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Article ; Online: Bioengineered small extracellular vesicles deliver multiple SARS-CoV-2 antigenic fragments and drive a broad immunological response.

Jackson, Hannah K / Long, Heather M / Yam-Puc, Juan Carlos / Palmulli, Roberta / Haigh, Tracey A / Gerber, Pehuén Pereyra / Lee, Jin S / Matheson, Nicholas J / Young, Lesley / Trowsdale, John / Lo, Mathew / Taylor, Graham S / Thaventhiran, James E / Edgar, James R

Journal of extracellular vesicles

2024 Volume 13, Issue 2, Page(s) e12412

Abstract: The COVID-19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence ... ...

Abstract	The COVID-19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence of SARS-CoV-2 breakthrough infections highlights the need for additional vaccine modalities to provide stronger, long-lived protective immunity. Here we report the design and preclinical testing of small extracellular vesicles (sEVs) as a multi-subunit vaccine. Cell lines were engineered to produce sEVs containing either the SARS-CoV-2 Spike receptor-binding domain, or an antigenic region from SARS-CoV-2 Nucleocapsid, or both in combination, and we tested their ability to evoke immune responses in vitro and in vivo. B cells incubated with bioengineered sEVs were potent activators of antigen-specific T cell clones. Mice immunised with sEVs containing both sRBD and Nucleocapsid antigens generated sRBD-specific IgGs, nucleocapsid-specific IgGs, which neutralised SARS-CoV-2 infection. sEV-based vaccines allow multiple antigens to be delivered simultaneously resulting in potent, broad immunity, and provide a quick, cheap, and reliable method to test vaccine candidates.
MeSH term(s)	Animals ; Humans ; Mice ; SARS-CoV-2 ; Pandemics ; COVID-19 ; Extracellular Vesicles ; Vaccines
Chemical Substances	Vaccines
Language	English
Publishing date	2024-02-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2683797-3
ISSN	2001-3078 ; 2001-3078
ISSN (online)	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12412
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Article ; Online: Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4

Chen, Yuan / Mason, Georgina H / Scourfield, D Oliver / Greenshields-Watson, Alexander / Haigh, Tracey A / Sewell, Andrew K / Long, Heather M / Gallimore, Awen M / Rizkallah, Pierre / MacLachlan, Bruce J / Godkin, Andrew

Cell reports

2023 Volume 42, Issue 8, Page(s) 112827

Abstract: ... ...

Abstract	CD4
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; HLA-DR1 Antigen ; Epitopes, T-Lymphocyte ; Peptides ; CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes
Chemical Substances	HLA-DR1 Antigen ; Epitopes, T-Lymphocyte ; Peptides
Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112827
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Article ; Online: Cytotoxic CD4+ T-cells specific for EBV capsid antigen BORF1 are maintained in long-term latently infected healthy donors.

Dowell, Alexander C / Haigh, Tracey A / Ryan, Gordon B / Turner, James E / Long, Heather M / Taylor, Graham S

PLoS pathogens

2021 Volume 17, Issue 12, Page(s) e1010137

Abstract: Epstein Barr Virus (EBV) infects more than 95% of the population whereupon it establishes a latent infection of B-cells that persists for life under immune control. Primary EBV infection can cause infectious mononucleosis (IM) and long-term viral ... ...

Abstract	Epstein Barr Virus (EBV) infects more than 95% of the population whereupon it establishes a latent infection of B-cells that persists for life under immune control. Primary EBV infection can cause infectious mononucleosis (IM) and long-term viral carriage is associated with several malignancies and certain autoimmune diseases. Current efforts developing EBV prophylactic vaccination have focussed on neutralising antibodies. An alternative strategy, that could enhance the efficacy of such vaccines or be used alone, is to generate T-cell responses capable of recognising and eliminating newly EBV-infected cells before the virus initiates its growth transformation program. T-cell responses against the EBV structural proteins, brought into the newly infected cell by the incoming virion, are prime candidates for such responses. Here we show the structural EBV capsid proteins BcLF1, BDLF1 and BORF1 are frequent targets of T-cell responses in EBV infected people, identify new CD8+ and CD4+ T-cell epitopes and map their HLA restricting alleles. Using T-cell clones we demonstrate that CD4+ but not CD8+ T-cell clones specific for the capsid proteins can recognise newly EBV-infected B-cells and control B-cell outgrowth via cytotoxicity. Using MHC-II tetramers we show a CD4+ T-cell response to an epitope within the BORF1 capsid protein epitope is present during acute EBV infection and in long-term viral carriage. In common with other EBV-specific CD4+ T-cell responses the BORF1-specific CD4+ T-cells in IM patients expressed perforin and granzyme-B. Unexpectedly, perforin and granzyme-B expression was sustained over time even when the donor had entered the long-term infected state. These data further our understanding of EBV structural proteins as targets of T-cell responses and how CD4+ T-cell responses to EBV change from acute disease into convalescence. They also identify new targets for prophylactic EBV vaccine development.
MeSH term(s)	CD4-Positive T-Lymphocytes/immunology ; DNA-Binding Proteins/immunology ; Epstein-Barr Virus Infections/immunology ; Herpesvirus 4, Human/immunology ; Humans ; Latent Infection/immunology ; T-Lymphocytes, Cytotoxic/immunology ; Viral Proteins/immunology ; Virus Latency/immunology
Chemical Substances	BORF1 protein, Epstein-Barr virus ; DNA-Binding Proteins ; Viral Proteins
Language	English
Publishing date	2021-12-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010137
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Article ; Online: Mutations in SARS-CoV-2 spike protein impair epitope-specific CD4

