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 2

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Culturing with M1 and BMLF1 peptides simultaneously promotes the growth ...
Culturing with M1 and BMLF1 peptides simultaneously promotes the growth of cross-reactive cells. A CD8+ T cell line derived from healthy donor D-002 was grown for 4 weeks in the presence of both M1 and BMLF1 peptide–pulsed T2 cells. Cells were stimulated for 5 hours with various peptides and then stained extracellularly with tetramers and intracellularly for the production of MIP-1β, IFN-γ, and TNF-α. We gated (indicated by a bold box) on (A) the percentage of CD8+ T cells that costained with both M1- and BMLF1-loaded tetramers, (B) the percentage of CD8+ T cells that stained with only M1-loaded tetramer, and (C) the percentage of CD8+ T cells that stained with only BMLF1-loaded tetramer. We then assessed the cytokine production of those cells in response to the following peptide stimulations: tyrosinase (gray profiles), M1 (dotted lines), and BMLF1 (solid lines). The percentage of CD8+ T cells producing each cytokine within the positive gate (horizontal lines) drawn is shown below each of the corresponding histograms. (D) This T cell line was stained extracellularly with EBV-BRLF1–loaded tetramer as a control.