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

Chatterjee, B; Deng, Y; Holler, A; Nunez, N; Azzi, T; Vanoaica, LD; Mueller, A; ... Munz, C; + view all (2019) CD8(+) T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo. PLOS Pathogens , 15 (5) , Article e1007748. 10.1371/journal.ppat.1007748. Green open access

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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.

Type: Article
Title: CD8(+) T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.ppat.1007748
Publisher version: https://doi.org/10.1371/journal.ppat.1007748
Language: English
Additional information: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10083640
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