Multiple immuno-regulatory defects in type-1 diabetes.
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.
Kukreja
Anjli
A
Department of Pediatrics, Weill College of Medicine of Cornell University, New York, New York, USA.
Cost
Giulia
G
Marker
John
J
Zhang
Chenhui
C
Sun
Zhong
Z
Lin-Su
Karen
K
Ten
Svetlana
S
Sanz
Maureen
M
Exley
Mark
M
Wilson
Brian
B
Porcelli
Steven
S
Maclaren
Noel
N
D000293:Adolescent; D000328:Adult; D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics; D055610:Antigens, CD1d; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000378:metabolism
D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma