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

Department of Pathology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 01/2006; 115(12):3602-12. DOI: 10.1172/JCI25078
Source: PubMed


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.

Download full-text


Available from: Markus Cornberg,
  • Source
    • "We used ovalbumin (OVA)257 (17), vaccinia virus (VV) A11R198 (18), Japanese encephalitis virus NS4B215 (19), and West Nile virus NS4B215 (19) peptides as H-2 class I-restricted peptide epitopes. We also used influenza A virus (IAV) M158 (20), IAV (PR8) NA231 (21), hepatitis C virus (HCV) core35 (22), HCV core132 (22), HCV (genotype 1b) NS31073 (21), HCV (genotype 1b) NS31406 (23), and Epstein-Barr virus BMLF1280 (20) peptides as HLA-A2-restricted peptide epitopes. Their sequences and MHC restrictions are summarized in Table I. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined the immunogenicity of H-2 class I-restricted and HLA-A2-restricted epitopes through peptide immunization of HLA-A2-transgenic mice that also express mouse H-2 class I molecules. All four of the tested epitopes restricted by H-2 class I robustly elicited T-cell responses, but four of seven epitopes restricted by HLA-A2 did not induce T-cell responses, showing that HLA-A2-restricted peptide epitopes tend to be poorly immunogenic in HLA-A2-transgenic mice. This finding was confirmed in HLA-A2-transgenic mice infected with a recombinant vaccinia virus expressing hepatitis C virus proteins. We examined the precursor frequency of epitope-specific naïve CD8(+) T cells in HLA-A2-transgenic and conventional C57BL/6 mice and found that the poor immunogenicity of HLA-A2-restricted peptide epitopes is related to the paucity of naïve CD8(+) T-cell precursors in HLA-A2-transgenic mice. These results provide direction for the improvement of mouse models to study epitope repertoires and the immunodominance of human T-cell responses.
    Immune Network 08/2014; 14(4):219-25. DOI:10.4110/in.2014.14.4.219
  • Source
    • "There are quite a few reported examples of cross-reactive T cell responses to different pathogens. In addition to the experiments of Selin and Welsh (69), cross-reactivity has been reported between influenza virus and hepatitis C virus (72), EBV (73) or HIV (74), LCMV and vaccinia virus (75), and coronavirus and human papillomavirus (76). It remains to be seen if the observed cases of cross-reactivity arise from a reporting bias (failure to observe cross-reactivity between two pathogens is unlikely to be reported) or because some of the assumptions of our model are incorrect and need to be modified. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to recognize and combat a diverse array of pathogens the immune system has a large repertoire of T cells having unique T cell receptors (TCRs) with only a few clones specific for any given antigen. We discuss how the number of different possible TCRs encoded in the genome (the potential repertoire) and the number of different TCRs present in an individual (the realized repertoire) can be measured. One puzzle is that the potential repertoire greatly exceeds the realized diversity of naïve T cells within any individual. We show that the existing hypotheses fail to explain why the immune system has the potential to generate far more diversity than is used in an individual, and propose an alternative hypothesis of "evolutionary sloppiness." Another immunological puzzle is why mice and humans have similar repertoires even though humans have over 1000-fold more T cells. We discuss how the idea of the "protecton," the smallest unit of protection, might explain this discrepancy and estimate the size of "protecton" based on available precursor frequencies data. We then consider T cell cross-reactivity - the ability of a T cell clone to respond to more than one epitope. We extend existing calculations to estimate the extent of expected cross-reactivity between the responses to different pathogens. Our results are consistent with two observations: a low probability of observing cross-reactivity between the immune responses to two randomly chosen pathogens; and the ensemble of memory cells being sufficiently diverse to generate cross-reactive responses to new pathogens.
    Frontiers in Immunology 12/2013; 4:485. DOI:10.3389/fimmu.2013.00485
  • Source
    • "The methodology used to assess antigen presentation by human MDMs is shown in Figure 1. In these experiments, the Epstein–Barr virus (EBV) derived, HLA-A2 restricted, peptide EBV-BMLF1280–288(GLCTLVAML) (GLC) (11) was used. GLC was selected in place of an IAV peptide so that antigen presentation was independent of the IAV peptides processed and presented as a result of infection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To understand the interactions between innate and adaptive immunity, and specifically how virally infected macrophages impact T cell function, novel assays examining the ability of macrophages to present antigen to CD8(+) T cells are needed. In the present study, we have developed a robust in vitro assay to measure how antigen presentation by human monocyte-derived macrophages (MDMs) affects the functional capacity of autologous CD8(+) T cells. The assay is based on the polyfunctional characteristics of antigen-specific CD8(+) T cells, and is thus called a Mac-CD8 Polyfunctionality Assay. Following purification of monocytes and their maturation to MDMs, MDMs were pulsed with an antigenic peptide to be presented to CD8(+) T cells. Peptide-pulsed MDMs were then incubated with antigen-specific CD8(+) T cells in order to assess the efficacy of antigen presentation to T cells. CD8(+) T cell polyfunctionality was assessed by staining with mAbs to IFN-γ, TNF-α, and CD107a in a multi-color intracellular cytokine staining assay. To highlight the utility of the Mac-CD8 Polyfunctionality Assay, we assessed the effects of influenza infection on the ability of human macrophages to present antigen to CD8(+) T cells. We found that influenza infection of human MDMs can alter the effector efficacy of MDMs to activate more CD8(+) T cells with cytotoxic capacity. This has important implications for understanding how the virus-infected macrophages affect adaptive immunity at the site of infection.
    Frontiers in Immunology 11/2013; 4:389. DOI:10.3389/fimmu.2013.00389
Show more