Bovine Immunoinhibitory Receptors Contribute to Suppression of Mycobacterium avium subsp. paratuberculosis-Specific T-Cell Responses.
Johne's disease (paratuberculosis) is a chronic enteritis in cattle that is caused by intracellular infection with Mycobacterium avium subsp. paratuberculosis. This infection is characterized by the functional exhaustion of T-cell responses to M. avium subsp. paratuberculosis antigens during late subclinical and clinical stages, presumably facilitating the persistence of this bacterium and the formation of clinical lesions. However, the mechanisms underlying T-cell exhaustion in Johne's disease are poorly understood. Thus, we performed expression and functional analyses of the immunoinhibitory molecules programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3)/major histocompatibility complex class II (MHC-II) in M. avium subsp. paratuberculosis-infected cattle during the late subclinical stage. Flow cytometric analyses revealed the upregulation of PD-1 and LAG-3 in T cells in infected animals, which suffered progressive suppression of interferon gamma (IFN-γ) responses to the M. avium subsp. paratuberculosis antigen. In addition, PD-L1 and MHC-II were expressed on macrophages from infected animals, consistent with PD-1 and LAG-3 pathways contributing to the suppression of IFN-γ responses during the subclinical stages of M. avium subsp. paratuberculosis infection. Furthermore, dual blockade of PD-L1 and LAG-3 enhanced M. avium subsp. paratuberculosis-specific IFN-γ responses in blood from infected animals, and in vitro LAG-3 blockade enhanced IFN-γ production from M. avium subsp. paratuberculosis-specific CD4(+) and CD8(+) T cells. Taken together, the present data indicate that M. avium subsp. paratuberculosis-specific T-cell exhaustion is in part mediated by PD-1/PD-L1 and LAG-3/MHC-II interactions and that LAG-3 is a molecular target for the control of M. avium subsp. paratuberculosis-specific T-cell responses.
Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Tomohiro
T
Okagawa
Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Satoru
S
Konnai
Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Asami
A
Nishimori
Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Ryoyo
R
Ikebuchi
Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Seiko
S
Mizorogi
Bacterial and Parasitic Disease Research Division, National Institute of Animal Health, Tsukuba, Japan.
Reiko
R
Nagata
Bacterial and Parasitic Disease Research Division, National Institute of Animal Health, Tsukuba, Japan.
Satoko
S
Kawaji
Kyushu Research Station, National Institute of Animal Health, Kagoshima, Japan.
Shogo
S
Tanaka
Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan North Lab, Sapporo, Japan.
Yumiko
Y
Kagawa
Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Shiro
S
Murata
Bacterial and Parasitic Disease Research Division, National Institute of Animal Health, Tsukuba, Japan.
Yasuyuki
Y
Mori
Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan okazu@vetmed.hokudai.ac.jp.
Kazuhiko
K
Ohashi
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002417:Cattle; D002418:Cattle Diseases / Q000276:immunology* / Q000382:microbiology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology; D008297:Male; D016927:Mycobacterium avium subsp. paratuberculosis / Q000276:immunology*; D010283:Paratuberculosis / Q000276:immunology* / Q000382:microbiology; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D060890:B7-H1 Antigen; D000949:Histocompatibility Antigens Class II; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein