- Email: [email protected]
Antigen processing and recognition
Antigen processing and recognition Recent developments Editorial overview Peter J van den Elsen and Alexander Rudensky Current Opinion in Immunology 2004, 16:63–66 This review comes from a themed issue on Antigen processing and recognition Edited by Peter van den Elsen and Alexander Rudensky 0952-7915/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2003.11.018
Peter J van den Elsen Division of Molecular Biology, Department of Immunohematology and Blood Transfusion, Building 1, E3-Q, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands e-mail: [email protected]
The current research interest of the members of Peter van den Elsen’s laboratory is in molecular mechanisms that control immune activation with an emphasis on antigen presentation by MHC class I and class II molecules. This research involves areas of cancer, autoimmune disease with emphasis on multiple sclerosis, transplantation and maternal-fetal interactions. Alexander Rudensky Howard Hughes Medical Institute, Box 357370, Health Science Building, I604I, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA e-mail: [email protected]
Research in Alexander Rudensky’s group is focused on the intracellular mechanisms of generation of CD4 Tcell receptor ligands and the role they play in CD4 T-cell differentiation and lineage commitment in the thymus and periphery.
www.sciencedirect.com
Abbreviations APC antigen-presenting cell CIITA class II transactivator DC dendritic cell DRiPs defective ribosomal products ER endoplasmic reticulum TCR T-cell receptor
T-cell recognition of antigens is dependent upon the expression of MHC molecules on the surface of antigen presenting cells (APCs). In these cells, class I and class II MHC molecules, and MHC-like CD1 molecules sample products of protein and glycolipid breakdown, respectively, and transport them to the cell surface for recognition by the T-cell receptors (TCRs). MHC class I molecules, which present peptides generated in the cytosol to CD8þ T cells, are expressed on the majority of nucleated cells. In contrast, MHC class II molecules, which present peptides generated in the endocytic compartment to CD4þ T cells, are found primarily on the surface of specialised APCs due to the tightly controlled expression of the class II transactivator (CIITA), which is essential for MHC class II transcription. The basic principles of these processes, summarily known as antigen processing and presentation, were established some time ago and many principal molecular players have been identified. Recent years have brought about a number of new exciting developments stemming from the application of sophisticated genetic, biochemical and imaging approaches for the analysis of MHC gene expression, intracellular generation and transport of TCR ligands, and T cell–APC interactions. This section of Current Opinion in Immunology highlights the remarkable progress in this mature yet vibrant field of immunobiology. The section starts with a review by van den Elsen and colleagues [1] discussing the regulatory elements and factors that drive the expression of MHC class I and class II genes with a major emphasis on the control of CIITA expression. It has become increasingly clear that CIITA, in addition its role in the regulation of MHC genes, modulates the expression of various non-MHC genes, and thereby plays a more global role in antigen presentation. This is illustrated by the observation that CIITA is involved in the transcriptional regulation of the semaphorin Plexin-A, which is required for efficient interactions of dendritic cells (DCs) with T cells. Further advances in understanding the molecular mechanisms of CIITA transcriptional regulation have resulted in the identification of regulatory elements and their interacting factors that control CIITA expression in a lineage- and Current Opinion in Immunology 2004, 16:63–66
64 Antigen processing and recognition
cell-type-specific fashion. Furthermore, several chromatin-remodelling enzymes have now been described that are involved in the function and transcriptional regulation of CIITA. In particular, CIITA acts as a platform for histone acetylase and histone deacetylase activities. In addition, association with bramha-related gene-1, a component of the ATP-dependent chromatin remodelling complex SWI/SNF, seems to be required for CIITA function. Moreover, there are several lines of evidence in support of epigenetic mechanisms, such as CpG DNA methylation and histone deacetylation, that account for the lack of CIITA and, therefore, MHC class II expression in several types of malignant tumours. Significant advances in the elucidation of proteolytic events leading to generation of MHC-class-I-binding peptides are reviewed by Kloetzel and Ossendorp [2]. Proteosomes, as well as cytosolic and endoplasmic reticulum (ER) aminopeptidases contribute to generation of these ligands. The authors discuss the regulation