Long-term carriers generate Epstein-Barr virus (EBV)-specific CD4(+) and CD8(+) polyfunctional T-cell responses which show immunodominance hierarchies of EBV proteins

Immunology. 2011 Oct;134(2):161-71. doi: 10.1111/j.1365-2567.2011.03476.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asians
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / virology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Carrier State / immunology*
  • Carrier State / virology
  • Chemokine CCL3 / biosynthesis
  • Chemokine CCL3 / immunology
  • Child
  • Epstein-Barr Virus Infections / immunology*
  • Epstein-Barr Virus Nuclear Antigens / immunology*
  • Female
  • Herpesvirus 4, Human / immunology*
  • Humans
  • Immunodominant Epitopes / immunology
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / immunology
  • Liver Transplantation / immunology
  • Lymphoproliferative Disorders / immunology
  • Lymphoproliferative Disorders / metabolism
  • Lymphoproliferative Disorders / virology
  • Lysosomal-Associated Membrane Protein 1 / immunology
  • Male
  • Middle Aged
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / immunology
  • Young Adult


  • Chemokine CCL3
  • Epstein-Barr Virus Nuclear Antigens
  • Immunodominant Epitopes
  • Interleukin-2
  • Lysosomal-Associated Membrane Protein 1
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma