title: Long-term carriers generate Epstein-Barr virus (EBV)-specific CD4(+) and CD8(+) polyfunctional T-cell responses which show immunodominance hierarchies of EBV proteins.
abstract: T cells simultaneously producing multiple cytokines and possessing cytotoxic capacity termed polyfunctional cells (PFCs) are increasingly recognized as the immune correlate of protection against pathogenic viruses. We investigated co-expression of four cytokines (interferon-γ, macrophage inflammatory protein 1-α, tumour necrosis factor-α and interleukin-2) and degranulation capacity (CD107a surface expression) of Epstein-Barr virus (EBV) -specific CD4(+) and CD8(+) T cells upon stimulation by overlapping peptides of EBV lytic (BZLF1) and latent (EBNA1, EBNA3 and LMP2) proteins, in 20 healthy Chinese long-term carriers. Two patients with post-transplant lymphoproliferative disorder (PTLD), who had impaired T-cell immunity, were studied for comparison. Both EBV-specific CD4(+) and CD8(+) PFCs were readily generated in long-term carriers and showed immunodominance hierarchies of latent proteins (EBNA1 > EBNA3/LMP2 and EBNA3 > LMP2 > EBNA1 for CD4(+) and CD8(+) T cells, respectively), as evidenced by a higher proportion of PFCs generated by immunodominant EBV proteins than by subdominant viral proteins. In contrast, the proportion of EBV-specific PFCs was markedly decreased in patients with PTLD. The EBV-specific PFCs produced more cytokine per cell than single-functional T cells and comprised different subsets. Five-functional CD4(+) and CD8(+) T cells were detected and four-functional CD4(+) T cells were mainly CD107a negative and expressed all four cytokines whereas four-functional CD8(+) T cells were mainly CD107a positive and expressed three of the four cytokines (interleukin-2-negative). We conclude that EBV-specific PFCs are generated in much higher proportions in the long-term carriers than in the patients with PTLD and maintain the immunodominant characteristics of the virus.
authors: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China.
authors: Raymond J
authors: RJ
authors: Ning
authors: Xue Q
authors: XQ
authors: Xu
authors: Kwok H
authors: KH
authors: Chan
authors: Alan K S
authors: AK
authors: Chiang
mesh_terms: D000328:Adult; D044466:Asian People; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002353:Carrier State / Q000276:immunology* / Q000821:virology; D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000276:immunology; D002648:Child; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology*; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000378:metabolism / Q000821:virology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D055815:Young Adult
chemical_list: D054405:Chemokine CCL3; D019309:Epstein-Barr Virus Nuclear Antigens; D016056:Immunodominant Epitopes; D007376:Interleukin-2; D052118:Lysosomal-Associated Membrane Protein 1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma