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

ABSTRACT 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 illnes...

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Autores principales:	Nuray Aslan, Levi B. Watkin, Anna Gil, Rabinarayan Mishra, Fransenio G. Clark, Raymond M. Welsh, Dario Ghersi, Katherine Luzuriaga, Liisa K. Selin
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	CD8 Epstein-Barr virus TCR repertoire cross-reactive heterologous immunity immune memory Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c3db3a6bc1614ba8b351bb1bf8e3f93e
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spelling	oai:doaj.org-article:c3db3a6bc1614ba8b351bb1bf8e3f93e2021-11-15T15:51:56ZSeverity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires10.1128/mBio.01841-172150-7511https://doaj.org/article/c3db3a6bc1614ba8b351bb1bf8e3f93e2017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01841-17https://doaj.org/toc/2150-7511ABSTRACT 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-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo 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. IMPORTANCE 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 selected different memory TCR repertoires in response to IAV infections encountered earlier. This heterologous immunity may explain variability in disease outcome and why young adults with more-developed IAV-specific memory T-cell pools have more-severe disease than children, who have less-developed memory pools. This study provides a new framework for understanding the role of heterologous immunity in human health and disease and highlights an important developing field examining the role of T-cell repertoires in the mediation of immunopathology.Nuray AslanLevi B. WatkinAnna GilRabinarayan MishraFransenio G. ClarkRaymond M. WelshDario GhersiKatherine LuzuriagaLiisa K. SelinAmerican Society for MicrobiologyarticleCD8Epstein-Barr virusTCR repertoirecross-reactiveheterologous immunityimmune memoryMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	CD8 Epstein-Barr virus TCR repertoire cross-reactive heterologous immunity immune memory Microbiology QR1-502
spellingShingle	CD8 Epstein-Barr virus TCR repertoire cross-reactive heterologous immunity immune memory Microbiology QR1-502 Nuray Aslan Levi B. Watkin Anna Gil Rabinarayan Mishra Fransenio G. Clark Raymond M. Welsh Dario Ghersi Katherine Luzuriaga Liisa K. Selin Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires
description	ABSTRACT 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-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo 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. IMPORTANCE 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 selected different memory TCR repertoires in response to IAV infections encountered earlier. This heterologous immunity may explain variability in disease outcome and why young adults with more-developed IAV-specific memory T-cell pools have more-severe disease than children, who have less-developed memory pools. This study provides a new framework for understanding the role of heterologous immunity in human health and disease and highlights an important developing field examining the role of T-cell repertoires in the mediation of immunopathology.
format	article
author	Nuray Aslan Levi B. Watkin Anna Gil Rabinarayan Mishra Fransenio G. Clark Raymond M. Welsh Dario Ghersi Katherine Luzuriaga Liisa K. Selin
author_facet	Nuray Aslan Levi B. Watkin Anna Gil Rabinarayan Mishra Fransenio G. Clark Raymond M. Welsh Dario Ghersi Katherine Luzuriaga Liisa K. Selin
author_sort	Nuray Aslan
title	Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires
title_short	Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires
title_full	Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires
title_fullStr	Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires
title_full_unstemmed	Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires
title_sort	severity of acute infectious mononucleosis correlates with cross-reactive influenza cd8 t-cell receptor repertoires
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/c3db3a6bc1614ba8b351bb1bf8e3f93e
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Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires

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