, M., Samraoui, B., Bennett, W., Strominger, J., and Wiley, D., 1987b, The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens, Nature 329:512–518.
Braciale, T, Braciale, V., Winkler, M., Strynowski, I., Hood, L., Sabrook, J., and Gething, M., 1987, On the role of the transmembrane anchor sequence of influenza hemagglutinin in target cell recognition by class I MHC restricted, hemagglutinin-specific cytotoxic T lymphocytes, J. Exp. Med. 166:678–692.
Brown, M., Driscoll, J., and Monaco, J., 1991, Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic Proteinase) complexes, Nature 353:355–357.
Cerundolo, V., Alexander, J., Anderson, K., Lamb, C., Cress well, P., McMichael, A., Gotch, F., and Townsend, A., 1990, Presentation of viral antigens controlled by a gene in the MHC, Nature 345:449–456.
Cerundolo, V., Elliott, T., Elvin, J., Bastin, J., Rammensee, H.-G., and Townsend, A., 1991, The binding affinity and dissociation rates of peptides for class I MHC molecules, Eur. J. Immunol. 21:2069–2075.
Chen, C., Chin, J., Ueda, K., Clark, D., Pastan, I., Gottesman, M., and Roninson, I., 1986, Internal duplication and homology with bacterial transport proteins in the mdrl (P glycoprotein) gene from multidrug resistance human gene, Cell 47:381–386.
Colonna, M., Bresnahan, M., Bahram, S., and Strominger, J., 1992, Allelic variants of the human putative transporter involved in antigen processing, Proc. Natl. Acad. Sci. USA 89:3932–3936.
Cox, J., Yewdell, J., Eisenlohr, L., Johnson, P., and Bennink, J., 1990, Antigen presentation requires transport of MHC class I molecules from the endoplasmic reticulum, Science 247:715–718.
Cox, J., Bennink, J., and Yewdell, J., 1991, Retention of adenovirus E19 glycoprotein in the endoplasmic reticulum is essential to its ability to block antigen presentation, J. Exp. Med. 174:1629–1637.
DeMars, R., Rudersdorf, R., Chang, C., Peterson, J., Strandtmann, J., Korn, N., Sidwell, B., and Orr, H., 1985, Mutations that impair a post transcriptional step in expression of HLA-A and-B antigens, Proc. Natl. Acad. Sci. USA 82:8183–8187.
Deverson, E., Gow, I., Coadwell, J., Monaco, J., Butcher, G., and Howard, J., 1990, MHC class II region encoding proteins related to the multidrug resistance family of transmembrane transporters, Nature 348:738–741.
Dick, L., Moomaw, C., DeMartino, G., and Slaughter, C., 1991, Degradation of oxidised insulin B chain by the multiproteinase complex macropain (proteasome), Biochemistry 30:2725–2734.
Elliott, T., Cerundolo, V., Elvin, J., and Townsend, A., 1991, Peptide-induced conformational change of the class I heavy chain, Nature 351:402–405.
Elliott, T., Elvin, J., Cerundolo, V., Allen, H., and Townsend, A., 1992, Structural requirements for the peptide induced conformational change of free MHC class I heavy chains, Eur. J. Immunol. 22:2085–2091.
Falk, K., Rötzschke, O., and Rammensee, H.-G., 1990, Cellular composition governed by major histocompatibility complex class I molecules, Nature 348:248–251.
Falk, K., Rötzschke, O., Stevanovic, S., Jung, G., and Rammensee, H.-G., 1991a, AUele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules, Nature 351:290–296.
Falk, K., Rötzschke, O., Deres, K., Metzger, I, Jung, G., and Rammensee, H.-G., 1991b, Identification of naturally processed viral nonapeptides allows their quantification in infected cells and suggests an allele-specific T cell epitope forecast, J. Exp. Med. 174:425–434.
