1. Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity.
- Author
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Wallberg M, Recino A, Phillips J, Howie D, Vienne M, Paluch C, Azuma M, Wong FS, Waldmann H, and Cooke A
- Subjects
- Animals, Female, Mice, Mice, Inbred NOD, Mice, SCID, Programmed Cell Death 1 Receptor biosynthesis, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor immunology, Antibodies immunology, CD3 Complex immunology, Inflammation immunology, Programmed Cell Death 1 Receptor metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Up-Regulation
- 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., (© 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.)- Published
- 2017
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