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 1

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NK T cell defect in IMD patients. (a) NK T cells in the peripheral blood...
NK T cell defect in IMD patients. (a) NK T cells in the peripheral blood were characterized by a three-color flow cytometry assay using mAbs to CD3 and to receptors bearing expressed Vα24 and Vβ11. The triple-positive population (CD3+Vα24+Vβ11+) showed marked reductions in both newly diagnosed (P < 0.0001) and long-term immune-mediated diabetic patients (P < 0.007) compared with controls. Nine multi-autoantibody–positive relatives of the 12 patients studied similarly had significantly reduced numbers of triple-positive cells (P < 0.0001). Whereas the type 2 diabetic patients also had lower levels than controls (P < 0.02), their deficiency was less marked than the IMD patients (P < 0.04). The horizontal lines represent means; n is the number of subjects in each group. (b) Comparisons are shown between NK T cells as defined by staining with CD3, Vα24, and mAb to the Vα24JαQ junction (6B11) to NK T cells defined by staining with CD3+Vα24+Vα11+ mAbs in patient and control groups. No differences were found in the NK T cell numbers as stained by the two different sets of mAbs. (c) A dot plot comparing the measurement of NK T cells using Vα24 and Vβ11 mAbs and Vα24 and the invariant JαQ junction mAb (6B11) in a representative normal control and a newly diagnosed IMD patient are shown. The patient has reduced doubly stained cells (upper-right quadrants) using either sets of mAbs. *P < 0.007, **P < 0.04.