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

Date Published: May 30, 2019

Publisher: Public Library of Science

Author(s): Bithi Chatterjee, Yun Deng, Angelika Holler, Nicolas Nunez, Tarik Azzi, Liliana Danusia Vanoaica, Anne Müller, Hana Zdimerova, Olga Antsiferova, Andrea Zbinden, Riccarda Capaul, Johannes H. Dreyer, David Nadal, Burkhard Becher, Mark D. Robinson, Hans Stauss, Christian Münz, Laurent Coscoy.


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.

Partial Text

Epstein-Barr virus (EBV) is a γ-herpes virus that persists in more than 90% of the world’s adult human population. Primary EBV infection mainly occurs asymptomatically in children. However, people in the Western world often contract EBV as a primary infection in their second decade of life or later, which can then lead to infectious mononucleosis (IM) [1]. Patients with IM have fever, swollen lymph nodes, and large numbers of CD8+ T cell lymphoblasts. Adults with a history of IM have a significantly increased incidence of Hodgkin’s lymphoma and multiple sclerosis [2–4]. EBV+ individuals are at increased risk to develop any number of EBV-associated malignancies, such as nasopharyngeal carcinoma, T cell lymphomas, or Burkitt’s lymphoma [5–7]. Immunocompromised individuals are at higher risk to develop certain EBV-associated conditions, such as post-transplantation lymphoproliferative disease (PTLD) [7]. Therefore, both insufficient and hyperactive EBV specific immune responses lead to virus associated pathologies such as lymphoproliferation and IM, respectively.

In contrast to previous studies devoted to other virus systems such as murine LCMV, we find that the frequency of cells that express PD-1 and other inhibitory receptors appears to increase and is sustained upon EBV infection. These PD-1+ cells retain their proliferative capacity as gauged by Ki67, are able to produce important cytokines such as IFNγ and TNFα, and also retain their cytotoxic abilities. Co-expression of Tim3 and KLRG1 does not seem to significantly compromise these functions. Furthermore, CXCR5 and TCF1 expression, as well as the involvement of BATF3 by a subset of these triple positive CD8+ T cells might maintain their protective abilities during primary EBV infection.




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