- Email: [email protected]
Antigen processing and recognition
Antigen processing and recognition Editorial overview Clifford V Harding and Jacques Neefjes Current Opinion in Immunology 2005, 17:55–57 This review comes from a themed issue on Antigen processing and recognition Edited by Clifford V Harding and Jacques Neefjes Available online 30th December 2004 0952-7915/$ – see front matter ß 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2004.12.007
Clifford V Harding Department of Pathology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4943, USA e-mail: [email protected]
Clifford Harding is interested in class I and II MHC antigen processing mechanisms and in the regulation of antigen-presenting cell function by adjuvants (e.g. CpG DNA) or in the setting of bacterial infection (e.g. Mycobacterium tuberculosis). Jacques Neefjes Division of Tumor Biology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands e-mail: [email protected]
Jacques Neefjes is interested in the cell biology of antigen presentation by MHC class I and II molecules. He is studying this in living cells using various biophysical techniques. The dynamics of protein degradation, peptide turnover and the loading of MHC molecules are studied in this context. In addition, the molecular mechanism controlling transport of MHC class II molecules is studied in the Neefjes laboratory.
www.sciencedirect.com
Abbreviations CIITA class II transactivator TAP transporter associated with antigen processing
The field of antigen processing and recognition includes a range of more specific topics, including: the control of expression of MHC molecules; the structure of MHC molecules and their antigen ligands (peptidic or nonpeptidic); biochemical and cell biological mechanisms of antigen processing that produce peptide–MHC complexes (including proteolytic mechanisms, roles of chaperones, such as HLA-DM and -DO, function of the class I MHC peptide-loading complex); antigen presentation mechanisms that allow recognition of peptide–MHC complexes when they are expressed on the plasma membrane (T-cell receptor interactions with peptide–MHC complexes, immune synapse function, co-stimulators and other accessory molecules); variations in antigen recognition that might contribute to autoimmunity; mechanisms of alloantigen recognition in organ transplantation; and, physiological or pathological regulation of antigen processing and recognition by microbes. The field of antigen presentation thus relates to many areas of cell biology, including protein synthesis and proteolysis, lipids, intracellular transport, protein folding and chaperones, microdomains, signaling and transcriptional regulation. In the past two decades this field has produced a number of important advances for immunology and cell biology. This section of Current Opinion in Immunology reviews areas in which major new insights into the system of antigen presentation by MHC class I, MHC class II or CD1 molecules have evolved. Some aspects of the topics listed above are now scientifically mature with basic mechanisms well defined, and attention has shifted to sophisticated molecular studies. For example, the transcriptional regulation of class II MHC is being dissected in increasing detail. Earlier studies established the critical role of the class II transactivator (CIITA) as a positive regulator or ‘master controller’ of class II MHC transcription [1], and deficiency of CIITA or other factors (e.g. RFX subunits) necessary for class II MHC transcription results in the immunodeficiency of bare lymphocyte syndrome [2]. Unlike classical transcription factors, CIITA does not directly bind DNA; rather, it interacts with RFX5, NF-Y and CREB, and it has been proposed to function as a scaffold to promote assembly of these transcription factors [3]. In this section, Zika and Ting [4] discuss the roles of epigenetic control of CIITA function, including the roles of histone acetylation and methylation. They develop the model that CIITA recruits chromatin Current Opinion in Immunology 2005, 17:55–57
56 Antigen processing and recognition
modifiers to regulate promoter accessibility. Interestingly, this topic relates to another recent discovery, the control of CIITA function by post-translational modifications, such as phosphorylation [5,6] and ubiquitination [7]. Thus, an increasingly complex and sophisticated model is emerging to explain control of class II MHC transcription. Despite extensive study and a good overall understanding of the class II MHC antigen processing pathway, unresolved issues remain. One of these questions is the enigmatic role of HLA-DO. The review by Karlsson [8] discusses recent advances in the study of HLA-DM and HLA-DO. HLA-DM facilitates removal of the class IIassociated invariant chain peptide (CLIP) fragment of invariant chain from nascent class II MHC molecules and association of other peptides. HLA-DM is thus a critical helper for MHC class II peptide loading and might promote the ‘editing’ of peptides associated with class II MHC molecules. This review discusses several topics related to HLA-DM function, including recent structural studies that clarify the interaction of HLA-DM