Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells.
Diabetogenic T-cells can be detected in pre-diabetic nonobese diabetic (NOD) mice after transfer in NOD-SCID recipients. Here we demonstrate that 6-week-old pre-diabetic NOD mice, >2 months before disease onset, already harbor pathogenic T-cells in equal numbers to overtly diabetic animals. The delay in diabetes appearance is explained by the presence of regulatory CD4+ CD25+ T-cells that control diabetogenic effectors and that are, in our hands, transforming growth factor (TGF)-beta-dependent. Our present results suggest, however, that diabetes onset is only partly explained by a decline in this regulatory T-cell activity. Another major factor appears to be the progressive resistance of diabetogenic cells to TGF-beta-dependent mediated inhibition. We propose that progression to overt disease correlates with the pathogenic T-cell's escape from TGF-beta-dependent T-cell-mediated regulation.
You
Sylvaine
S
INSERM U580, Paris, France.
Belghith
Mériam
M
Cobbold
Stephen
S
Alyanakian
Marie-Alexandra
MA
Gouarin
Christine
C
Barriot
Samia
S
Garcia
Corinne
C
Waldmann
Herman
H
Bach
Jean-François
JF
Chatenoud
Lucienne
L
D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000097:blood; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D016207:Cytokines; D015375:Receptors, Interleukin-2