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- Title
Cooperation of PD-1 and LAG-3 in the exhaustion of CD4<sup>+</sup> and CD8<sup>+</sup> T cells during bovine leukemia virus infection.
- Authors
Okagawa, Tomohiro; Konnai, Satoru; Nishimori, Asami; Maekawa, Naoya; Goto, Shinya; Ikebuchi, Ryoyo; Kohara, Junko; Suzuki, Yasuhiko; Yamada, Shinji; Kato, Yukinari; Murata, Shiro; Ohashi, Kazuhiko
- 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.
- Subjects
BOVINE leukemia virus; CD4 antigen; CD8 antigen; PROGRAMMED cell death 1 receptors; DISEASE progression; FLOW cytometry
- Publication
Veterinary Research, 2018, Vol 49, Issue 1, pN.PAG
- ISSN
0928-4249
- Publication type
Article
- DOI
10.1186/s13567-018-0543-9