of proteasome activity and the role of IFN-g in this process, in particular the conversion of ‘constitutive proteasomes’ to ‘immunoproteasomes’. Immunoproteasomes can affect the generation of CD8þ T-cell epitopes by facilitating the generation of some antigenic peptides while destroying others. In addition, proteosome composition may vary depending on a particular cell type, and this may lead to a cell-type-specific differences in the generation of CTL epitopes. Despite the highly efficient generation of peptides by proteosomes, however, only a small fraction ultimately associate with MHC class I molecules and are displayed on the APC surface to T lymphocytes. This is due to a variety of factors, including peptide destruction by cytosolic endo- and exopeptidases. The next key question is the source of proteins from which the presented peptides are derived. As discussed by Lehner and Cresswell [3], the major source of peptides presented by MHC class I molecules is a pool of polypeptides referred to as ‘defective ribosomal products’ or DRiPs. DRiPs encompass any polypeptide that is unable to fold properly, including erroneous translation products derived from non-coding regions of mRNA as well as alternative reading frames. DRiPs make up a sizeable portion of cytosolic peptides and contribute to the vast repertoire of peptides presented by MHC class I molecules. As a continuation of the theme touched upon by Kloetzel and Ossendrop [2], Cresswell and Lehner [3] discuss in further detail the low efficiency of generating a specific peptide–MHC complex from a particular gene product harbouring the class I epitope sequence. Apparently it takes 2000 copies of polypeptide to generate a single peptide–MHC class I complex. Another long-standing problem in the MHC class I presentation field is the elusive cellular mechanism(s) of cross-presentation, the fundamental phenomenon originCurrent Opinion in Immunology 2004, 16:63–66
ally discovered by Bevan [4,5]. This phenomenon, central to the development of CD8þ T-cell responses to infection and to tolerance induction, infers that MHC class I molecules expressed on DCs and macrophages are capable of presenting peptides derived from phagocytosed or endocytosed protein antigens. It requires the transfer of the internalized antigens from the endocytic pathway into the cytosol and proteosomal degradation followed by TAP (transporter associated with antigen processing)dependent ER translocation of the resulting peptides. The recently demonstrated recruitment of ER membrane components, in particular the Sec61 complex, to the phagosomes finally provided a mechanistic explanation for the retrotranslocation of phagosomal proteins into the cytosol. Finally, Lehner and Cresswell [3] discuss the mechanisms that the emerging family of viral K3-immunoevasion genes employ to compromise MHC-class-I-mediated presentation. These virus-encoded membrane-associated ubiquitin E3 ligases affect the cell-surface expression of MHC class I molecules. Furthermore, cellular homologues of these viral genes have been recently identified, and their role in ubiquitination of MHC class I and other important immunoregulatory molecules is being investigated. In contrast to classical MHC class I molecules, MHCclass-I-like CD1 molecules bind their ligands in the endosomal/lysosomal compartment. In their review, Brenner and co-workers [6] present new insights into the CD1 presentation pathway. CD1 molecules bind acyl chains and, therefore, this ‘third arm’ of antigen presentation allows T cells to recognise fatty acids, glycolipids and lipopeptide antigens of foreign or self origin. This presentation pathway is of a major importance for antimycobacterial immunity. Recent studies demonstrated that different CD1 isoforms in humans sample different aspects of the endocytic pathway, including early and late endosomes, and lysosomes. This is achieved by differential trafficking of CD1a, CD1b, CD1c and CD1d molecules, which is mediated by distinct tyrosine-based motifs within their cytoplasmic tails that are capable of interacting with different adaptor complexes (AP-2 and AP-3). Defects in some of these pathways, such as in patients with Hermansky-Pudlak syndrome type 2, affect lipid antigen sampling by CD1 molecules while MHC class II function remains normal. Recent advances in proteolytic mechanisms of MHC class II presentation, intracellular assembly and export of peptide MHC class II complexes to the plasma membrane in various APC types are reviewed by Bryant and Ploegh [7]. These topics include the roles that Ig receptor signalling and the chaperone molecule HLA-DO play in regulation of the HLA-DM and MHC class II peptide loading during antigen-dependent and -independent B-cell differentiation. The facilitation of MHC class II presentation www.sciencedirect.com
Editorial overview van den Elsen and Rudensky 65
