Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through SOCS2

Sci Signal. 2016 Jun 21;9(433):ra61. doi: 10.1126/scisignal.aad0612.


Type 1 diabetes (T1D) is a T cell-dependent autoimmune disease that is characterized by the destruction of insulin-producing β cells in the pancreas. The administration to patients of ex vivo-differentiated FoxP3(+) regulatory T (Treg) cells or tolerogenic dendritic cells (DCs) that promote Treg cell differentiation is considered a potential therapy for T1D; however, cell-based therapies cannot be easily translated into clinical practice. We engineered nanoparticles (NPs) to deliver both a tolerogenic molecule, the aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and the β cell antigen proinsulin (NPITE+Ins) to induce a tolerogenic phenotype in DCs and promote Treg cell generation in vivo. NPITE+Ins administration to 8-week-old nonobese diabetic mice suppressed autoimmune diabetes. NPITE+Ins induced a tolerogenic phenotype in DCs, which was characterized by a decreased ability to activate inflammatory effector T cells and was concomitant with the increased differentiation of FoxP3(+) Treg cells. The induction of a tolerogenic phenotype in DCs by NPs was mediated by the AhR-dependent induction of Socs2, which resulted in inhibition of nuclear factor κB activation and proinflammatory cytokine production (properties of tolerogenic DCs). Together, these data suggest that NPs constitute a potential tool to reestablish tolerance in T1D and potentially other autoimmune disorders.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / agonists
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / pathology
  • Mice, Inbred NOD
  • Nanoparticles / chemistry
  • Nanoparticles / therapeutic use
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / immunology
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Thiazoles / chemistry
  • Thiazoles / pharmacology


  • 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester
  • AHR protein, human
  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Indoles
  • Receptors, Aryl Hydrocarbon
  • SOCS2 protein, human
  • Socs2 protein, mouse
  • Suppressor of Cytokine Signaling Proteins
  • Thiazoles