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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IM patients have an augmented number of M1-specific cells in their blood...
IM patients have an augmented number of M1-specific cells in their bloodstream. PBMCs were isolated from 8 healthy donors or from 8 patients experiencing IM. Blood from IM patients was collected at various points after presentation with symptoms of IM. Please note that the number of data points for each patient is variable. (A–C) CD8+ cells were first isolated from PBMCs and then immediately stained with tetramer. The percentages of tetramer-positive cells were used to calculate the total number of either M1- or BMLF1-specific cells per ml of blood. (A) The difference between the means of the 2 subject groups was determined to be statistically significant using an unpaired, 2-tailed Student’s t test. #P = 0.02. Patient E1197 had an M1-specific memory population that grew out in culture but was undetectable ex vivo; therefore, this patient was excluded from calculation of the mean. (D) PBMCs were used to costain with CD3 and CD8+ antibodies and calculate the total number of CD8+ T cells per ml of blood.