Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infection

Abstract Bovine leukemia virus (BLV) is a retrovirus that infects B cells in cattle and causes bovine leukosis after a long latent period. Progressive exhaustion of T cell functions is considered to facilitate disease progression of BLV infection. Programmed death-1 (PD-1) and lymphocyte activation...

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Main Authors: Tomohiro Okagawa, Satoru Konnai, Asami Nishimori, Naoya Maekawa, Shinya Goto, Ryoyo Ikebuchi, Junko Kohara, Yasuhiko Suzuki, Shinji Yamada, Yukinari Kato, Shiro Murata, Kazuhiko Ohashi
Format: Article
Language:English
Published: BMC 2018-06-01
Series:Veterinary Research
Online Access:http://link.springer.com/article/10.1186/s13567-018-0543-9
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spelling doaj-f4608a6016e34b98a040c72bdc125abb2020-11-25T01:20:32ZengBMCVeterinary Research1297-97162018-06-0149111210.1186/s13567-018-0543-9Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infectionTomohiro Okagawa0Satoru Konnai1Asami Nishimori2Naoya Maekawa3Shinya Goto4Ryoyo Ikebuchi5Junko Kohara6Yasuhiko Suzuki7Shinji Yamada8Yukinari Kato9Shiro Murata10Kazuhiko Ohashi11Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityAnimal Research Center, Agriculture Research Department, Hokkaido Research OrganizationDivision of Bioresources, Research Center for Zoonosis Control, Hokkaido UniversityDepartment of Antibody Drug Development, Graduate School of Medicine, Tohoku UniversityDepartment of Antibody Drug Development, Graduate School of Medicine, Tohoku UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityAbstract Bovine leukemia virus (BLV) is a retrovirus that infects B cells in cattle and causes bovine leukosis after a long latent period. Progressive exhaustion of T cell functions is considered to facilitate disease progression of BLV infection. Programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3) are immunoinhibitory receptors that contribute to T-cell exhaustion caused by BLV infection in cattle. However, it is unclear whether the cooperation of PD-1 and LAG-3 accelerates disease progression of BLV infection. In this study, multi-color flow cytometric analyses of PD-1- and LAG-3-expressing T cells were performed in BLV-infected cattle at different stages of the disease. The frequencies of PD-1+LAG-3+ heavily exhausted T cells among CD4+ and CD8+ T cells was higher in the blood of cattle with B-cell lymphoma over that of BLV-uninfected and BLV-infected cattle without lymphoma. In addition, blockade assays of peripheral blood mononuclear cells were performed to examine whether inhibition of the interactions between PD-1 and LAG-3 and their ligands by blocking antibodies could restore T-cell function during BLV infection. Single or dual blockade of the PD-1 and LAG-3 pathways reactivated the production of Th1 cytokines, interferon-γ and tumor necrosis factor-α, from BLV-specific T cells of the infected cattle. Taken together, these results indicate that PD-1 and LAG-3 cooperatively mediate the functional exhaustion of CD4+ and CD8+ T cells and are associated with the development of B-cell lymphoma in BLV-infected cattle.http://link.springer.com/article/10.1186/s13567-018-0543-9
collection DOAJ
language English
format Article
sources DOAJ
author Tomohiro Okagawa
Satoru Konnai
Asami Nishimori
Naoya Maekawa
Shinya Goto
Ryoyo Ikebuchi
Junko Kohara
Yasuhiko Suzuki
Shinji Yamada
Yukinari Kato
Shiro Murata
Kazuhiko Ohashi
spellingShingle Tomohiro Okagawa
Satoru Konnai
Asami Nishimori
Naoya Maekawa
Shinya Goto
Ryoyo Ikebuchi
Junko Kohara
Yasuhiko Suzuki
Shinji Yamada
Yukinari Kato
Shiro Murata
Kazuhiko Ohashi
Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infection
Veterinary Research
author_facet Tomohiro Okagawa
Satoru Konnai
Asami Nishimori
Naoya Maekawa
Shinya Goto
Ryoyo Ikebuchi
Junko Kohara
Yasuhiko Suzuki
Shinji Yamada
Yukinari Kato
Shiro Murata
Kazuhiko Ohashi
author_sort Tomohiro Okagawa
title Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infection
title_short Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infection
title_full Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infection
title_fullStr Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infection
title_full_unstemmed Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infection
title_sort cooperation of pd-1 and lag-3 in the exhaustion of cd4+ and cd8+ t cells during bovine leukemia virus infection
publisher BMC
series Veterinary Research
issn 1297-9716
publishDate 2018-06-01
description Abstract Bovine leukemia virus (BLV) is a retrovirus that infects B cells in cattle and causes bovine leukosis after a long latent period. Progressive exhaustion of T cell functions is considered to facilitate disease progression of BLV infection. Programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3) are immunoinhibitory receptors that contribute to T-cell exhaustion caused by BLV infection in cattle. However, it is unclear whether the cooperation of PD-1 and LAG-3 accelerates disease progression of BLV infection. In this study, multi-color flow cytometric analyses of PD-1- and LAG-3-expressing T cells were performed in BLV-infected cattle at different stages of the disease. The frequencies of PD-1+LAG-3+ heavily exhausted T cells among CD4+ and CD8+ T cells was higher in the blood of cattle with B-cell lymphoma over that of BLV-uninfected and BLV-infected cattle without lymphoma. In addition, blockade assays of peripheral blood mononuclear cells were performed to examine whether inhibition of the interactions between PD-1 and LAG-3 and their ligands by blocking antibodies could restore T-cell function during BLV infection. Single or dual blockade of the PD-1 and LAG-3 pathways reactivated the production of Th1 cytokines, interferon-γ and tumor necrosis factor-α, from BLV-specific T cells of the infected cattle. Taken together, these results indicate that PD-1 and LAG-3 cooperatively mediate the functional exhaustion of CD4+ and CD8+ T cells and are associated with the development of B-cell lymphoma in BLV-infected cattle.
url http://link.springer.com/article/10.1186/s13567-018-0543-9
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