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: 13.77). 01/2006; 115(12):3602-12. DOI: 10.1172/JCI25078
Source: PubMed

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 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, Aug 16, 2015
1 Follower
  • Source
    • "This T-cell frequency is dependent on thymic selection, but is also a function of whether the host has experienced a T-cell expansion to an identical or to a non-homologous cross-reactive epitope. This pattern of immunodominance in a virus infection can thus be greatly altered by previous exposures to other viruses that may encode cross-reactive epitopes [20] [21] [49]. The specificity of T cells can be very degenerative, and it has been calculated that a single TCR has the potential to react with as many as 10 6 peptide – MHC combinations [50] [51]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heterologous immunity is a common phenomenon present in all infections. Most of the time it is beneficial, mediating protective immunity, but in some individuals that have the wrong crossreactive response it leads to a cascade of events that result in severe immunopathology. Infections have been associated with autoimmune diseases such as diabetes, multiple sclerosis and lupus erythematosis, but also with unusual autoimmune like pathologies where the immune system appears dysregulated, such as, sarcoidosis, colitis, panniculitis, bronchiolitis obliterans, infectious mononucleosis and even chronic fatigue syndrome. Here we review the evidence that to better understand these autoreactive pathologies it requires an evaluation of how T cells are regulated and evolve during sequential infections with different pathogens under the influence of heterologous immunity.
    Autoimmunity 06/2011; 44(4):328-47. DOI:10.3109/08916934.2011.523277
  • Source
    • "Interestingly, the specificity of cross-reactive CD8 + T cell clones between LCMV and vaccinia virus varies among individual inbred mice, suggesting that cross-reactivity between different infectious agents may not be uncommon (Kim et al., 2005). Indeed, cross-reactive human CD8 + T cell clones have been detected that recognize epitopes from both influenza A virus and Epstein-Barr virus (Clute et al., 2005). These observations suggest that primary responses among individuals with a diverse repertoire of memory CD8 + T cells may contain re-activated secondary clonal expansions of rare cross-reactive pre-existing memory T cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The adaptive immune response meets the needs of the organism to generate effector cells capable of controlling pathogens but also leads to production of memory cells, which mediate more effective protection during rechallenge. In this review, we focus on the generation, maintenance, and function of memory T cells, with a special emphasis on the increasing evidence for great diversity among functional memory T cell subsets.
    Immunity 12/2009; 31(6):859-71. DOI:10.1016/j.immuni.2009.11.007
  • Source
    • "A complex pattern of T-cell cross-reactivity was found that depended in part on the specificity of private T-cell repertoires of individual mice (Lin and Welsh, 1998; Kim et al., 2005). An example of observed differences in T-cell crossreactivity between human subjects has been reported in the context of cells recognizing related influenza and Epstein–Barr virus epitopes and attributed to the private specificity of individual TCR repertoires (Clute et al., 2005). In short, there is ample precedent for the concept that individuals' T-cells may differ in their degree of cross-reactivity to two closely related epitopes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Two HLA-A*02-restricted epitopes have been identified within the VP1 polypeptide of a human polyomavirus, BK virus, which is associated with polyomavirus-associated nephropathy in kidney transplant patients. Immunization of transgenic mice with recombinant modified vaccinia Ankara expressing BKV VP1 (rMVA-BKV VP1) elicited functional CTL populations recognizing the sequences LLMWEAVTV (amino acids residues 108-116, BKV VP1p108) and AITEVECFL (residues 44-52, BKV VP1p44) and cross-reactive to the previously described JC virus VP1 homologs. Flow-based analyses of PBMC from a panel of thirty healthy HLA-A*02 human volunteers indicated that the majority of these subjects harbored functional CTL populations recognizing the BKV epitopes and cross-reactive with the JCV homologs. CTL recognizing the JCV VP1p100 and JCV VP1p36 epitopes have previously been associated with prolonged survival in progressive multifocal leukoencephalopathy patients. These findings suggest that infection with BKV or JCV could potentially induce cross-protective T-cell immunity against diseases associated with these viruses.
    Virology 07/2006; 350(1):128-36. DOI:10.1016/j.virol.2006.02.040
Show more