Tye, Emily X C / Jinks, Elizabeth / Haigh, Tracey A / Kaul, Baksho / Patel, Prashant / Parry, Helen M / Newby, Maddy L / Crispin, Max / Kaur, Nayandeep / Moss, Paul / Drennan, Samantha J / Taylor, Graham S / Long, Heather M

Nature immunology

2022

Abstract: ... ...

Abstract	CD4
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-022-01351-7
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Article ; Online: The role of tetraspanin CD63 in antigen presentation via MHC class II.

Petersen, Sven H / Odintsova, Elena / Haigh, Tracey A / Rickinson, Alan B / Taylor, Graham S / Berditchevski, Fedor

European journal of immunology

2011 Volume 41, Issue 9, Page(s) 2556–2561

Abstract: Interactions between MHC class II (MHC II)-positive APCs and CD4(+) T cells are central to adaptive immune responses. Using an Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell line (LCL) as MHC II-positive APCs and CD4(+) T-cell clones ... ...

Abstract	Interactions between MHC class II (MHC II)-positive APCs and CD4(+) T cells are central to adaptive immune responses. Using an Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell line (LCL) as MHC II-positive APCs and CD4(+) T-cell clones specific for two endogenously expressed EBV antigens, we found that shRNA knockdown of the tetraspanin protein CD63 in LCL cells consistently led to increased CD4(+) T-cell recognition. This effect was not due to enhanced antigen processing nor to changes in MHC II expression since CD63 knockdown did not influence the amount or dimerization of MHC II in LCL cells. We therefore investigated the possible involvement of exosomes, small MHC II- and tetraspanin-abundant vesicles which are secreted by LCL cells and which we found could themselves activate the CD4(+) T-cell clones in an MHC II-dependent manner. While equal loadings of exosomes purified from the control and CD63(low) LCLs stimulated T cells to a comparable degree, we found that exosome production significantly increased following CD63-knockdown, suggesting that this may underlie the greater T-cell stimulatory capacity of the CD63(low) LCLs. Taken together, our data reveal a new insight into the mechanisms by which tetraspanins are involved in the regulation of MHC II-dependent T-cell stimulation.
MeSH term(s)	Adaptive Immunity ; Antigen Presentation/genetics ; Antigens, Viral/immunology ; Antigens, Viral/metabolism ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; B-Lymphocytes/ultrastructure ; B-Lymphocytes/virology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/pathology ; CD4-Positive T-Lymphocytes/virology ; Cell Line, Transformed ; Clone Cells ; Exosomes/immunology ; Exosomes/metabolism ; Exosomes/ultrastructure ; Herpesvirus 4, Human/immunology ; Histocompatibility Antigens Class II/immunology ; Histocompatibility Antigens Class II/metabolism ; Humans ; Lymphocyte Activation/genetics ; Microscopy, Electron ; RNA, Small Interfering/genetics ; Tetraspanin 30/genetics ; Tetraspanin 30/immunology ; Tetraspanin 30/metabolism
Chemical Substances	Antigens, Viral ; Histocompatibility Antigens Class II ; RNA, Small Interfering ; Tetraspanin 30
Language	English
Publishing date	2011-08-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201141438
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Article ; Online: Nuclear location of an endogenously expressed antigen, EBNA1, restricts access to macroautophagy and the range of CD4 epitope display.