in phagocytic cells, macrophages and DCs, in addition to B cells, also requires signalling. These signals are provided upon the binding of pathogens to specific patternrecognition and endocytic receptors, leading to activation of the MHC class II presentation pathway and internalisation of the pathogen. Antigens derived from phagocytosed particles or pathogens can be loaded directly onto MHC class II molecules in the phagosome or released and transferred to the classical endocytic compartments for loading onto MHC class II molecules. Immature DCs are efficient at endocytosing antigens and/or pathogens, yet they are not capable of efficiently generating peptide– MHC class II complexes. In the course of DC maturation, MHC class II molecules are redistributed to the late endocytic peptide-loading MHC class II compartment (MIIC) in conjunction with an increase in its protein degradative activity. These events, which greatly enhance the efficiency of peptide–MHC class II complex assembly, are followed by the directed transport of these complexes to the site of the APC contact with the T cell, facilitated by the remarkable vectorial tubulation of the endosomal membranes. It turns out that exported peptide–MHC class II complexes are not randomly distributed on the surface of APCs. As discussed by Poloso and Roche [8], peptide– MHC class II complexes formed in MIIC are contained within cholesterol-rich plasma membrane microdomains, the so-called lipid rafts. Depletion of cholesterol from the plasma membrane disrupts lipid rafts and affects the capacity of antigen-loaded APCs to activate T cells. However, the diminution of T-cell responses occurs only when the numbers of specific peptide–MHC class II complexes are low, but not when high numbers of these complexes are presented. To explain this phenomenon, a model has been put forward that integrates the known biochemical properties of antigen processing, peptide loading and MHC class II molecule trafficking. The directed transport of peptide–MHC class II complexes within lipid rafts and their continuing ‘clustered’ expression of the cell surface is thought to increase the efficiency of antigen recognition by T cells, which face an enormous task of distinguishing a very small number of antigenic peptide from thousands of peptides derived form self-proteins. In addition to T-cell activation, T-cell recognition of raftassociated MHC-class-II–peptide complexes activates signalling pathways within APCs. Al-Daccak and colleagues [9] suggest that signalling through MHC class II molecules plays an important role in regulation of the immune response. At the molecular level, MHC class II signalling is linked to the activation of the protein tyrosine kinase (PTK), protein kinase C (PKC) and mitogenactivated protein kinase (MAPK) pathways, thereby affecting various cellular functions, ranging from cytokine production, proliferation and differentiation to cell death. www.sciencedirect.com
Major advances in imaging technology have made it possible to visualise molecular interactions between T cells and APCs in vitro, and to investigate the dynamic movements of molecules involved in T-cell recognition and signalling at the T cell–APC interface dubbed the immunological synapse. Gascoigne and Zal [10] review the application of fluorescence resonance energy transfer (FRET) imaging to study these processes. They discuss a body of data suggesting that synapse formation is preceded by certain early signalling events resulting in the elaborately orchestrated rearrangement and clustering of several key molecules involved in T cell–APC interactions within the immunological synapse and in its proximity. This clustering leads to stabilisation of the synapse and sustained signalling which is required for the full Tcell activation. The review by Germain and Jenkins [11] further highlights advances in the visualisation of antigen presentation events in vivo. This has become possible through the development of monoclonal antibodies (mAb) specific for defined peptide–MHC complexes and the application of powerful imaging approaches such as two-photon microscopy. These mAb reagents make it possible to monitor the expression of specific peptide–MHC class II complexes on APC (e.g. distinct subsets of DC) in the course of the immune response in vivo. The two-photon imaging enables documentation of the movement of immune T cells and their interactions with APCs in secondary lymphoid organs in real time. These studies have revealed the high mobility of naı¨ve T cells in the absence of antigen, leading to transient contact with DCs and suggesting that naı¨ve T cells constantly probe DCs in a search for the relevant peptide–MHC complexes. In the presence of antigen, however, specific T cell–APC contacts lasted for many hours, which is critical for the initiation and maintenance of a productive T-cell response. Future application of these powerful approaches and their further development will provide novel insights into the dynamics of antigen presentation and T-cell activation in vivo.
