Up-regulation of c-FLIPshort and reduction of activation-induced cell death in T-cells from patients with Type 1 diabetes.
AICD of T-cells is an efficient way of removing activated T-lymphocytes. In this study we investigated the molecular basis of AICD upon reactivation in peripheral T-lymphocytes from newly diagnosed T1DM patients and age-matched healthy controls. In an in vitro model system, PHA-stimulated T-cells, upon prolonged culture in IL-2, acquire a sensitive phenotype to Fas-mediated apoptosis. This phenomenon is less pronounced in T1DM T-cells. Moreover, the restimulation of activated T-cells via TCR/CD3 and/or via CD28 inhibits Fas-mediated apoptosis in T1DM in comparison to control T-cells. After Fas triggering, the generation of the active sub-units of caspase-8 is significantly reduced in T1DM T-cells restimulated via TCR/CD3 and/or CD28. In parallel, we found that the amount of c-FLIPshort protein is significantly increased in the DISC only in T1DM T-cells restimulated via TCR/CD3 and via CD28. These data suggest that increased levels of c-FLIPshort may prevent recruitment of pro-caspase-8 in T1DM CD3-treated T-cells and provide new insight into the molecular mechanisms of apoptosis resistance in stimulated T-cells from T1DM patients.
Richiusa
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P
Laboratory of ImmunoEndocrinology, Department of Endocrinology, School of Medicine, Università degli Studi di Palermo, Piazza delle Cliniche 2, I-90127 Palermo, Italy.
Pizzolanti
G
G
Misiano
G
G
Mattina
A
A
Citarrella
R
R
Galluzzo
A
A
Giordano
C
C
D000293:Adolescent; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens; C506386:CFLAR protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases