Bioengineering Platelets Presenting PD‐L1, Galectin‐9 and BTLA to Ameliorate Type 1 Diabetes

Abstract Autoimmune destruction of pancreatic β‐cells leads to impaired insulin production and onset of type 1 diabetes (T1D). Hence, immunomodulation of pancreas‐infiltrated immune cells especially the β‐cells autoreactive‐T cells is a promising way to hinder and reverse the progress of T1D. Herein, megakaryocytes are primed with interferon‐γ (IFN‐γ) to produce platelets presenting high levels of immunosuppressive checkpoint ligands including programmed death‐ligand 1 (PD‐L1), Programmed Death‐Ligand 2 (PD‐L2), the B and T lymphocyte attenuator (BTLA) and Galectin‐9 (Gal‐9), termed as IFN‐γ platelets. The IFN‐γ platelets bound and interacted with T cells through immune checkpoint ligands and receptors, which efficaciously induced T cell exhaustion and apoptosis in vitro. Virtually, NOD diabetes mice received IFN‐γ platelets treatments prominently preserved β‐cell integrity and insulin production, ultimately hindering the progress to hyperglycemia. Intriguingly, both the amount and activity of the pancreas infiltrate‐T cells intensively reduced, whereas the magnitude of regulatory T cells (Tregs) remarkably increased, which is attributed to IFN‐γ platelets treatments. Moreover, IFN‐γ platelets treatment instigated macrophage polarization toward an anti‐inflammatory M2 phenotype that may stimulate pancreatic angiogenesis, and promote β‐cell proliferation, consequently ameliorating the new‐onset T1D.