Anti‐CD3 treatment up‐regulates programmed cell death protein‐1 expression on activated effector T cells and severely impairs their inflammatory capacity

Abstract

SummaryT 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.

Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice

“…Consistent with recent publications from our group and others, this unresponsiveness may be associated with the presence of anergic or exhausted-like T cells expressing inhibitory receptors, such as programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1)/LAG-3/T cell immunoreceptor with Ig and ITIM domains (TIGIT), as well as the transcription factor eomesodermin (Eomes) [35][36][37]. Another field of investigation concerns the impact of the combination therapy on glucose metabolism as CD3 antibodies have been shown to downregulate the expression of components of the glycolysis pathway, such as the glucose transporter GLUT1, in effector T cells and HDACi are able to inhibit GLUT1mediated glucose transport [37,38].…”

Targeting dendritic cells with a PD-L1 based bispecific antibody rejuvenates specific anti-tumor T cells

“…Even though ErbxCD3 and PDL1xCD3 have similar EC50 in T cell activation markers and tumor cell killing, the IFNγ level in PDL1xCD3 group was much higher than that of ErbxCD3 group ( Figure 1I). Since T cells express PD-1 upon activation and IFNγ also upregulate PD-L1 on tumor cell, the PD-1/PD-L1 signal may inhibit T cells from secreting IFNγ in ErbxCD3 group 41 (Figure 2A). Moreover, PDL1xCD3 treatment not only improved the overall survival rate but also reduced side effects compared to systemic anti-CD3 treatment ( Figure 2B).…”

Gene expression profile of human T cells following a single stimulation of peripheral blood mononuclear cells with anti-CD3 antibodies

“…The induction of a more regulatory environment by anti-CD3 antibodies could produce antigen-specific tolerance and alleviate the immune response. More recent data on human clinical data suggest that other mechanisms such as T cell exhaustion 11,12 or the induction of inhibitory receptors on T cells 13,14 could also contribute to the suppression of the immune response.…”