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.