Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires

• Published in: mBio 2017-12, Vol.8 (6)
• Main Authors: Aslan, Nuray, Watkin, Levi B, Gil, Anna, Mishra, Rabinarayan, Clark, Fransenio G, Welsh, Raymond M, Ghersi, Dario, Luzuriaga, Katherine, Selin, Liisa K
• Format: Article
• Language: English
• Subjects: Antigens, Viral - immunology; CD8; CD8-Positive T-Lymphocytes - immunology; Cross Reactions - immunology; cross-reactive; Epitopes, T-Lymphocyte - immunology; Epitopes, T-Lymphocyte - metabolism; Epstein-Barr virus; Female; Herpesvirus 4, Human - immunology; heterologous immunity; HLA-A2 Antigen - immunology; Humans; immune memory; Immunity, Heterologous; Immunologic Memory; Infectious Mononucleosis - immunology; Influenza A virus - immunology; Influenza, Human - immunology; Interferon-gamma - metabolism; Lymphocyte Activation; Male; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Severity of Illness Index; TCR repertoire; Viral Matrix Proteins - immunology; Young Adult
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.01841-17

Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M1 (IAV-M1) and EBV BMLF1 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter. The pathogenic impact of immune responses that by chance cross-react to unrelated viruses has not been established in human infections. Here, we demonstrate that the severity of acute infectious mononucleosis (AIM), an Epstein-Barr virus (EBV)-induced disease prevalent in young adults but not children, is associated with increased frequencies of T cells cross-reactive to EBV and the commonly acquired influenza A virus (IAV). The T-cell receptor (TCR) repertoire and functions of these cross-reactive T cells differed between mild- and severe-AIM patients, most likely because these two groups of patients had selec