Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis

J Clin Invest. 2005 Dec;115(12):3602-12. doi: 10.1172/JCI25078. Epub 2005 Nov 23.


The marked proliferation of activated CD8+ T cells is pathognomonic of EBV-associated infectious mononucleosis (IM), common in young adults. Since the diversity and size of the memory CD8+ T cell population increase with age, we questioned whether IM was mediated by the reactivation of memory CD8+ T cells specific to previously encountered pathogens but cross-reactive with EBV. Of 8 HLA-A2+ IM patients, 5 had activated T cells specific to another common virus, as evidenced by a significantly higher number of peripheral blood influenza A virus M1(58-66)-specific T cells compared with healthy immune donors. Two patients with an augmented M1 response had tetramer-defined cross-reactive cells recognizing influenza M1 and EBV-BMLF1(280-288), which accounted for up to one-third of their BMLF1-specific population and likely contributed to a skewed M1-specific T cell receptor repertoire. These epitopes, with only 33% sequence similarity, mediated differential effects on the function of the cross-reactive T cells, which may contribute to alterations in disease outcome. EBV could potentially encode an extensive pool of T cell epitopes that activate other cross-reactive memory T cells. Our results support the concept that cross-reactive memory CD8+ T cells activated by EBV contribute to the characteristic lymphoproliferation of IM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology*
  • Cell Proliferation
  • Chemokine CCL4
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / chemistry
  • Flow Cytometry
  • Genes, MHC Class I
  • HLA-A2 Antigen / chemistry
  • Herpesvirus 4, Human / metabolism*
  • Humans
  • Immunologic Memory
  • Infectious Mononucleosis / virology*
  • Influenza A virus / immunology
  • Interferon-gamma / metabolism
  • K562 Cells
  • Leukocytes, Mononuclear / cytology
  • Lymphocyte Activation
  • Lymphocytes / cytology*
  • Lymphocytes / virology*
  • Macrophage Inflammatory Proteins / metabolism
  • Orthomyxoviridae / genetics*
  • Peptides / chemistry
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / virology
  • Time Factors


  • Chemokine CCL4
  • Epitopes
  • HLA-A2 Antigen
  • Macrophage Inflammatory Proteins
  • Peptides
  • Receptors, Antigen, T-Cell
  • Interferon-gamma