Leung, Carol S / Haigh, Tracey A / Mackay, Laura K / Rickinson, Alan B / Taylor, Graham S

Proceedings of the National Academy of Sciences of the United States of America

2010 Volume 107, Issue 5, Page(s) 2165–2170

Abstract: Whereas exogenously acquired proteins are the major source of antigens feeding the MHC class II pathway in antigen-presenting cells, some endogenously expressed antigens also access that pathway but the rules governing such access are poorly understood. ... ...

Abstract	Whereas exogenously acquired proteins are the major source of antigens feeding the MHC class II pathway in antigen-presenting cells, some endogenously expressed antigens also access that pathway but the rules governing such access are poorly understood. Here we address this using Epstein-Barr virus (EBV)-coded nuclear antigen EBNA1, a protein naturally expressed in EBV-infected B lymphoblastoid cell lines (LCLs) and a source of multiple CD4(+) T cell epitopes. Using CD4(+) T cell clones against three indicator epitopes, we find that two epitopes are weakly displayed on the LCL surface whereas the third is undetectable, a pattern of limited epitope presentation that is maintained even when nuclear expression of EBNA1 is induced to high supraphysiological levels. Inhibitor and siRNA studies show that, of the two epitopes weakly presented under these conditions, one involves macroautophagy, and the second involves antigen delivery to the MHC II pathway by another endogenous route. In contrast, when EBNA1 is expressed as a cytoplasmic protein, all three CD4 epitopes are processed and presented much more efficiently, and all involve macroautophagy. We conclude that EBNA1's nuclear location limits its accessibility to the macroautophagy pathway and, in consequence, limits the level and range of EBNA1 CD4 epitopes naturally displayed on the infected cell surface.
MeSH term(s)	Antigen Presentation ; Autophagy/immunology ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/virology ; CD4 Antigens/metabolism ; Cell Line ; Cell Nucleus/immunology ; Cell Nucleus/virology ; Epitopes, T-Lymphocyte/genetics ; Epitopes, T-Lymphocyte/metabolism ; Epstein-Barr Virus Nuclear Antigens/genetics ; Epstein-Barr Virus Nuclear Antigens/metabolism ; HLA-DR Antigens/metabolism ; Herpesvirus 4, Human/immunology ; Humans
Chemical Substances	CD4 Antigens ; Epitopes, T-Lymphocyte ; Epstein-Barr Virus Nuclear Antigens ; HLA-DR Antigens ; EBV-encoded nuclear antigen 1 (O5GA75RST7)
Language	English
Publishing date	2010-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0909448107
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Article ; Online: Robust T-cell stimulation by Epstein-Barr virus-transformed B cells after antigen targeting to DEC-205.

Leung, Carol S / Maurer, Michael A / Meixlsperger, Sonja / Lippmann, Anne / Cheong, Cheolho / Zuo, Jianmin / Haigh, Tracey A / Taylor, Graham S / Münz, Christian

Blood

2013 Volume 121, Issue 9, Page(s) 1584–1594

Abstract: DEC-205 is a type I transmembrane multilectin receptor that is predominantly expressed on dendritic cells (DCs). Therefore, previous studies primarily focused on processing of DEC-205–targeted antigens by this potent antigen presenting cell type. Here we ...

Abstract	DEC-205 is a type I transmembrane multilectin receptor that is predominantly expressed on dendritic cells (DCs). Therefore, previous studies primarily focused on processing of DEC-205–targeted antigens by this potent antigen presenting cell type. Here we show that Epstein-Barr virus (EBV) transformed lymphoblastoid B-cell lines (LCLs) not only express DEC-205 at similar levels to DCs, but also efficiently present targeted EBV nuclear antigen 1 (EBNA1) and EBV-latent membrane protein 1 (LMP1) to EBNA1- and LMP1-specific CD4+ and CD8+ T-cell clones in vitro. Targeting of antigens to DEC-205 on B cells led to more efficient MHC class II than I loading, and stimulated T cells more efficiently than targeting to DEC-205 on DCs. Although LCLs internalized DEC-205–targeted antigens less efficiently than DCs, they retained them for longer time periods and delivered them to endosomal compartments that receive also B-cell receptor targeted proteins. This could facilitate prolonged T-cell stimulation and efficient MHC class II loading, and, indeed, CD4+ T-cell expansion by DEC-205–targeted vaccination was significantly compromised in B-cell deficient mice. These studies suggest that B cells, activated by virus transformation or other means, can contribute to T-cell stimulation after DEC-205 targeting of antigens during vaccination.
MeSH term(s)	Animals ; Antigen Presentation/physiology ; Antigens, CD/immunology ; Antigens, CD/metabolism ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; B-Lymphocytes/virology ; Cell Line, Transformed ; Cell Transformation, Viral/immunology ; Cells, Cultured ; Dendritic Cells/immunology ; Dendritic Cells/physiology ; Herpesvirus 4, Human/immunology ; Herpesvirus 4, Human/physiology ; Lectins, C-Type/immunology ; Lectins, C-Type/metabolism ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Minor Histocompatibility Antigens ; Molecular Targeted Therapy ; Receptors, Antigen, B-Cell/immunology ; Receptors, Antigen, B-Cell/metabolism ; Receptors, Cell Surface/immunology ; Receptors, Cell Surface/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/physiology ; Vaccination/methods
Chemical Substances	Antigens, CD ; DEC-205 receptor ; Lectins, C-Type ; Minor Histocompatibility Antigens ; Receptors, Antigen, B-Cell ; Receptors, Cell Surface
Language	English
Publishing date	2013-01-07
Publishing country	United States
Document type	Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2012-08-450775
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Article: Nuclear location of an endogenously expressed antigen, EBNA1, restricts access to macroautophagy and the range of CD4 epitope display

