title: Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity.
abstract: T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)+islet-specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time-points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti-CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon-γ. Programmed cell death protein 1 (PD-1) expression was up-regulated on the effector cells from anti-CD3-treated mice, and diabetes induced through anti-PD-L1 antibody could only be reversed with anti-CD3 antibody if the anti-CD3 treatment lasted beyond the point when the anti-PD-L1 antibody was washed out of the system. This suggests that PD-1/PD-L1 interaction plays an important role in the anti-CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti-CD3 therapy can reverse diabetogenesis.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Maja
authors.identifier: 0000-0001-8297-7859
authors.initials: M
authors.lastname: Wallberg
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Asha
authors.initials: A
authors.lastname: Recino
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Phillips
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Howie
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Margaux
authors.initials: M
authors.lastname: Vienne
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Paluch
authors.affiliation: Department of Molecular Immunology Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.affiliation: Diabetes Research Group, Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Cooke
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D017252:CD3 Complex; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
keywords: antibodies; diabetes; tolerance/suppression/anergy; transgenic/knockout mouse