References 1.
van den Elsen PJ, Holling TM, Kuipers HF, van der Stoep N: Transcriptional regulation of antigen presentation. Curr Opin Immunol 2004, 16:67-75.
2.
Kloetzel P-M, Ossendorp F: Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr Opin Immunol 2004, 16:76-81.
3.
Lehner PJ, Cresswell P: Recent developments in MHC-class-Imediated antigen presentation. Curr Opin Immunol 2004, 16:82-89.
4.
Bevan MJ: Minor H antigens introduced on H-2 different stimulating cells cross-react at the cytotoxic T cell level during in vivo priming. J Immunol 1976, 117:2233-2238.
5.
Bevan MJ: Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J Exp Med 1976, 143:1283-1288. Current Opinion in Immunology 2004, 16:63–66
66 Antigen processing and recognition
6.
Sugita M, Cernadas M, Brenner MB: New insights into pathways for CD1-mediated antigen presentation. Curr Opin Immunol 2004, 16:90-95.
9.
7.
Bryant P, Ploegh H: Class II MHC peptide loading by the professionals. Curr Opin Immunol 2004, 16:96-102.
8.
Poloso NJ, Roche PA: Association of MHC class II–peptide complexes with plasma membrane lipid microdomains. Curr Opin Immunol 2004, 16:103-107.
10. Gascoigne NRJ, Zal T: Molecular interactions at the T cell– antigen-presenting cell interface. Curr Opin Immunol 2004, 16:114-119.
Current Opinion in Immunology 2004, 16:63–66
Al-Daccak R, Mooney N, Charron D: MHC class II signaling in antigen-presenting cells. Curr Opin Immunol 2004, 16:108-113.
11. Germain RN, Jenkins MK: In vivo antigen presentation. Curr Opin Immunol 2004, 16:120-125.
www.sciencedirect.com
Peter J van den Elsen Division of Molecular Biology, Department of Immunohematology and Blood Transfusion, Building 1, E3-Q, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands e-mail: [email protected]
The current research interest of the members of Peter van den Elsen’s laboratory is in molecular mechanisms that control immune activation with an emphasis on antigen presentation by MHC class I and class II molecules. This research involves areas of cancer, autoimmune disease with emphasis on multiple sclerosis, transplantation and maternal-fetal interactions. Alexander Rudensky Howard Hughes Medical Institute, Box 357370, Health Science Building, I604I, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA e-mail: [email protected]
Research in Alexander Rudensky’s group is focused on the intracellular mechanisms of generation of CD4 Tcell receptor ligands and the role they play in CD4 T-cell differentiation and lineage commitment in the thymus and periphery.
