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

Chatterjee, Bithi; Deng, Yun; Holler, Angelika; Núñez, Nicolás Gonzalo; Azzi, Tarik; Vanoaica, Liliana Danusia; Müller, Anne; Zdimerova, Hana; Antsiferova, Olga; Zbinden, Andrea; Capaul, Riccarda; Dreyer, Johannes H; Nadal, David; Becher, Burkhard; Robinson, Mark D; Stauss, Hans; Münz, Christian (2019). CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo. PLoS Pathogens, 15(5):e1007748.

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.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
07 Faculty of Science > Institute of Molecular Life Sciences
04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Parasitology
Life Sciences > Microbiology
Life Sciences > Immunology
Life Sciences > Molecular Biology
Life Sciences > Genetics
Life Sciences > Virology
Language:English
Date:May 2019
Deposited On:15 Nov 2019 10:21
Last Modified:20 Apr 2025 01:39
Publisher:Public Library of Science (PLoS)
ISSN:1553-7366
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.ppat.1007748
PubMed ID:31145756
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  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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