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

摘要

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 (1 alpha,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 Foxp(3+) 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-gamma 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.