www.sciencedirect.com
Abbreviations APC antigen-presenting cell CIITA class II transactivator DC dendritic cell DRiPs defective ribosomal products ER endoplasmic reticulum TCR T-cell receptor
T-cell recognition of antigens is dependent upon the expression of MHC molecules on the surface of antigen presenting cells (APCs). In these cells, class I and class II MHC molecules, and MHC-like CD1 molecules sample products of protein and glycolipid breakdown, respectively, and transport them to the cell surface for recognition by the T-cell receptors (TCRs). MHC class I molecules, which present peptides generated in the cytosol to CD8þ T cells, are expressed on the majority of nucleated cells. In contrast, MHC class II molecules, which present peptides generated in the endocytic compartment to CD4þ T cells, are found primarily on the surface of specialised APCs due to the tightly controlled expression of the class II transactivator (CIITA), which is essential for MHC class II transcription. The basic principles of these processes, summarily known as antigen processing and presentation, were established some time ago and many principal molecular players have been identified. Recent years have brought about a number of new exciting developments stemming from the application of sophisticated genetic, biochemical and imaging approaches for the analysis of MHC gene expression, intracellular generation and transport of TCR ligands, and T cell–APC interactions. This section of Current Opinion in Immunology highlights the remarkable progress in this mature yet vibrant field of immunobiology. The section starts with a review by van den Elsen and colleagues [1] discussing the regulatory elements and factors that drive the expression of MHC class I and class II genes with a major emphasis on the control of CIITA expression. It has become increasingly clear that CIITA, in addition its role in the regulation of MHC genes, modulates the expression of various non-MHC genes, and thereby plays a more global role in antigen presentation. This is illustrated by the observation that CIITA is involved in the transcriptional regulation of the semaphorin Plexin-A, which is required for efficient interactions of dendritic cells (DCs) with T cells. Further advances in understanding the molecular mechanisms of CIITA transcriptional regulation have resulted in the identification of regulatory elements and their interacting factors that control CIITA expression in a lineage- and Current Opinion in Immunology 2004, 16:63–66
64 Antigen processing and recognition
cell-type-specific fashion. Furthermore, several chromatin-remodelling enzymes have now been described that are involved in the function and transcriptional regulation of CIITA. In particular, CIITA acts as a platform for histone acetylase and histone deacetylase activities. In addition, association with bramha-related gene-1, a component of the ATP-dependent chromatin remodelling complex SWI/SNF, seems to be required for CIITA function. Moreover, there are several lines of evidence in support of epigenetic mechanisms, such as CpG DNA methylation and histone deacetylation, that account for the lack of CIITA and, therefore, MHC class II expression in several types of malignant tumours. Significant advances in the elucidation of proteolytic events leading to generation of MHC-class-I-binding peptides are reviewed by Kloetzel and Ossendorp [2]. Proteosomes, as well as cytosolic and endoplasmic reticulum (ER) aminopeptidases contribute to generation of these ligands. The authors discuss the regulation of proteasome activity and the role of IFN-g in this process, in particular the conversion of ‘constitutive proteasomes’ to ‘immunoproteasomes’. Immunoproteasomes can affect the generation of CD8þ T-cell epitopes by facilitating the generation of some antigenic peptides while destroying others. In addition, proteosome composition may vary depending on a particular cell type, and this may lead to a cell-type-specific differences in the generation of CTL epitopes. Despite the highly efficient generation of peptides by proteosomes, however, only a small fraction ultimately associate with MHC class I molecules and are displayed on the APC surface to T lymphocytes. This is due to a variety of factors, including peptide destruction by cytosolic endo- and exopeptidases. The next key question is the source of proteins from which the presented peptides are derived. As discussed by Lehner and Cresswell [3], the major source of peptides presented by MHC class I molecules is a pool of polypeptides referred to as ‘defective ribosomal products’ or DRiPs. DRiPs encompass any polypeptide that is unable to fold properly, including erroneous translation products derived from non-coding regions of mRNA as well as alternative reading frames. DRiPs make up a sizeable portion of cytosolic peptides and contribute to the vast repertoire of peptides presented by MHC class I molecules. As a continuation of the theme touched upon by Kloetzel and Ossendrop [2], Cresswell and Lehner [3] discuss in further detail the low efficiency of generating a specific peptide–MHC complex from a particular gene product harbouring the class I epitope sequence. Apparently it takes 2000 copies of polypeptide to generate a single peptide–MHC class I complex. Another long-standing problem in the MHC class I presentation field is the elusive cellular mechanism(s) of cross-presentation, the fundamental phenomenon originCurrent Opinion in Immunology 2004, 16:63–66