and class II MHC molecules. HLA-DO is an HLA-DM co-chaperone that modulates HLA-DM activity and peptide loading of class II MHC molecules. The reason for the existence of HLA-DO and its role in vivo are puzzling, raising one of the most intriguing current questions concerning the class II MHC antigen processing pathway. Great advances have been made by recent studies of the class I MHC antigen processing pathway that have revealed properties of the peptide-loading complex, which is assembled in the endoplasmic reticulum. This multiprotein complex contains nascent class I MHC (heavy chain and b2-microglobulin), tapasin, transporter associated with antigen processing (TAP; a heterodimer of TAP1 and TAP2), calreticulin and ERp57. Study of the assembly, structure and function of the peptide-loading complex continues to be a major topic in this field. The attention in this section, however, is on how viruses interfere with these mechanisms. Many viruses are known to disrupt class I MHC antigen processing and presentation by various mechanisms at numerous steps. Hansen and colleagues [9] focus on a subset of viral molecules that interfere with early steps in the assembly of class I MHC–peptide complexes and the function of the peptide-loading complex. These molecules are referred to as viral proteins interfering with antigen presentation (VIPRs). One of the most exciting areas of research concerns mechanisms that exploit endoplasmicreticulum-associated degradation pathways involving dislocation of proteins from the endoplasmic reticulum into the cytosol, where proteasome-mediated degradation can occur. This review also discusses the interesting hypothesis that class I MHC molecules that are less dependent on an intact peptide loading complex might have arisen as a host response to counter microbial disCurrent Opinion in Immunology 2005, 17:55–57
ruption of the peptide-loading complex. Where pathogens invest in finding ways to disrupt presentation of their antigens, the MHC system responds by finding other ways to cope with this. At the microscale, we see evolution at work! Although there have been many advances in the molecular description of immune evasion by viruses, there is much less knowledge about the mechanisms used by bacterial pathogens to inhibit antigen processing or recognition. Bacteria have considerably larger genomes than viruses and, therefore, in principle, many more possibilities to design strategies for immune escape (although they might be less efficient in hijacking host genes and mutating these for their own use). Kaufman and Schaible [10] review the broad range of types of antigen recognition that are involved in anti-bacterial immune responses. These include glycolipid-specific CD1-restricted T cells and phospholigand-specific gd T cells as well as ‘conventional’ class I and II MHC-restricted (CD8+ and CD4+) T cells. Other antigen recognition events include the presentation of N-formylated peptides by non-classical MHC Ib molecules and the recent fascinating demonstration that zwitterionic bacterial polysaccharides are presented by class II MHC molecules [11]. Kaufman and Schaible [10] discuss the significance of bacterial interference with antigen presentation and develop the advantages that accrue to the host by the ability of T cells to use multiple antigen recognition mechanisms and T-cell subsets to recognize a wide range of antigen types (lipids and carbohydrates as well as the conventional peptide determinants of T-cell stimulation). Antigen presentation of bacterial antigens is diverse as are the pathogens. Evolution of the host–pathogen relationship has produced a complex and interesting relationship between pathogenic bacteria and host antigen-presenting cells. The recognition of non-peptidic determinants is further developed by Brenner and colleagues [12], who discuss CD1 presentation of lipid antigens. This is a field in rapid development now that the mechanisms involved in the lipid-loading of CD1 molecules have been discovered. CD1 molecules traffic through specific vacuolar compartments in a manner analogous to class II MHC molecules. In transit they acquire lipid antigens. Brenner and colleges describe recent advances in our understanding of CD1 assembly and lipid loading to generate CD1–antigen complexes, including structural analysis of the binding of lipids to CD1 and the manner in which lipids with different hydrocarbon chain lengths can be accommodated. In addition, they discuss fascinating recent analyses of the role of sphingolipid activator proteins and microsomal triglyceride transfer protein in loading CD1 with lipid antigens. These mechanisms contribute to the recognition of microbial lipid antigens, enlarging the spectrum of antigenic determinants that can generate T-cell responses to aid host defense against bacterial www.sciencedirect.com
Editorial overview Harding and Neefjes 57
infection. Interestingly, CD1 molecules share many strategies with MHC molecules with respect to the use of chaperones for antigen loading, structures, and the use of pockets in the antigen-binding domain for selective binding. Yet, they also differ in many aspects as discussed in this review.
