Regulatory T Cells Induced by Single-Peptide Liposome Immunotherapy Suppress Islet-Specific T Cell Responses to Multiple Antigens and Protect from Autoimmune Diabetes

Ag-specific tolerizing immunotherapy is considered the optimal strategy to control type 1 diabetes, a childhood disease involving autoimmunity toward multiple islet antigenic peptides. To understand whether tolerizing immunotherapy with a single peptide could control diabetes driven by multiple Ags, we coencapsulated the high-affinity CD4 + mimotope (BDC2.5 mim ) of islet autoantigen chromogranin A (ChgA) with or without calcitriol (1α,25-dihydroxyvitamin D3) into liposomes. After liposome administration, we followed the endogenous ChgA-specific immune response with specific tetramers. Liposome administration s.c., but not i.v., induced ChgA-specific Foxp3 + and Foxp3 - PD1 + CD73 + ICOS + IL-10 + peripheral regulatory T cells in prediabetic mice, and liposome administration at the onset of hyperglycemia significantly delayed diabetes progression. After BDC2.5 mim /calcitriol liposome administration, adoptive transfer of CD4 + T cells suppressed the development of diabetes in NOD severe combined immunodeficiency mice receiving diabetogenic splenocytes. After BDC2.5 mim /calcitriol liposome treatment and expansion of ChgA-specific peripheral regulatory T cells. IFN-γ production and expansion of islet-specific glucose-6-phosphatase catalytic subunit-related protein-specific CD8 + T cells were also suppressed in pancreatic draining lymph node, demonstrating bystander tolerance at the site of Ag presentation. Thus, liposomes encapsulating the single CD4 + peptide, BDC2.5 mim , and calcitriol induce ChgA-specific CD4 + T cells that regulate CD4 + and CD8 + self-antigen specificities and autoimmune diabetes in NOD mice.