Garrett, T., Saper, M., Bjorkman, P., Strominger, J., and Wiley, D., 1989, Specificity pockets for the side chains of peptide antigens in HLA-Aw68, Nature 342:692–696.
Glynne, R., Powis, S., Beck, S., Kelly, A., Kerr, L., and Trowsdale, J., 1991, A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC, Nature 353:357–360.
Gould, K., Cossins, J., Bastin, J., Brownlee, G., and Townsend, A., 1989, A 15 amino acid fragment of influenza nucleoprotein synthesized in the cytoplasm is presented to class I-restricted cyiotoxic T lymphocytes, J. Exp. Med. 170:1051–1056.
Gros, P., Croop, J., and Housman, D., 1986, Mammalian multi drug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins, Cell 47:371–380.
Heinemeyer, W., Kleinschmidt, J., Sasidiwsky, J., Escher, C., and Wolf, D., 1991, Proteinase yscE, the yeast proteasome/multicatalytic-multifunctional Proteinase: Mutants unravel its function in stress induced proteolysis and uncover its necessity for cell survival, EMBO J. 10:555–567.
Henderson, R., Michel, H., Sakaguchi, K., Shabanowitz, J., Appella, E., Hunt, D., and Engelhard, V., 1992, HLA-A2.1-associated peptides from a mutant cell line: A second pathway of antigen presentation, Science 255:1264–1266.
Higgins, C., Haag, P., Nikaido, K., Ardeshir, F., Garcia, G., and Ames, G., 1982, Complete nucleotide sequence and identification of the histidine transport Operon of S. typhimurium, Nature 298:723–727.
Higgins, C., Gallagher, M., Mimmack, M., and Pearce, S., 1988, A family of closely related ATP-binding subunits from prokaryotic and eukaryotic cells, BioEssay 8:111–116.
Higgins, C., Hyde, S., Mimmack, M., Gileadi, U., Gill, D., and Gallagher, M., 1990, Binding 2protein dependent transport system, J. Bioenerg. Biomembr. 22:571–592.
Hiles, I., Gallagher, M., Jamieson, D., and Higgins, C., 1987, Molecular characterization of the oligo-peptide permease of Salmonella typhimurium, J. Mol. Biol. 195:125–129.
Hyde, S., Emsley, P., Hartshorn, M., Mimmack, M., Gileadi, U., Pearce, R., Gallagher, P., Gill, D., Hubbard, R., and Higgins, C., 1990, Structural model of ATP-binding associated with cystic fibrosis, multidrug resistance and bacterial transport, Nature 346:362–365.
Jardetzky, T., Lan, W., Robinson, R., Madden, D., and Wiley, D., 1991, Identification of selfpeptides bound to purified HLA-B27, Nature 353:326–329.
Karre, K., Ljunggren, H. G., Ointek, G., and Kiessling, R., 1986, Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy, Nature 319:675.
Kelly, A., Powis, S., Glynne, R., Radley, E., Beck, S., and Trowsdale, J., 1991, Second proteasome-related gene in the human MHC class II region, Nature 353:667–668.
Kelly, A., Powis, S., Kerr, L., Mockridge, I., Elliott, T., Bastin, J., Uchanska-Ziegler, B., Ziegler, A., Trowsdale, J., and Townsend, A., 1992, Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex, Nature 355:641–644.
Kleijmeer, M., Kelly, A., Geuze, H., Slot, J., Townsend, A., and Trowsdale, J., 1992, MHC-encoded transporters are located in the ER and cis-Golgi, Nature 357:342–344.
Klein, J., 1986, Natural History of the Major Histocompatibility Complex, Wiley, New York.
Levy, F., Gabathuler, R., Larsoon, R., and Kvist, S., 1991, ATP is required for in vitro assembly of MHC class I antigens but not for transfer of peptides across the ER membrane, Cell 67:265–274.
Lippincott-Schwartz, J., Yuan, L., Bonifacino, J., and Klausner, R., 1989, Rapid redistribution of Golgi proteins in the ER in cell treated with brefeldin A: Evidence for membrane cycling from Golgi to ER, Cell 56:801–813.