Leung, Carol S / Haigh, Tracey A / Mackay, Laura K / Rickinson, Alan B / Taylor, Graham S

Proceedings of the National Academy of Sciences of the United States of America. 2010 Feb. 2, v. 107, no. 5

2010

Abstract	Whereas exogenously acquired proteins are the major source of antigens feeding the MHC class II pathway in antigen-presenting cells, some endogenously expressed antigens also access that pathway but the rules governing such access are poorly understood. Here we address this using Epstein-Barr virus (EBV)-coded nuclear antigen EBNA1, a protein naturally expressed in EBV-infected B lymphoblastoid cell lines (LCLs) and a source of multiple CD4âº T cell epitopes. Using CD4âº T cell clones against three indicator epitopes, we find that two epitopes are weakly displayed on the LCL surface whereas the third is undetectable, a pattern of limited epitope presentation that is maintained even when nuclear expression of EBNA1 is induced to high supraphysiological levels. Inhibitor and siRNA studies show that, of the two epitopes weakly presented under these conditions, one involves macroautophagy, and the second involves antigen delivery to the MHC II pathway by another endogenous route. In contrast, when EBNA1 is expressed as a cytoplasmic protein, all three CD4 epitopes are processed and presented much more efficiently, and all involve macroautophagy. We conclude that EBNA1's nuclear location limits its accessibility to the macroautophagy pathway and, in consequence, limits the level and range of EBNA1 CD4 epitopes naturally displayed on the infected cell surface.
Keywords	CD4-positive T-lymphocytes ; Human herpesvirus 4 ; antigen-presenting cells ; clones ; epitopes ; proteins ; small interfering RNA
Language	English
Dates of publication	2010-0202
Size	p. 2165-2170.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0909448107
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Article ; Online: Epstein-Barr virus evades CD4+ T cell responses in lytic cycle through BZLF1-mediated downregulation of CD74 and the cooperation of vBcl-2.

Zuo, Jianmin / Thomas, Wendy A / Haigh, Tracey A / Fitzsimmons, Leah / Long, Heather M / Hislop, Andrew D / Taylor, Graham S / Rowe, Martin

PLoS pathogens

2011 Volume 7, Issue 12, Page(s) e1002455

Abstract: Evasion of immune T cell responses is crucial for viruses to establish persistence in the infected host. Immune evasion mechanisms of Epstein-Barr virus (EBV) in the context of MHC-I antigen presentation have been well studied. In contrast, viral ... ...