ally discovered by Bevan [4,5]. This phenomenon, central to the development of CD8þ T-cell responses to infection and to tolerance induction, infers that MHC class I molecules expressed on DCs and macrophages are capable of presenting peptides derived from phagocytosed or endocytosed protein antigens. It requires the transfer of the internalized antigens from the endocytic pathway into the cytosol and proteosomal degradation followed by TAP (transporter associated with antigen processing)dependent ER translocation of the resulting peptides. The recently demonstrated recruitment of ER membrane components, in particular the Sec61 complex, to the phagosomes finally provided a mechanistic explanation for the retrotranslocation of phagosomal proteins into the cytosol. Finally, Lehner and Cresswell [3] discuss the mechanisms that the emerging family of viral K3-immunoevasion genes employ to compromise MHC-class-I-mediated presentation. These virus-encoded membrane-associated ubiquitin E3 ligases affect the cell-surface expression of MHC class I molecules. Furthermore, cellular homologues of these viral genes have been recently identified, and their role in ubiquitination of MHC class I and other important immunoregulatory molecules is being investigated. In contrast to classical MHC class I molecules, MHCclass-I-like CD1 molecules bind their ligands in the endosomal/lysosomal compartment. In their review, Brenner and co-workers [6] present new insights into the CD1 presentation pathway. CD1 molecules bind acyl chains and, therefore, this ‘third arm’ of antigen presentation allows T cells to recognise fatty acids, glycolipids and lipopeptide antigens of foreign or self origin. This presentation pathway is of a major importance for antimycobacterial immunity. Recent studies demonstrated that different CD1 isoforms in humans sample different aspects of the endocytic pathway, including early and late endosomes, and lysosomes. This is achieved by differential trafficking of CD1a, CD1b, CD1c and CD1d molecules, which is mediated by distinct tyrosine-based motifs within their cytoplasmic tails that are capable of interacting with different adaptor complexes (AP-2 and AP-3). Defects in some of these pathways, such as in patients with Hermansky-Pudlak syndrome type 2, affect lipid antigen sampling by CD1 molecules while MHC class II function remains normal. Recent advances in proteolytic mechanisms of MHC class II presentation, intracellular assembly and export of peptide MHC class II complexes to the plasma membrane in various APC types are reviewed by Bryant and Ploegh [7]. These topics include the roles that Ig receptor signalling and the chaperone molecule HLA-DO play in regulation of the HLA-DM and MHC class II peptide loading during antigen-dependent and -independent B-cell differentiation. The facilitation of MHC class II presentation www.sciencedirect.com
Editorial overview van den Elsen and Rudensky 65
in phagocytic cells, macrophages and DCs, in addition to B cells, also requires signalling. These signals are provided upon the binding of pathogens to specific patternrecognition and endocytic receptors, leading to activation of the MHC class II presentation pathway and internalisation of the pathogen. Antigens derived from phagocytosed particles or pathogens can be loaded directly onto MHC class II molecules in the phagosome or released and transferred to the classical endocytic compartments for loading onto MHC class II molecules. Immature DCs are efficient at endocytosing antigens and/or pathogens, yet they are not capable of efficiently generating peptide– MHC class II complexes. In the course of DC maturation, MHC class II molecules are redistributed to the late endocytic peptide-loading MHC class II compartment (MIIC) in conjunction with an increase in its protein degradative activity. These events, which greatly enhance the efficiency of peptide–MHC class II complex assembly, are followed by the directed transport of these complexes to the site of the APC contact with the T cell, facilitated by the remarkable vectorial tubulation of the endosomal membranes. It turns out that exported peptide–MHC class II complexes are not randomly distributed on the surface of APCs. As discussed by Poloso and Roche [8], peptide– MHC class II complexes formed in MIIC are contained within cholesterol-rich plasma membrane microdomains, the so-called lipid rafts. Depletion of cholesterol from the plasma membrane disrupts lipid rafts and affects the capacity of antigen-loaded APCs to activate