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 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.

Cytomegalovirus-Seropositive Children Show Inhibition of In Vitro EBV Infection That Is Associated with CD8+CD57+ T Cell Enrichment and IFN-γ

“…This has been shown with herpesvirus infections, either due to cross-recognition of epitopes or through bystander activation mediated by the cytokine environment (28,47,48). Specific memory T cells could also be activated as a result of reactivating latent pathogen.…”

Vaccination and heterologous immunity: educating the immune system

“…The mechanisms of heterologous immunity can vary, but the focus of this review is on experimental systems where both beneficial and detrimental heterologous immunity are mediated by crossreactive T cells. 22,23 More than 20 years of research have delineated basic principles of heterologous immunity, such as (1) T cell crossreactivity is quite common between unrelated pathogens and alters T cell immunodominance; 24 (2) networks of crossreactive T cells alter the efficacy of the T cell response and influence protective immunity and immunopathology; [25][26][27][28][29][30] (3) T cell crossreactivity can lead to narrowing of the T cell repertoire and generation of viral escape mutants; 31 (4) the private specificity of crossreactive T cells can determine an individual's disease outcome in regards to protective immunity and immunopathology; [31][32][33] (5) heterologous immunity can reduce the effectiveness of vaccines due to immunodominant skewing of undesired T cell responses; 29,34 (6) peptide-dependent interventions or cytokine Transactions of the Royal Society of Tropical Medicine and Hygiene blocking therapy can be used to prevent severe pathology caused by heterologous immunity; 25,30,34 and (7) the immune response to each new pathogen impacts the frequencies, distributions and activities of memory T cells to previous infections. 22,35,36 The contention is that heterologous immunity is the norm, not the exception, but given the diversity in human genetics, MHC and infection histories, is it too complicated an issue to address?…”

“…There have been a number of studies that have already correlated several human disease syndromes to crossreactive epitopes presented by a single MHC molecule. 27,[37][38][39][40][41][42][43][44][45][46] For detrimental heterologous immunity, a pathogenic epitope response might be dominant and not be obscured by other protective epitopes and MHC molecules. Recent papers show high frequencies of virus-specific memory T cells in non-immune individuals and a crossreactive epitope spanning many types of herpes viruses.…”

“…40,47 Clear networks of crossreactive epitopes and patterns of beneficial or detrimental heterologous immunity have been defined in specific virus sequences in mouse models (Supplementary Figure 1). [24][25][26][27][28][29][30][31][32][33][34][48][49][50][51][52][53] For example, in the C57BL/6 mouse (H2 b ), CD8 T cell crossreactive epitopes have been defined between LCMV and Pichinde virus (PICV), LCMV and vaccinia virus (VACV), LCMV and murine cytomegalovirus (MCMV), LCMV and IAV, IAV and MCMV, and PICV and VACV, and complex networks of mouse or human T cell crossreactivity can exist between two viruses. 23,24,27,28,34,[54][55][56] Furthermore, structural studies on crossreactivity between LCMV and VACV epitopes can pinpoint the target of crossreactivity and render the OVA SIINFEKL epitope crossreactive with LCMV by an amino acid substitution.…”

“…27,28 These responses were activated and proliferated during severe infections like acute infectious mononucleosis (IM) or influenza A infection. Unique EBV/IAV crossreactive populations have been identified in different HLA-A2+ patient populations, suggesting that crossreactive patterns may be predicted during human infections (Supplementary Figure 2).…”