Anti‐ CD 3 treatment up‐regulates programmed cell death protein‐1 expression on activated effector T cells and severely impairs their inflammatory capacity

Summary T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD 3 component of the T‐cell receptor complex provides one therapeutic approach. Anti‐ CD 3 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‐ CD 3 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‐ CD 3 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‐ CD 3‐treated mice, and diabetes induced through anti‐ PD ‐L1 antibody could only be reversed with anti‐ CD 3 antibody if the anti‐ CD 3 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‐ CD 3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti‐ CD 3 therapy can reverse diabetogenesis.