Multiple Immuno-Regulatory Defects in type-1 Diabetes

J Clin Invest. 2002 Jan;109(1):131-40. doi: 10.1172/JCI13605.

Abstract

Susceptibility to immune-mediated diabetes (IMD) in humans and NOD mice involves their inherently defective T cell immunoregulatory abilities. We have followed natural killer (NK) T cell numbers in patients with IMD, both by flow cytometry using mAbs to the characteristic junctions found in the T cell receptors of this cell subtype, and by semiquantitative RT-PCR for the corresponding transcripts. Both before and after clinical onset, the representation of these cells in patients' PBMCs is reduced. We also report low numbers of resting CD4(+) CD25(+) T cells in IMD patients, a subset of T cells shown to have important immunoregulatory functions in abrogating autoimmunities in 3-day thymectomized experimental mice. Whereas a biased Th1 to Th2 cytokine profile has been suggested to underlie the pathogenesis of IMD in both species, we found defective production of IFN-gamma in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-gamma and IL-4 deficiencies in V(alpha)24(+) NK T-enriched cells. These data suggest that multiple immunoregulatory T (Treg) cell defects underlie islet cell autoimmunity leading to IMD in humans and that these lesions may be part of a broad T cell defect.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antigens, CD1 / genetics
  • Antigens, CD1d
  • Base Sequence
  • CD4-Positive T-Lymphocytes / immunology
  • Case-Control Studies
  • Child
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / immunology
  • Female
  • Humans
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology
  • Lymphocyte Subsets / immunology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Middle Aged
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Interleukin-2 / metabolism

Substances

  • Antigens, CD1
  • Antigens, CD1d
  • CD1D protein, human
  • RNA, Messenger
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Interleukin-2
  • Interferon-gamma