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Cooperation of PD-1 and LAG-3 in the exhaustion of CD4(+) and CD8(+) T cells during bovine leukemia virus infection
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 (L...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006750/ https://www.ncbi.nlm.nih.gov/pubmed/29914540 http://dx.doi.org/10.1186/s13567-018-0543-9 |
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author | Okagawa, Tomohiro Konnai, Satoru Nishimori, Asami Maekawa, Naoya Goto, Shinya Ikebuchi, Ryoyo Kohara, Junko Suzuki, Yasuhiko Yamada, Shinji Kato, Yukinari Murata, Shiro Ohashi, Kazuhiko |
author_facet | Okagawa, Tomohiro Konnai, Satoru Nishimori, Asami Maekawa, Naoya Goto, Shinya Ikebuchi, Ryoyo Kohara, Junko Suzuki, Yasuhiko Yamada, Shinji Kato, Yukinari Murata, Shiro Ohashi, Kazuhiko |
author_sort | Okagawa, Tomohiro |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13567-018-0543-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6006750 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-60067502018-06-26 Cooperation of PD-1 and LAG-3 in the exhaustion of CD4(+) and CD8(+) T cells during bovine leukemia virus infection Okagawa, Tomohiro Konnai, Satoru Nishimori, Asami Maekawa, Naoya Goto, Shinya Ikebuchi, Ryoyo Kohara, Junko Suzuki, Yasuhiko Yamada, Shinji Kato, Yukinari Murata, Shiro Ohashi, Kazuhiko Vet Res Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13567-018-0543-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-06-19 2018 /pmc/articles/PMC6006750/ /pubmed/29914540 http://dx.doi.org/10.1186/s13567-018-0543-9 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Okagawa, Tomohiro Konnai, Satoru Nishimori, Asami Maekawa, Naoya Goto, Shinya Ikebuchi, Ryoyo Kohara, Junko Suzuki, Yasuhiko Yamada, Shinji Kato, Yukinari Murata, Shiro Ohashi, Kazuhiko Cooperation of PD-1 and LAG-3 in the exhaustion of CD4(+) and CD8(+) T cells during bovine leukemia virus infection |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006750/ https://www.ncbi.nlm.nih.gov/pubmed/29914540 http://dx.doi.org/10.1186/s13567-018-0543-9 |
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