Reversal of autoimmunity by boosting memory-like autoregulatory T cells

Immunity. 2010 Apr 23;32(4):568-80. doi: 10.1016/j.immuni.2010.03.015. Epub 2010 Apr 8.


Blunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8(+) T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals. pMHC-NP therapy was inconsequential in mice engineered to bear an immune system unresponsive to the corresponding epitope, owing to absence of epitope-experienced autoregulatory T cells. pMHC-NP-expanded autoregulatory T cells suppressed local presentation of autoantigens in an interferon-gamma-, indoleamine 2,3-dioxygenase-, and perforin-dependent manner. Nanoparticles coated with human diabetes-relevant pHLA complexes restored normoglycemia in a humanized model of diabetes. These observations expose a paradigm in the pathogenesis of autoimmunity amenable for therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigen Presentation
  • Autoimmunity*
  • Base Sequence
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • Diabetes Mellitus, Type 1 / immunology
  • Female
  • Glucose-6-Phosphatase / chemistry
  • Glucose-6-Phosphatase / immunology
  • Humans
  • Immunologic Memory*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Interferon-gamma / immunology
  • Major Histocompatibility Complex / immunology
  • Mice
  • Mice, Inbred NOD
  • Molecular Sequence Data
  • Perforin / immunology
  • Proteins / chemistry
  • Proteins / immunology
  • T-Lymphocytes, Regulatory / immunology*


  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Proteins
  • Perforin
  • Interferon-gamma
  • Glucose-6-Phosphatase
  • G6pc2 protein, mouse