title: Cooperation of PD-1 and LAG-3 Contributes to T-Cell Exhaustion in Anaplasma marginale-Infected Cattle.
abstract: The CD4(+) T-cell response is central for the control of Anaplasma marginale infection in cattle. However, the infection induces a functional exhaustion of antigen-specific CD4(+) T cells in cattle immunized with A. marginale outer membrane proteins or purified outer membranes (OMs), which presumably facilitates the persistence of this rickettsia. In the present study, we hypothesize that T-cell exhaustion following infection is induced by the upregulation of immunoinhibitory receptors on T cells, such as programmed death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3). OM-specific T-cell responses and the kinetics of PD-1-positive (PD-1(+)) LAG-3(+) exhausted T cells were monitored in A. marginale-challenged cattle previously immunized with OMs. Consistent with data from previous studies, OM-specific proliferation of peripheral blood mononuclear cells (PBMCs) and interferon gamma (IFN-γ) production were significantly suppressed in challenged animals by 5 weeks postinfection (wpi). In addition, bacteremia and anemia also peaked in these animals at 5 wpi. Flow cytometric analysis revealed that the percentage of PD-1(+) LAG-3(+) T cells in the CD4(+), CD8(+), and γδ T-cell populations gradually increased and also peaked at 5 wpi. A large increase in the percentage of LAG-3(+) γδ T cells was also observed. Importantly, in vitro, the combined blockade of the PD-1 and LAG-3 pathways partially restored OM-specific PBMC proliferation and IFN-γ production at 5 wpi. Taken together, these results indicate that coexpression of PD-1 and LAG-3 on T cells contributes to the rapid exhaustion of A. marginale-specific T cells following infection and that these immunoinhibitory receptors regulate T-cell responses during bovine anaplasmosis.
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okagawa
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Konnai
authors.affiliation: Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Deringer
authors.affiliation: Animal Disease Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Pullman, Washington, USA.
authors.forename: Massaro W
authors.initials: MW
authors.lastname: Ueti
authors.affiliation: Animal Disease Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Pullman, Washington, USA.
authors.forename: Glen A
authors.initials: GA
authors.lastname: Scoles
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Murata
authors.affiliation: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington, USA wbrown@vetmed.wsu.edu.
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Brown
mesh_terms: D042322:Anaplasma marginale / Q000276:immunology*; D000712:Anaplasmosis / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism*; D016470:Bacteremia / Q000382:microbiology; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002417:Cattle; D002418:Cattle Diseases / Q000382:microbiology*; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007114:Immunization / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015854:Up-Regulation; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; D001425:Bacterial Outer Membrane Proteins; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein