Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets

Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13838-43. doi: 10.1073/pnas.251531798. Epub 2001 Nov 13.

Abstract

CD1d-restricted invariant NKT (iNKT) cells are immunoregulatory cells whose loss exacerbates diabetes in nonobese diabetic (NOD) female mice. Here, we show that the relative numbers of iNKT cells from the pancreatic islets of NOD mice decrease at the time of conversion from peri-insulitis to invasive insulitis and diabetes. Conversely, NOD male mice who have a low incidence of diabetes showed an increased frequency of iNKT cells. Moreover, administration of alpha-galactosylceramide, a potent activating ligand presented by CD1d, ameliorated the development of diabetes in NOD female mice and resulted in the accumulation of iNKT cells and myeloid dendritic cells (DC) in pancreatic lymph nodes (PLN), but not in inguinal lymph nodes. Strikingly, injection of NOD female mice with myeloid DC isolated from the PLN, but not those from the inguinal lymph nodes, completely prevented diabetes. Thus, the immunoregulatory role of iNKT cells is manifested by the recruitment of tolerogenic myeloid DC to the PLN and the inhibition of ongoing autoimmune inflammation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD1 / immunology*
  • Antigens, CD1d
  • Chemotaxis, Leukocyte / immunology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetes Mellitus, Type 1 / prevention & control
  • Disease Progression
  • Female
  • Galactosylceramides / pharmacology
  • Islets of Langerhans / cytology
  • Islets of Langerhans / immunology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Lymphocyte Activation / immunology*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Pancreas / cytology
  • Pancreas / drug effects
  • Pancreas / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*

Substances

  • Antigens, CD1
  • Antigens, CD1d
  • Galactosylceramides