References
and transactivation function. Int Immunol 2003, 15:1195-1205. 6.
Greer SF, Harton JA, Linhoff MW, Janczak CA, Ting JP, Cressman DE: Serine residues 286, 288, and 293 within the CIITA: a mechanism for down-regulating CIITA activity through phosphorylation. J Immunol 2004, 173:376-383.
7.
Greer SF, Zika E, Conti B, Zhu XS, Ting JP: Enhancement of CIITA transcriptional function by ubiquitin. Nat Immunol 2003, 4:1074-1082.
1.
Ting JP, Trowsdale J: Genetic control of MHC class II expression. Cell 2002, 109:S21-S33.
8.
Karlsson L: DM and DO shape the repertoire of peptide-MHC class II complexes. Curr Opin Immunol 2005, 17:65-70.
2.
Reith W, Mach B: The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol 2001, 19:331-373.
9.
Lybarger L, Wang X, Harris M, Hansen TH: Viral immune evasion molecules attack the ER peptide-loading complex and exploit ER-associated degradation pathways. Curr Opin Immunol 2005, 17:71-78.
3.
Zhu XS, Linhoff MW, Li G, Chin KC, Maity SN, Ting JP: Transcriptional scaffold: CIITA interacts with NF-Y, RFX, and CREB to cause stereospecific regulation of the class II major histocompatibility complex promoter. Mol Cell Biol 2000, 20:6051-6061.
4.
Zika E, Ting J P-Y: Epigenetic control of MHC-II: interplay between CIITA and histone modifying enzymes. Curr Opin Immunol 2005, 17:58-64.
5.
Sisk TJ, Nickerson K, Kwok RP, Chang CH: Phosphorylation of class II transactivator regulates its interaction ability
www.sciencedirect.com
10. Kaufmann SHE, Schaible UE: Antigen presentation and recognition in bacterial infections. Curr Opin Immunol 2005, 17:79-87. 11. Cobb BA, Wang Q, Tzianabos AO, Kasper DL: Polysaccharide processing and presentation by the MHCII pathway. Cell 2004, 117:677-687. 12. Hava DL, Brigl M, van den Elzen P, Zajonc DM, Wilson IA, Brenner MB: CD1 assembly and the formation of CD1–antigen complexes. Curr Opin Immunol 2005, 17:88-94.
Current Opinion in Immunology 2005, 17:55–57
Clifford V Harding Department of Pathology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4943, USA e-mail: [email protected]
Clifford Harding is interested in class I and II MHC antigen processing mechanisms and in the regulation of antigen-presenting cell function by adjuvants (e.g. CpG DNA) or in the setting of bacterial infection (e.g. Mycobacterium tuberculosis). Jacques Neefjes Division of Tumor Biology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands e-mail: [email protected]
Jacques Neefjes is interested in the cell biology of antigen presentation by MHC class I and II molecules. He is studying this in living cells using various biophysical techniques. The dynamics of protein degradation, peptide turnover and the loading of MHC molecules are studied in this context. In addition, the molecular mechanism controlling transport of MHC class II molecules is studied in the Neefjes laboratory.
