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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Acute EBV infection augments the number of cross-reactive cells that rec...
Acute EBV infection augments the number of cross-reactive cells that recognize M1 and BMLF1. CD8+ T cells were isolated ex vivo from patient E1101 at various time points after presentation with symptoms of IM. (A) The total number of antigen-specific T cells per ml of blood was calculated using the frequencies of tetramer-positive cells. BMLF1+, tetramer positive; M1+ BMLF1+, double-tetramer positive; ND, not determined because the frequency was below the limit of detection using this technique. (B) The percentages of CD8+ T cells staining positive when costained with M1- and BMLF1-loaded tetramers are shown. The number of events shown is variable because the maximum number possible was collected for each sample. (C) CD8+ T cells isolated at days 22, 165, and 349, were cultured for 3 weeks in the presence of M1 peptide–pulsed T2 cells. Following the RNA isolation and cDNA synthesis of those T cell lines, the CDR3β region of Vβ17+ subclones was sequenced. The pie charts illustrate the percentages of unique Vβ17+ subclones using each Jβ family, where n = the total number of unique subclones. The complete CDR3 sequences of all the subclones analyzed are displayed in Supplemental Table 1, structured according to Chothia et al. (57).