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PLoS Pathog. 2019 May 30;15(5):e1007748. doi: 10.1371/journal.ppat.1007748. eCollection 2019 May.

CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo.

Author information

1
Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, Switzerland.
2
Institute of Immunity and Transplantation, Royal Free Campus, University College London, United Kingdom.
3
Inflammation Research, Institute of Experimental Immunology, University of Zurich, Switzerland.
4
Division of Infectious Diseases and Hospital Epidemiology, Children's Research Center, University Children's Hospital Zurich, Switzerland.
5
Institute of Medical Virology, University of Zurich, Switzerland.
6
Institute for Pathology, Unfallkrankenhaus Berlin, Berlin, Germany.
7
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
8
SIB Swiss Institute of Bioinformatics, Zurich, Switzerland.

Abstract

Epstein Barr virus (EBV) is one of the most ubiquitous human pathogens in the world, persistently infecting more than 90% of the adult human population. It drives some of the strongest human CD8+ T cell responses, which can be observed during symptomatic primary infection known as infectious mononucleosis (IM). Despite high viral loads and prolonged CD8+ T cell stimulation during IM, EBV enters latency and is under lifelong immune control in most individuals that experience this disease. We investigated whether changes in T cell function, as frequently characterized by PD-1 up-regulation, occur during IM due to the prolonged exposure to high antigen levels. We readily detected the expansion of PD-1 positive CD8+ T cells together with high frequencies of Tim-3, 2B4, and KLRG1 expression during IM and in mice with reconstituted human immune system components (huNSG mice) that had been infected with a high dose of EBV. These PD-1 positive CD8+ T cells, however, retained proliferation, cytokine production, and cytotoxic abilities. Multiple subsets of CD8+ T cells expanded during EBV infection, including PD-1+Tim-3+KLRG1+ cells that express CXCR5 and TCF-1 germinal center homing and memory markers, and may also contain BATF3. Moreover, blocking the PD-1 axis compromised EBV specific immune control and resulted in virus-associated lymphomagenesis. Finally, PD-1+, Tim-3+, and KLRG1+ CD8+ T cell expansion coincided with declining viral loads during low dose EBV infection. These findings suggest that EBV infection primes PD-1 positive CD8+ T cell populations that rely on this receptor axis for the efficient immune control of this ubiquitous human tumor virus.

PMID:
31145756
PMCID:
PMC6542544
DOI:
10.1371/journal.ppat.1007748
[Indexed for MEDLINE]
Free PMC Article

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