www.sciencedirect.com
Abbreviations CIITA class II transactivator TAP transporter associated with antigen processing
The field of antigen processing and recognition includes a range of more specific topics, including: the control of expression of MHC molecules; the structure of MHC molecules and their antigen ligands (peptidic or nonpeptidic); biochemical and cell biological mechanisms of antigen processing that produce peptide–MHC complexes (including proteolytic mechanisms, roles of chaperones, such as HLA-DM and -DO, function of the class I MHC peptide-loading complex); antigen presentation mechanisms that allow recognition of peptide–MHC complexes when they are expressed on the plasma membrane (T-cell receptor interactions with peptide–MHC complexes, immune synapse function, co-stimulators and other accessory molecules); variations in antigen recognition that might contribute to autoimmunity; mechanisms of alloantigen recognition in organ transplantation; and, physiological or pathological regulation of antigen processing and recognition by microbes. The field of antigen presentation thus relates to many areas of cell biology, including protein synthesis and proteolysis, lipids, intracellular transport, protein folding and chaperones, microdomains, signaling and transcriptional regulation. In the past two decades this field has produced a number of important advances for immunology and cell biology. This section of Current Opinion in Immunology reviews areas in which major new insights into the system of antigen presentation by MHC class I, MHC class II or CD1 molecules have evolved. Some aspects of the topics listed above are now scientifically mature with basic mechanisms well defined, and attention has shifted to sophisticated molecular studies. For example, the transcriptional regulation of class II MHC is being dissected in increasing detail. Earlier studies established the critical role of the class II transactivator (CIITA) as a positive regulator or ‘master controller’ of class II MHC transcription [1], and deficiency of CIITA or other factors (e.g. RFX subunits) necessary for class II MHC transcription results in the immunodeficiency of bare lymphocyte syndrome [2]. Unlike classical transcription factors, CIITA does not directly bind DNA; rather, it interacts with RFX5, NF-Y and CREB, and it has been proposed to function as a scaffold to promote assembly of these transcription factors [3]. In this section, Zika and Ting [4] discuss the roles of epigenetic control of CIITA function, including the roles of histone acetylation and methylation. They develop the model that CIITA recruits chromatin Current Opinion in Immunology 2005, 17:55–57
56 Antigen processing and recognition
modifiers to regulate promoter accessibility. Interestingly, this topic relates to another recent discovery, the control of CIITA function by post-translational modifications, such as phosphorylation [5,6] and ubiquitination [7]. Thus, an increasingly complex and sophisticated model is emerging to explain control of class II MHC transcription. Despite extensive study and a good overall understanding of the class II MHC antigen processing pathway, unresolved issues remain. One of these questions is the enigmatic role of HLA-DO. The review by Karlsson [8] discusses recent advances in the study of HLA-DM and HLA-DO. HLA-DM facilitates removal of the class IIassociated invariant chain peptide (CLIP) fragment of invariant chain from nascent class II MHC molecules and association of other peptides. HLA-DM is thus a critical helper for MHC class II peptide loading and might promote the ‘editing’ of peptides associated with class II MHC molecules. This review discusses several topics related to HLA-DM function, including recent structural studies that clarify the interaction of HLA-DM and class II MHC molecules. HLA-DO is an HLA-DM co-chaperone that modulates HLA-DM activity and peptide loading of class II MHC molecules. The reason for the existence of HLA-DO and its role in vivo are puzzling, raising one of the most intriguing current questions concerning the class II MHC antigen processing pathway. Great advances have been made by recent studies of the class I MHC antigen processing pathway that have revealed properties of the peptide-loading complex, which is assembled in the endoplasmic reticulum. This multiprotein complex contains nascent class I MHC (heavy chain and b2-microglobulin), tapasin, transporter associated with antigen processing (TAP; a heterodimer of TAP1 and TAP2), calreticulin and ERp57. Study of the assembly, structure and function of the peptide-loading complex continues to be a major topic in this field. The attention in this section, however, is on how viruses interfere with these mechanisms. Many viruses are known to disrupt class I MHC antigen processing and presentation by various mechanisms at numerous steps. Hansen and colleagues [9] focus on a subset of viral molecules that interfere with early steps in the assembly of class I MHC–peptide complexes and the function of the peptide-loading complex. These molecules are referred to as viral proteins interfering with antigen presentation (VIPRs). One of the most exciting areas of research concerns mechanisms that exploit endoplasmicreticulum-associated degradation pathways involving dislocation of proteins from the endoplasmic reticulum into the cytosol, where proteasome-mediated degradation can occur. This review also discusses the interesting hypothesis that class I MHC molecules that are less dependent on an intact peptide loading complex might have arisen as a host response to counter microbial disCurrent Opinion in Immunology 2005, 17:55–57
