PD‐L1 blockade overrides Salmonella typhimurium‐mediated diabetes prevention in NOD mice: No role for Tregs

Abstract

Increasingly, evidence suggests that there is a strong environmental component to the development of the autoimmune disease type 1 diabetes. Our previous data showed that NOD mice are protected from developing diabetes after infection with Salmonella typhimurium and there is some evidence that changes within the DC compartment play a crucial role in this protective effect. This paper further characterises this Salmonella‐modulated protective phenotype. We find that, contrary to other infection‐mediated models of type 1 diabetes protection, there was no expansion of Foxp3+ Tregs. Furthermore, transcriptome analysis of DCs identified a distinct Salmonella‐induced signature in which the inhibitory receptor PD‐L1 was up‐regulated. This was confirmed by flow cytometry. In vivo blockade of the PD1/PD‐L1 interaction was found to ablate the protective function of Salmonella infection. These data provide evidence for a novel regulatory DC phenotype proficient at controlling autoreactive T cells for an extended duration in the NOD mouse model of diabetes.

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

“…A recent report described that signalling though PD‐1 leads to down‐regulation of glycolysis in T cells, and in our studies we find that PD‐1 is up‐regulated in the anti‐CD3‐treated effector cells. Previous studies have demonstrated that blockade of PD‐1/PD‐L1 interaction increases the interaction time between T cells and antigen‐presenting cells and enhances activation, and expression of PD‐L1 is important for regulating anti‐islet immune responses . Our results show that anti‐CD3 treatment up‐regulates PD‐1 on effector T cells, and that anti‐CD3 treatment is not effective if the PD‐1/PD‐L1 pathway is inhibited.…”

“…Previous studies have demonstrated that blockade of PD-1/PD-L1 interaction increases the interaction time between T cells and antigen-presenting cells and enhances activation, 33,47 and expression of PD-L1 is important for regulating anti-islet immune responses. [28][29][30][31][32] Our results show that anti-CD3 treatment up-regulates PD-1 on effector T cells, and that Figure 6. Agly anti-CD3 treatment increases programmed death 1 (PD-1) expression on islet-specific effector T cells, and blockade of PD-1 activation overcomes agly anti-CD3-induced protection from diabetes.…”

“…Expression of PD-L1 on antigen-presenting cells is an important regulator of anti-islet immune responses, 13,[28][29][30][31] and blockade of this interaction can precipitate diabetes in prone strains. 29,32 Furthermore, blockade of PD-1/PD-L1 increases the interaction time between T cells and antigenpresenting cells, so indirectly enhancing activation. 33 We used the same experimental set up described in Fig.…”

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

“…We found by antibody blocking that PD-L1 signalling maintains low rates of T1D development in NOD low mice. Similarly, previous work had shown that PD-L1 blockade unmasks T1D in pre-diabetic NOD high mice and reverses suppression of T1D by Salmonella typhimurium [32]. PD-L1 mediates local immune regulation in pancreatic lymph nodes at a young age, and systemic regulation in older prediabetic NOD mice [46].…”

“…As described previously [32], mice were injected intra-peritoneally with a PD-L1 blocking monoclonal antibody (clone MIH5) at a dose of 2 mg/mouse. Development of diabetes was followed for 24 days post injection.…”