Multiple immuno-regulatory defects in type-1 diabetes
Anjli Kukreja, … , Steven Porcelli, Noel Maclaren
Anjli Kukreja, … , Steven Porcelli, Noel Maclaren
Published January 1, 2002
Citation Information: J Clin Invest. 2002;109(1):131-140. https://doi.org/10.1172/JCI13605.
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Article

Multiple immuno-regulatory defects in type-1 diabetes

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.

Authors

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

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Figure 4

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Defective Th1 cytokine production in IMD patients at various stages of t...
Defective Th1 cytokine production in IMD patients at various stages of the disease. PBMCs from various groups were stimulated with PMA + I and were analyzed for the cell surface expression of CD3 and intracellular IFN-γ and IL-4 cytokines. Each dot represents one subject. (a) This figure depicts IFN-γ production in the patient groups. The percentage of T cells secreting IFN-γ was significantly reduced in newly diagnosed (P < 0.001) and long-standing IMD patients (P < 0.03) compared with the normal controls. CD3+ T cells were further characterized into CD4+ (b) and CD8+ (c) subsets for the cytokine production. CD4+ T cells showed significantly reduced IFN-γ production in both newly diagnosed (P < 0.003) and long-standing IMD patients (P < 0.005). Three out of seven ICA+ relatives so tested also had reduced numbers of T cells secreting IFN-γ (P < 0.01), while the other four were in the normal range. (d) Percentage of IL-4–secreting T cells was not reduced in IMD patient groups compared with controls. The horizontal bars represent the mean of that group.