title: Programmed Death-1 antibody blocks therapeutic effects of T-regulatory cells in cockroach antigen-induced allergic asthma.
abstract: We recently reported that the adoptive transfer of T-regulatory cells (Tregs) isolated from lung and spleen tissue of green fluorescent protein-transgenic mice reversed airway hyperresponsiveness and airway inflammation. Because Programmed Death-1 (PD-1) is a pivotal receptor regulating effector T-cell activation by Tregs, we evaluated whether PD-1 is involved in the therapeutic effect of naturally occurring Tregs (NTregs) and inducible Tregs (iTregs) in cockroach (CRA)-sensitized and challenged mice. The CD4(+)CD25(+) NTregs and CD4(+)CD25(-) iTregs isolated from the lungs and spleens of BALB/c mice were adoptively transferred into CRA-sensitized and CRA-challenged mice with and without anti-PD-1 antibody (100 μg/mice). The CD4(+)CD25(+) T cells in the lung were phenotyped after adoptive transfer. Concentrations of IL-4, IL-5, IL-10, IFN-γ, and IL-13 in bronchoalveolar lavage fluid (BALF) were measured using ELISA. The NTregs and iTregs from either lung or spleen tissue reversed airway hyperresponsiveness for at least 4 wk. However, the therapeutic effect was blocked by administering the anti-PD-1 antibody. The administration of Tregs-recipient mice with anti-PD-1 antibody significantly decreased cytotoxic T-lymphocyte antigen-4 expression, with low concentrations of Forkhead-winged transcriptional factor box 3 (Foxp3) mRNA transcripts in lung CD4(+)CD25(+) T cells. These mice had substantially higher concentrations of BALF IL-4, IL-5, and IL-13, but significantly decreased levels of BALF IL-10. Adoptive therapy recipients without the anti-PD-1 antibody exhibited high levels of CTLA-4 expression and Foxp3 transcripts in lung CD4(+)CD25(+) T cells, with a significant decrease in BALF IL-4, IL-5, and IL-13 concentrations and a substantial increase in BALF IL-10 concentrations. These data suggest that the reversal of airway hyperresponsiveness and airway inflammation by Tregs is mediated in part by PD-1, because other costimulatory molecules (e.g., inducible costimulatory molecule [ICOS] or CTLA-4) have been shown to play a role in Treg-mediated suppression.
authors.affiliation: Department of Biomedical Sciences, Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Halvor S
authors.initials: HS
authors.lastname: McGee
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Shao
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D052179:Antigens, Plant; D000954:Antigens, Surface / Q000276:immunology* / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015704:CD4 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen; D002469:Cell Separation; D003058:Cockroaches / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D000485:Allergens; D000906:Antibodies; D015703:Antigens, CD; D052179:Antigens, Plant; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C060835:allergen CRa, cockroach