Abstract	Evasion of immune T cell responses is crucial for viruses to establish persistence in the infected host. Immune evasion mechanisms of Epstein-Barr virus (EBV) in the context of MHC-I antigen presentation have been well studied. In contrast, viral interference with MHC-II antigen presentation is less well understood, not only for EBV but also for other persistent viruses. Here we show that the EBV encoded BZLF1 can interfere with recognition by immune CD4+ effector T cells. This impaired T cell recognition occurred in the absence of a reduction in the expression of surface MHC-II, but correlated with a marked downregulation of surface CD74 on the target cells. Furthermore, impaired CD4+ T cell recognition was also observed with target cells where CD74 expression was downregulated by shRNA-mediated inhibition. BZLF1 downregulated surface CD74 via a post-transcriptional mechanism distinct from its previously reported effect on the CIITA promoter. In addition to being a chaperone for MHC-II αβ dimers, CD74 also functions as a surface receptor for macrophage Migration Inhibitory Factor and enhances cell survival through transcriptional upregulation of Bcl-2 family members. The immune-evasion function of BZLF1 therefore comes at a cost of induced toxicity. However, during EBV lytic cycle induced by BZLF1 expression, this toxicity can be overcome by expression of the vBcl-2, BHRF1, at an early stage of lytic infection. We conclude that by inhibiting apoptosis, the vBcl-2 not only maintains cell viability to allow sufficient time for synthesis and accumulation of infectious virus progeny, but also enables BZLF1 to effect its immune evasion function.
MeSH term(s)	Antigens, Differentiation, B-Lymphocyte/biosynthesis ; Antigens, Differentiation, B-Lymphocyte/genetics ; Antigens, Differentiation, B-Lymphocyte/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/virology ; Down-Regulation/genetics ; Down-Regulation/immunology ; Epstein-Barr Virus Infections/genetics ; Epstein-Barr Virus Infections/immunology ; Epstein-Barr Virus Infections/metabolism ; Herpesvirus 4, Human/genetics ; Herpesvirus 4, Human/immunology ; Herpesvirus 4, Human/metabolism ; Histocompatibility Antigens Class II/biosynthesis ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/immunology ; Humans ; Immune Evasion ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/immunology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Trans-Activators/genetics ; Trans-Activators/immunology ; Trans-Activators/metabolism
Chemical Substances	Antigens, Differentiation, B-Lymphocyte ; BZLF1 protein, Herpesvirus 4, Human ; Histocompatibility Antigens Class II ; Proto-Oncogene Proteins c-bcl-2 ; Trans-Activators ; invariant chain
Language	English
Publishing date	2011-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1002455
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Article: A role for intercellular antigen transfer in the recognition of EBV-transformed B cell lines by EBV nuclear antigen-specific CD4+ T cells.

Taylor, Graham S / Long, Heather M / Haigh, Tracey A / Larsen, Martin / Brooks, Jill / Rickinson, Alan B

Journal of immunology (Baltimore, Md. : 1950)

2006 Volume 177, Issue 6, Page(s) 3746–3756

Abstract: The CD4+ T cell response to EBV may have an important role in controlling virus-driven B lymphoproliferation because CD4+ T cell clones to a subset of EBV nuclear Ag (EBNA) epitopes can directly recognize virus-transformed lymphoblastoid cell lines (LCLs) ...

Abstract	The CD4+ T cell response to EBV may have an important role in controlling virus-driven B lymphoproliferation because CD4+ T cell clones to a subset of EBV nuclear Ag (EBNA) epitopes can directly recognize virus-transformed lymphoblastoid cell lines (LCLs) in vitro and inhibit their growth. In this study, we used a panel of EBNA1, 2, 3A, and 3C-specific CD4+ T cell clones to study the route whereby endogenously expressed EBNAs access the HLA class II-presentation pathway. Two sets of results spoke against a direct route of intracellular access. First, none of the clones recognized cognate Ag overexpressed in cells from vaccinia vectors but did recognize Ag fused to an endo/lysosomal targeting sequence. Second, focusing on clones with the strongest LCL recognition that were specific for EBNA2- and EBNA3C-derived epitopes LCL recognition was unaffected by inhibiting autophagy, a postulated route for intracellular Ag delivery into the HLA class II pathway in LCL cells. Subsequently, using these same epitope-specific clones, we found that Ag-negative cells with the appropriate HLA-restricting allele could be efficiently sensitized to CD4+ T cell recognition by cocultivation with Ag-positive donor lines or by exposure to donor line-conditioned culture medium. Sensitization was mediated by a high m.w. antigenic species and required active Ag processing by recipient cells. We infer that intercellular Ag transfer plays a major role in the presentation of EBNA-derived CD4 epitopes by latently infected target cells.
MeSH term(s)	Antigen Presentation/genetics ; Antigen Presentation/immunology ; Antigens, Viral/biosynthesis ; Antigens, Viral/genetics ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; B-Lymphocyte Subsets/virology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/virology ; Cell Line, Transformed ; Cell Line, Tumor ; Clone Cells ; Coculture Techniques ; Epitopes, T-Lymphocyte/immunology ; Epitopes, T-Lymphocyte/metabolism ; Epstein-Barr Virus Nuclear Antigens/genetics ; Epstein-Barr Virus Nuclear Antigens/immunology ; Epstein-Barr Virus Nuclear Antigens/metabolism ; Extracellular Space/genetics ; Extracellular Space/immunology ; Genetic Vectors ; Humans ; Lymphocyte Activation/genetics ; Vaccinia virus/genetics
Chemical Substances	Antigens, Viral ; Epitopes, T-Lymphocyte ; Epstein-Barr Virus Nuclear Antigens
Language	English
Publishing date	2006-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.177.6.3746
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