Lippincott-Schwartz, J., Donaldson, J., Schweizer, A., Berger, E., Hauri, H., Yuan, L., and Klausner, R., 1990, Microtubule-dependent retrograde transport of proteins into the ER in the presence of brefeldin A suggests a ER recycling pathway, Cell 60:821–836.
Lippincott-Schwartz, J., Yuan, L., Tipper, C., Amherdt, M., Orci, L., and Klausner, R., 1991, Brefeldin A effects on endosomes, lysosomes, and the TGN suggest a general mechanism for regulating organelle structure and membrane traffic, Cell 67:601–616.
Livingstone, A., Powis, S., Diamond, A., Butcher, G., and Howard, J., 1989, A trans acting major histocompatibility complex-linked gene whose alleles determine gain and loss changes in the antigenic structure of a classical class I molecule, J. Exp. Med. 170:777–795.
Ljunggren, H., Paabo, S., Cochet, M., Kling, G., Kourilsky, P., and Karre, K., 1989, Molecular analysis of H-2 deficit lymphoma lines. Distinct defects in biosynthesis and dissociation of MHC class I heavy chains and β-2m observed in cells with increased sensitivity to NK cell lysis, J. Immunol. 142:2911–2915.
Madden, D., Gorga, J., Strominger, J., and Wiley, D., 1991, The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation, Nature 353:321–325.
Martinez, C., and Monaco, J., 1991, Homology of the proteasome subunits to a major histocompatibility complex-linked LMP gene, Nature 353:664–667.
Monaco, J., and McDevitt, H., 1984, H-2-linked low-molecular weight Polypeptide antigens assemble into an unusual macromolecular complex, Nature 309:797–799.
Monaco, J., Cho, J., and Attaya, M., 1990, Transport protein genes in the murine MHC: Possible implications for antigen processing, Science 250:1723–1726.
Moore, M., Carbone, F., and Bevan, M., 1988, Introduction of soluble protein into the class I pathway of antigen presentation, Cell 54:777–785.
Morrison, L., Lukacker, A., Braciale, V., Fan, D., and Braciale, T., 1986, Differences in antigen presentation to MHC class I and class II restricted influenza virus-specific cytotoxic T lymphocyte clones, J. Exp. Med. 163:903–910.
Neefjes, J., Stollofz, V., Peters, P., Geuze, H., and Ploegh, H., 1990, The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route, Cell 61:171–183.
Nutchern, J., Bonifacino, J., Biddison, W., and Klausner, R., 1989, Brefeldin A implicates egress from endoplasmic reticulum in class I restricted antigen presentation, Nature 339:223–226.
Ohlen, C., Bastin, J., Ljunggren, H.-G., Imreh, S., Klein, G., Townsend, A., and Karre, K., 1990, Restoration of H-2b expression and processing of endogenous antigens in the MHC class I pathway by fusion of a lymphoma mutant to L cells of the H-2k haplotype, Eur. J. Immunol. 20:1873–1876.
Ortiz-Navarrete, V., Seeling, A., Gernold, M., Frentzel, S., Kloetzel, P., and Hammerling, G., 1991, Subunits of the “20S” proteasome (multicatalytic proteinase) encoded by the major histocompatibility complex, Nature 353:662–664.
Owen, M., Kissonerghis, A., and Lodish, H., 1980, Biosynthesis of HLA-A and HLA-B antigens in vivo, J. Biol. Chem. 255:9678–9684.
Parnes, J., and Seidman, J., 1982, Structure of wild-type and mutant mouse β-2 microglobulin genes, Cell 29:661–669.
Pelham, H. R. B., 1989, Control of protein exit from the endoplasmic reticulum, Annu. Rev. Cell Biol. 5:1–23.
Pelham, H. R. B., 1991, Recycling of proteins between the endoplasmic reticulum and Golgi complex, Curr. Biol. 3:585–591.