ruption of the peptide-loading complex. Where pathogens invest in finding ways to disrupt presentation of their antigens, the MHC system responds by finding other ways to cope with this. At the microscale, we see evolution at work! Although there have been many advances in the molecular description of immune evasion by viruses, there is much less knowledge about the mechanisms used by bacterial pathogens to inhibit antigen processing or recognition. Bacteria have considerably larger genomes than viruses and, therefore, in principle, many more possibilities to design strategies for immune escape (although they might be less efficient in hijacking host genes and mutating these for their own use). Kaufman and Schaible [10] review the broad range of types of antigen recognition that are involved in anti-bacterial immune responses. These include glycolipid-specific CD1-restricted T cells and phospholigand-specific gd T cells as well as ‘conventional’ class I and II MHC-restricted (CD8+ and CD4+) T cells. Other antigen recognition events include the presentation of N-formylated peptides by non-classical MHC Ib molecules and the recent fascinating demonstration that zwitterionic bacterial polysaccharides are presented by class II MHC molecules [11]. Kaufman and Schaible [10] discuss the significance of bacterial interference with antigen presentation and develop the advantages that accrue to the host by the ability of T cells to use multiple antigen recognition mechanisms and T-cell subsets to recognize a wide range of antigen types (lipids and carbohydrates as well as the conventional peptide determinants of T-cell stimulation). Antigen presentation of bacterial antigens is diverse as are the pathogens. Evolution of the host–pathogen relationship has produced a complex and interesting relationship between pathogenic bacteria and host antigen-presenting cells. The recognition of non-peptidic determinants is further developed by Brenner and colleagues [12], who discuss CD1 presentation of lipid antigens. This is a field in rapid development now that the mechanisms involved in the lipid-loading of CD1 molecules have been discovered. CD1 molecules traffic through specific vacuolar compartments in a manner analogous to class II MHC molecules. In transit they acquire lipid antigens. Brenner and colleges describe recent advances in our understanding of CD1 assembly and lipid loading to generate CD1–antigen complexes, including structural analysis of the binding of lipids to CD1 and the manner in which lipids with different hydrocarbon chain lengths can be accommodated. In addition, they discuss fascinating recent analyses of the role of sphingolipid activator proteins and microsomal triglyceride transfer protein in loading CD1 with lipid antigens. These mechanisms contribute to the recognition of microbial lipid antigens, enlarging the spectrum of antigenic determinants that can generate T-cell responses to aid host defense against bacterial www.sciencedirect.com
Editorial overview Harding and Neefjes 57
infection. Interestingly, CD1 molecules share many strategies with MHC molecules with respect to the use of chaperones for antigen loading, structures, and the use of pockets in the antigen-binding domain for selective binding. Yet, they also differ in many aspects as discussed in this review.
References
and transactivation function. Int Immunol 2003, 15:1195-1205. 6.
Greer SF, Harton JA, Linhoff MW, Janczak CA, Ting JP, Cressman DE: Serine residues 286, 288, and 293 within the CIITA: a mechanism for down-regulating CIITA activity through phosphorylation. J Immunol 2004, 173:376-383.
7.
Greer SF, Zika E, Conti B, Zhu XS, Ting JP: Enhancement of CIITA transcriptional function by ubiquitin. Nat Immunol 2003, 4:1074-1082.
1.
Ting JP, Trowsdale J: Genetic control of MHC class II expression. Cell 2002, 109:S21-S33.
8.
Karlsson L: DM and DO shape the repertoire of peptide-MHC class II complexes. Curr Opin Immunol 2005, 17:65-70.
2.
Reith W, Mach B: The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol 2001, 19:331-373.
9.
Lybarger L, Wang X, Harris M, Hansen TH: Viral immune evasion molecules attack the ER peptide-loading complex and exploit ER-associated degradation pathways. Curr Opin Immunol 2005, 17:71-78.
3.
Zhu XS, Linhoff MW, Li G, Chin KC, Maity SN, Ting JP: Transcriptional scaffold: CIITA interacts with NF-Y, RFX, and CREB to cause stereospecific regulation of the class II major histocompatibility complex promoter. Mol Cell Biol 2000, 20:6051-6061.
4.
Zika E, Ting J P-Y: Epigenetic control of MHC-II: interplay between CIITA and histone modifying enzymes. Curr Opin Immunol 2005, 17:58-64.
5.
Sisk TJ, Nickerson K, Kwok RP, Chang CH: Phosphorylation of class II transactivator regulates its interaction ability
www.sciencedirect.com
10. Kaufmann SHE, Schaible UE: Antigen presentation and recognition in bacterial infections. Curr Opin Immunol 2005, 17:79-87. 11. Cobb BA, Wang Q, Tzianabos AO, Kasper DL: Polysaccharide processing and presentation by the MHCII pathway. Cell 2004, 117:677-687. 12. Hava DL, Brigl M, van den Elzen P, Zajonc DM, Wilson IA, Brenner MB: CD1 assembly and the formation of CD1–antigen complexes. Curr Opin Immunol 2005, 17:88-94.
Current Opinion in Immunology 2005, 17:55–57