Multiple immuno-regulatory defects in type-1 diabetes

Anjli Kukreja, Giulia Cost, John Marker, Chenhui Zhang, Zhong Sun, Karen Lin-Su, Svetlana Ten, Maureen Sanz, Mark Exley, Brian Wilson, Steven Porcelli, Noel Maclaren

Research output: Contribution to journalArticlepeer-review

591 Scopus citations

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-γ in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-γ and IL-4 deficiencies in Vα24+ 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.

Original languageEnglish (US)
Pages (from-to)131-140
Number of pages10
JournalJournal of Clinical Investigation
Volume109
Issue number1
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Medicine(all)

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