Ploegh, H., Cannon, E., and Strominger, J., 1979, Cell-free translation of the mRNAs for the heavy and light chains of HLA-A and HLA-B antigens, Proc. Natl. Acad. Sci. USA 76:2273–2277.
Powis, S., Howard, J., and Butcher, G., 1991a, The major histocompatibility complex class II linked cim locus controls the kinetics of intracellular transport of a classical class I molecule, J. Exp. Med. 173:913–921.
Powis, S., Townsend, A., Deverson, E., Bastin, J., Butcher, G., and Howard, J., 1991b, Restoration of antigen presentation to the mutant cell line RMA-S by an MHC-linked transporter, Nature 354:356.
Powis, S., Deverson, E., Coadwell, J., Ciruela, A., Huskisson, N., Smith, H., Butcher, G., and Howard, J., 1992a, Effect of polymorphism of an MHC-linked transporter on the peptides assembled in a class I molecule, Nature 357:211–215.
Powis, S., Mockridge, I., Kelly, A., Kerr, L., Glynne, R., Gileadi, U., Beck, S., and Trowsdale, J., 1992b, Polymorphism in a second ABC transporter gene located within the class II region of the human MHC, Proc. Natl. Acad. Sci. USA 89:1463–1467.
Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J. L., Drumm, M., Iannuzzi, M., Collins, F. S., and Tsui, L. C., 1989, Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA, Science 245:1066–1073.
Rivett, J., 1989, The multicatalytic proteinase, J. Biol. Chem. 264:12215–12219.
Rötzschke, O., Falk, K., Wallny, H., Faath, S., and Rammensee, H.-G., 1990a, Characterization of naturally occurring minor histocompatibility peptides including H-4 and H-Y, Science 249:283–287.
Rötzschke, O., Falk, K., Deres, K., Schild, H., Norda, M., Metzger, J., Jung, G., and Rammensee, H.-G., 1990b, Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells, Nature 348:252–254.
Sadegh-Nasseri, S., and Germain, R., 1991, A role for peptide in determining MHC class II structure, Nature 353:167–169.
Saper, M., Bjorkman, P., and Wiley, D., 1991, Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 Å resolution, J. Mol. Biol. 219:277–319.
Salter, R., and Cresswell, P., 1986, Impaired assembly and transport of HLA-A and-B antigens in a mutant T x B cell hybrid, EMBO J. 5:943–949.
Spies, T., and DeMars, R., 1991, Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter, Nature 351:323–324.
Spies, T., Bresnahan, M., Bahram, S., Arnold, D., Blank, G., Mellins, E., Pious, D., and DeMars, R., 1990, A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway, Nature 348:744–747.
Spies, T., Cerundolo, V., Colonna, M., Cresswell, P., Townsend, A., and DeMars, R., 1992, Presentation of viral antigen by MHC class I molecules is dependent on a putative peptide transporter heterodimer, Nature 355:644–646.
Stearz, U., Karasuyama, H., and Garner, A., 1988, Cytotoxic T lymphocytes against a soluble protein, Nature 329:449–450.
Tevethia, S., Flyer, D., and Tjian, R., 1980, Biology of simian virus 40 (SV40) transplantation antigen (TrAg). VI. Mechanism of induction of SV40 transplantation immunity in mice by purified SV40 T antigen (D2 protein), Virology 107:13–18.
Townsend, A., 1992, A new presentation pathway? Nature 356:386–387.
Townsend, A., and Skehel, J., 1982, Influenza A specific cytotoxic T-cell clones that do not recognize viral glycoproteins, Nature 300:655–657.
Townsend, A., Gotch, F., and Davey, J., 1985, Cytotoxic T cells recognize fragments of influenza nucleoprotein, Cell 42:457–467.
Townsend, A., Rothbard, J., Gotch, F., Bahadur, G., Wraith, D., and McMichael, A., 1986a, The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides, Cell 44:959–968.