T cells. However, the diminution of T-cell responses occurs only when the numbers of specific peptide–MHC class II complexes are low, but not when high numbers of these complexes are presented. To explain this phenomenon, a model has been put forward that integrates the known biochemical properties of antigen processing, peptide loading and MHC class II molecule trafficking. The directed transport of peptide–MHC class II complexes within lipid rafts and their continuing ‘clustered’ expression of the cell surface is thought to increase the efficiency of antigen recognition by T cells, which face an enormous task of distinguishing a very small number of antigenic peptide from thousands of peptides derived form self-proteins. In addition to T-cell activation, T-cell recognition of raftassociated MHC-class-II–peptide complexes activates signalling pathways within APCs. Al-Daccak and colleagues [9] suggest that signalling through MHC class II molecules plays an important role in regulation of the immune response. At the molecular level, MHC class II signalling is linked to the activation of the protein tyrosine kinase (PTK), protein kinase C (PKC) and mitogenactivated protein kinase (MAPK) pathways, thereby affecting various cellular functions, ranging from cytokine production, proliferation and differentiation to cell death. www.sciencedirect.com
Major advances in imaging technology have made it possible to visualise molecular interactions between T cells and APCs in vitro, and to investigate the dynamic movements of molecules involved in T-cell recognition and signalling at the T cell–APC interface dubbed the immunological synapse. Gascoigne and Zal [10] review the application of fluorescence resonance energy transfer (FRET) imaging to study these processes. They discuss a body of data suggesting that synapse formation is preceded by certain early signalling events resulting in the elaborately orchestrated rearrangement and clustering of several key molecules involved in T cell–APC interactions within the immunological synapse and in its proximity. This clustering leads to stabilisation of the synapse and sustained signalling which is required for the full Tcell activation. The review by Germain and Jenkins [11] further highlights advances in the visualisation of antigen presentation events in vivo. This has become possible through the development of monoclonal antibodies (mAb) specific for defined peptide–MHC complexes and the application of powerful imaging approaches such as two-photon microscopy. These mAb reagents make it possible to monitor the expression of specific peptide–MHC class II complexes on APC (e.g. distinct subsets of DC) in the course of the immune response in vivo. The two-photon imaging enables documentation of the movement of immune T cells and their interactions with APCs in secondary lymphoid organs in real time. These studies have revealed the high mobility of naı¨ve T cells in the absence of antigen, leading to transient contact with DCs and suggesting that naı¨ve T cells constantly probe DCs in a search for the relevant peptide–MHC complexes. In the presence of antigen, however, specific T cell–APC contacts lasted for many hours, which is critical for the initiation and maintenance of a productive T-cell response. Future application of these powerful approaches and their further development will provide novel insights into the dynamics of antigen presentation and T-cell activation in vivo.
References 1.
van den Elsen PJ, Holling TM, Kuipers HF, van der Stoep N: Transcriptional regulation of antigen presentation. Curr Opin Immunol 2004, 16:67-75.
2.
Kloetzel P-M, Ossendorp F: Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr Opin Immunol 2004, 16:76-81.
3.
Lehner PJ, Cresswell P: Recent developments in MHC-class-Imediated antigen presentation. Curr Opin Immunol 2004, 16:82-89.
4.
Bevan MJ: Minor H antigens introduced on H-2 different stimulating cells cross-react at the cytotoxic T cell level during in vivo priming. J Immunol 1976, 117:2233-2238.
5.
Bevan MJ: Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J Exp Med 1976, 143:1283-1288. Current Opinion in Immunology 2004, 16:63–66
66 Antigen processing and recognition
6.
Sugita M, Cernadas M, Brenner MB: New insights into pathways for CD1-mediated antigen presentation. Curr Opin Immunol 2004, 16:90-95.
9.
7.
Bryant P, Ploegh H: Class II MHC peptide loading by the professionals. Curr Opin Immunol 2004, 16:96-102.
8.
Poloso NJ, Roche PA: Association of MHC class II–peptide complexes with plasma membrane lipid microdomains. Curr Opin Immunol 2004, 16:103-107.
10. Gascoigne NRJ, Zal T: Molecular interactions at the T cell– antigen-presenting cell interface. Curr Opin Immunol 2004, 16:114-119.
Current Opinion in Immunology 2004, 16:63–66
Al-Daccak R, Mooney N, Charron D: MHC class II signaling in antigen-presenting cells. Curr Opin Immunol 2004, 16:108-113.
11. Germain RN, Jenkins MK: In vivo antigen presentation. Curr Opin Immunol 2004, 16:120-125.
www.sciencedirect.com