title: Increased expression of the regulatory T cell-associated marker CTLA-4 in bovine leukemia virus infection.
abstract: Regulatory T cells (Tregs) play a critical role in the maintenance of the host's immune system. Tregs, particularly CD4(+)CD25(+)Foxp3(+) T cells, have been reported to be involved in the immune evasion mechanism of tumors and several pathogens that cause chronic infections. Recent studies showed that a Treg-associated marker, cytotoxic T-lymphocyte antigen 4 (CTLA-4), is closely associated with the progression of several diseases. We recently reported that the proportion of Foxp3(+)CD4(+) cells was positively correlated with the number of lymphocytes, virus titer, and virus load but inversely correlated with IFN-γ expression in cattle infected with bovine leukemia virus (BLV), which causes chronic infection and lymphoma in its host. Here the kinetics of CTLA-4(+) cells were analyzed in BLV-infected cattle. CTLA-4 mRNA was predominantly expressed in CD4(+) T cells in BLV-infected cattle, and the expression was positively correlated with Foxp3 mRNA expression. To test for differences in the protein expression level of CTLA-4, we measured the proportion of CTLA-4-expressing cells by flow cytometry. In cattle with persistent lymphocytosis (PL), mean fluorescence intensities (MFIs) of CTLA-4 on CD4(+) and CD25(+) T cells were significantly increased compared with that in control and aleukemic (AL) cattle. The percentage of CTLA-4(+) cells in the CD4(+) T cell subpopulation was positively correlated with TGF-β mRNA expression, suggesting that CD4(+)CTLA-4(+) T cells have a potentially immunosuppressive function in BLV infection. In the limited number of cattle that were tested, the anti-CTLA-4 antibody enhanced the expression of CD69, IL-2, and IFN-γ mRNA in anti-programmed death ligand 1 (PD-L1) antibody-treated peripheral blood mononuclear cells from BLV-infected cattle. Together with previous findings, the present results indicate that Tregs may be involved in the inhibition of T cell function during BLV infection.
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: suzuki.saori.56z@st.kyoto-u.ac.jp.
authors.forename: Saori
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: konnai@vetmed.hokudai.ac.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Konnai
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: okagawa@vetmed.hokudai.ac.jp.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okagawa
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: ikebuchi@vetmed.hokudai.ac.jp.
authors.forename: Ryoyo
authors.initials: R
authors.lastname: Ikebuchi
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: asami_4013@ec.hokudai.ac.jp.
authors.forename: Asami
authors.initials: A
authors.lastname: Nishimori
authors.affiliation: Hokkaido Research Organization, Agriculture Research Department, Animal Research Center, Shintoku 081-0038, Japan. Electronic address: kohara-junko@hro.or.jp.
authors.forename: Junko
authors.initials: J
authors.lastname: Kohara
authors.affiliation: Philippine Carabao Center National Headquarters and Gene Pool, Science City of Munoz, 3120 Nueva Ecija, Philippines. Electronic address: cnmingala@hotmail.com.
authors.forename: Claro N
authors.initials: CN
authors.lastname: Mingala
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: murata@vetmed.hokudai.ac.jp.
authors.forename: Shiro
authors.initials: S
authors.lastname: Murata
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: okazu@vetmed.hokudai.ac.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ohashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D003001:Cloning, Molecular; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016583:Enzootic Bovine Leukosis / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D001909:Leukemia Virus, Bovine / Q000276:immunology*; D008969:Molecular Sequence Data; D010802:Phylogeny; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D060908:CTLA-4 Antigen; D016207:Cytokines; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger
keywords: BLV; CTLA-4; Foxp3; TGF-β; Treg