CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo
| العنوان: | CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo |
|---|---|
| المؤلفون: | Riccarda Capaul, Johannes H. Dreyer, Hana Zdimerova, Anne Müller, Bithi Chatterjee, Yun Deng, Andrea Zbinden, Olga Antsiferova, Nicolás Gonzalo Núñez, Mark D. Robinson, Christian Münz, Tarik Azzi, Liliana D. Vanoaica, David Nadal, Hans J. Stauss, Burkhard Becher, Angelika Holler |
| المساهمون: | University of Zurich, Münz, Christian |
| المصدر: | PLoS Pathogens PLoS Pathogens, Vol 15, Iss 5, p e1007748 (2019) |
| بيانات النشر: | Public Library of Science (PLoS), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 10028 Institute of Medical Virology, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Physiology, Receptor expression, Programmed Cell Death 1 Receptor, 2405 Parasitology, Mice, SCID, CD8-Positive T-Lymphocytes, 10263 Institute of Experimental Immunology, medicine.disease_cause, Immune Receptors, Biochemistry, White Blood Cells, Mice, Animal Cells, Mice, Inbred NOD, Immune Physiology, Medicine and Health Sciences, Cytotoxic T cell, Biology (General), Pathology and laboratory medicine, Innate Immune System, 0303 health sciences, Immune System Proteins, T Cells, 2404 Microbiology, 030302 biochemistry & molecular biology, Cell Differentiation, Medical microbiology, Viral Load, 10124 Institute of Molecular Life Sciences, 3. Good health, medicine.anatomical_structure, Viruses, Cytokines, Cellular Types, Pathogens, Inflammation Mediators, Coreceptors, Research Article, Signal Transduction, Adult, Herpesviruses, QH301-705.5, Immune Cells, T cell, Immunology, Cytotoxic T cells, 610 Medicine & health, Biology, Microbiology, Virus, 03 medical and health sciences, Immune system, 1311 Genetics, Virology, 1312 Molecular Biology, Genetics, medicine, Epstein-Barr virus, Animals, Humans, Molecular Biology, 030304 developmental biology, 2403 Immunology, Blood Cells, Gene Expression Profiling, Organisms, Viral pathogens, Biology and Life Sciences, Proteins, Germinal center, CD coreceptors, Cell Biology, RC581-607, Molecular Development, Epstein–Barr virus, Microbial pathogens, T Cell Receptors, Immune System, Case-Control Studies, 2406 Virology, 570 Life sciences, biology, Parasitology, Immunologic diseases. Allergy, DNA viruses, Viral Transmission and Infection, CD8, Developmental Biology, T-Lymphocytes, Cytotoxic |
| الوصف: | 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. Author summary Since its discovery as a tumor virus by Epstein and colleagues in 1964, Epstein-Barr virus (EBV) has been implicated in many serious diseases, including infectious mononucleosis, Burkitt’s lymphoma, and post-transplant lymphoproliferative disease. Currently, in vivo studies are lacking to understand the comprehensive immune control of EBV in most healthy virus carriers, and, in particular, the characteristics of the CD8+ T cells involved in this process. We find that even though CD8+ T cells express multiple inhibitory receptors including PD-1 during primary EBV infection, they appear to retain an ability to produce cytokines, to kill infected cells, and to proliferate. Importantly, blocking the PD-1 pathway leads to defects in EBV-specific control and increased virus-induced tumor formation, indicating that this axis is important for viral control. This is in contrast to previous studies where releasing an inhibitory block is important for reinvigorating immune responses against cancer. Because PD-1 function is required to keep EBV in check, this study provides evidence against blocking co-inhibitory pathways in disease settings that require improved immune control of chronic virus infections. |
| وصف الملف: | journal.ppat.1007748.pdf - application/pdf |
| تدمد: | 1553-7374 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::874c9f5ed8e6affeb62d027abadd074fTest https://doi.org/10.1371/journal.ppat.1007748Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....874c9f5ed8e6affeb62d027abadd074f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537374 |
|---|