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 2

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PBMC and CD4–CD8– DN T cells from patients and normal controls were exam...
PBMC and CD4–CD8– DN T cells from patients and normal controls were examined for Vα24JαQ expression by the Southern blot technique. (a and c) Vα24JαQ TCR transcripts are shown. (b and d) For the housekeeping gene HPRT expressions in the same subjects. (a) Expression of Vα24JαQ mRNA in the peripheral blood of IMD patients (lanes 1, 2, 4, 5, 6, 9, 10, and 11) are compared with normal controls (lanes 3 and 12). Lanes 7 and 8 compare the TCR expression in the DN population between controls and patients, respectively. Lane 13 is the negative control. (c) This figure part compares the expression of canonical Vα24JαQ transcripts in the patients with type 2 diabetes (lanes 1, 2, and 3) with a normal control (lane 4). Lane 5 is the negative control. The arrows indicate the position of the invariant Vα24JαQ and HPRT bands. (e) The relative expression intensities of the canonical Vα24JαQ TCR as normalized to HPRT gene expression in controls, IMD patients, and patients with type 2 diabetes are shown. The mRNA levels were all determined by RT-PCR followed by quantification of radiolabel by phosphorimaging. Shown in e are the mean levels of Vα24JαQ calibrated to the amount of HPRT gene expression in the sample. The bars indicate means plus 1 SE. Significant differences from the normal control group are *P < 0.05 and ** P < 0.01.