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

J Immunol. 2020 Apr 1;204(7):1787-1797. doi: 10.4049/jimmunol.1901128. Epub 2020 Feb 28.


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 (BDC2.5mim) 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 BDC2.5mim/calcitriol liposome administration, adoptive transfer of CD4+ T cells suppressed the development of diabetes in NOD severe combined immunodeficiency mice receiving diabetogenic splenocytes. After BDC2.5mim/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, BDC2.5mim, and calcitriol induce ChgA-specific CD4+ T cells that regulate CD4+ and CD8+ self-antigen specificities and autoimmune diabetes in NOD mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / immunology*
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / therapy
  • Autoimmunity / immunology*
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / therapy
  • Female
  • Immune Tolerance / immunology
  • Immunotherapy / methods
  • Islets of Langerhans / immunology*
  • Liposomes / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Peptides / immunology
  • T-Lymphocytes, Regulatory / immunology*


  • Autoantigens
  • Liposomes
  • Peptides