Townsend, A., Bastin, J., Gould, K., and Brownlee, G., 1986b, Cytotoxic T lymphocytes recognize influenza hemagglutinin that lacks a signal sequence, Nature 234:575–577.
Townsend, A., Bastin, J., Gould, K., Brownlee, G., Andrew, M., Coupar, D., Boyle, D., Chan, S., and Smith, G., 1988, Defective presentation to class I restricted cytotoxic T lymphocytes in vaccinia-infected cells is overcome by enhanced degradation of antigen, J. Exp. Med. 168:1211–1218.
Townsend, A., Ohlen, C., Bastin, J., Ljunggren, H., Foster, L., and Karre, K., 1989a, Association of class I major histocompatibility heavy and light chains induced by viral peptides, Nature 340:443–448.
Townsend, A., Ohlen, C., Foster, L., Bastin, J., Ljunggren, H. G., and Karre, K., 1989b, A mutant cell in which association of class I heavy and light chains is induced by viral peptides, Cold Spring Harbor Symp. Quant. Biol. 54:299–308.
Townsend, A., Elliott, T., Cerundolo, V., Foster, L., Barber, B., and Tse, A., 1990, Assembly of MHC class I molecules analyzed in vitro, Cell 62:195–295.
Trowsdale, J., Hanson, I., Mockridge, I., Beck, S., Townsend, A., and Kelly, A., 1990, Sequences encoded in the class II region of the MHC related to the “ABC” superfamily of transporters, Nature 348:741–744.
Van Bleek, G., and Nathenson, S., 1990, Isolation of an endogenously processed immunodominant viral peptide from the class I H-2 Kb molecule, Nature 348:213–216.
Vitiello, A., Potter, T., and Sherman, L., 1990, The role of β-2-microglobulin in peptide binding by class I molecules, Science 250:1423–1425.
Wallny, H., and Rammensee, H. G., 1990, Identification of classical minor histocompatibility antigen as cell-derived peptide, Nature 343:275–278.
Wei, M., and Cress well, P., 1992, HLA-A2 molecules in an antigen-processing mutant cell contain signal sequence-derived peptides, Nature 356:441–442.
Wraith, D., and Vessey, A., 1986, Influenza virus-specific cytotoxic T-cell recognition: Stimulation of nucleoprotein-specific clones with intact antigen, Immunology 59:173–177.
Yang, Y., Früh, K., Chambers, J., Waters, J., Wu, L., Spies, T., and Peterson, P., 1992, Major histocompatibility complex (MHC)-encoded HAM2 is necessary for antigenic peptide loading onto class I MHC molecules, J. Biol. Chem. 267:11669–11672.
Yewdell, J., and Bennick, J., 1989, Brefeldin A specifically inhibits presentation of protein antigens to cytotoxic T lymphocytes, Science 244:1072–1075.
Yewdell, J., Bennick, J., and Hosaka, Y, 1988, Cells process exogenous proteins for recognition by cytotoxic T lymphocytes, Science 239:637.
Yide, J., Wai-Kuo, S., and Berkower, I., 1988, Human T cell response to the surface antigen of hepatitis B (HBsAg). Endosomal and nonendosomal processing pathways are accessible to both endogenous and exogenous antigen, J. Exp. Med. 168:293–297.
Zinkernagel, R., and Doherty, P., 1974, Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis, Nature 251:547–549.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer Science+Business Media New York
About this chapter
Cite this chapter
Cerundolo, V. (1993). Antigen Processing and Presentation the Role of the Endoplasmic Reticulum. In: Borgese, N., Harris, J.R. (eds) Endoplasmic Reticulum. Subcellular Biochemistry, vol 21. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2912-5_10
Download citation
DOI: https://doi.org/10.1007/978-1-4615-2912-5_10
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6263-0
Online ISBN: 978-1-4615-2912-5
eBook Packages: Springer Book Archive