Cytotoxic CD4+ T-cells specific for EBV capsid antigen BORF1 are maintained in long-term latently infected healthy donors
Autor: | Alexander C. Dowell, Tracey A. Haigh, Gordon B. Ryan, James E. Turner, Heather M. Long, Graham S. Taylor |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
CD4-Positive T-Lymphocytes
Epstein-Barr Virus Infections Herpesvirus 4 Human B Cells Biochemistry Viral Packaging White Blood Cells Animal Cells hemic and lymphatic diseases Medicine and Health Sciences Enzyme-Linked Immunoassays Biology (General) Pathology and laboratory medicine T Cells Medical microbiology Virus Latency DNA-Binding Proteins Viruses Structural Proteins Cellular Types Pathogens Research Article Herpesviruses QH301-705.5 Immune Cells Immunology Cytotoxic T cells Research and Analysis Methods Microbiology Viral Proteins Virology Genetics Epstein-Barr virus Humans Antibody-Producing Cells Molecular Biology Techniques Immunoassays Molecular Biology Blood Cells Organisms Viral pathogens Biology and Life Sciences Proteins Cell Biology RC581-607 Viral Replication Microbial pathogens Immunologic Techniques Latent Infection Parasitology Immunologic diseases. Allergy DNA viruses Cloning T-Lymphocytes Cytotoxic |
Zdroj: | PLoS Pathogens, Vol 17, Iss 12, p e1010137 (2021) PLoS Pathogens |
ISSN: | 1553-7374 1553-7366 |
Popis: | 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. Author summary Epstein-Barr virus is a widespread herpesvirus carried by most individuals. Whilst infection is usually asymptomatic, development of a prophylactic vaccine against EBV is desirable because of the virus’s association with infectious mononucleosis in primary infection and several cancers and autoimmune diseases during long-term virus carriage. Identifying T-cell responses that can recognise newly infected B-cells at very early stages of infection may provide novel targets for T-cell vaccination. Here we characterise T-cell responses against three virus proteins, BcLF1, BDLF1 and BORF1 that, as structural proteins of the virus particle, are delivered into the cell by the infecting virus. We find that all three proteins are recognised by T-cells from infected individuals. Moreover, isolated structural antigen-specific CD4+ T-cells rapidly recognise newly infected B-cells and prevent their outgrowth in vitro. As reported for CD4+ T-cells against other EBV proteins, structural antigen-specific CD4+ T-cells induced by primary EBV infection have cytotoxic function. However, we also demonstrate that, unusually, this cytotoxic function is retained in memory T-cells present in long-term infected individuals. Structural antigens may therefore represent useful targets for prophylactic EBV vaccine development to induce CD4+ T-cells able to rapidly eliminate virus-infected cells. |
Databáze: | OpenAIRE |
Externí odkaz: |