Cross-reactive influenza virus–specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus–associated infectious mononucleosis
Shalyn C. Clute, … , Raymond M. Welsh, Liisa K. Selin
Shalyn C. Clute, … , Raymond M. Welsh, Liisa K. Selin
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3602-3612. https://doi.org/10.1172/JCI25078.
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Research Article Immunology

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

Abstract

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 M158–66–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-BMLF1280–288, 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.

Authors

Shalyn C. Clute, Levi B. Watkin, Markus Cornberg, Yuri N. Naumov, John L. Sullivan, Katherine Luzuriaga, Raymond M. Welsh, Liisa K. Selin

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Figure 1

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T cell lines grown in the presence of 1 peptide can respond to stimulati...
T cell lines grown in the presence of 1 peptide can respond to stimulation with a second unrelated peptide. (A) CD8+ T cells were isolated ex vivo from healthy donor D-002 and costained with M1- and BMLF1-loaded tetramers; 106 events were collected. (B and C) Fresh CD8+ T cell lines derived from donor D-002 were grown for 3–4 weeks in the presence of (B) M1 peptide–pulsed or (C) BMLF1 peptide–pulsed T2 cells and then stained intracellularly for the production of IFN-γ or MIP-1β following 5 hours of stimulation with various HLA-A2–restricted peptides at a 5 μM final concentration. Percentages of CD8+ T cells producing each cytokine are shown. (D) Titration of peptide concentrations in an intracellular IFN-γ assay using an M1-specific T cell line derived from donor D-002 demonstrated a slight difference in avidity for M1 versus BMLF1. Filled triangles, tyrosinase; open circles, M1; and filled circles, BMLF1 stimulation.