Deficient activation and resistance to activation-induced apoptosis of CD8+ T cells is associated with defective peripheral tolerance in nonobese diabetic mice.
Activation-induced cell death (AICD) is a mechanism of homeostasis that limits the clonal expansion of autoreactive T cells and regulates central and peripheral tolerance. In nonobese diabetic (NOD) mice, defects in central and peripheral tolerance are associated with a proliferative hyporesponsiveness of thymocytes and peripheral T cells elicited upon TCR activation. We investigated whether these defects in tolerance induction and hyporesponsiveness of NOD T cells manifest in an altered susceptibility to TCR-induced AICD. TCR-activated NOD splenic CD4+ and CD8+ T cells are more resistant to AICD than control strain C57BL/6, BALB/c, and NOR T cells. NOR CD4+ but not CD8+ T cells are resistant to TCR-induced AICD. Whereas c-FLIP expression is reduced in activated T cells from control strains, it persists in activated NOD CD8+ T cells and is accompanied by diminished activity of caspase-3 and -8. IL-4 reduces this c-FLIP expression and increases caspase-3 and -8 activity in activated NOD CD8+ T cells. Moreover, IL-4 and CD28 costimulation restores the susceptibility of NOD CD8+ T cells to AICD, and this is associated with increased expression of CD25, CD95, CD95L, and TNFR2. Thus, deficient activation of CD8+ T cells and their greater resistance to TCR-induced AICD may mediate defective peripheral tolerance and the development of T1D in NOD mice.
Arreaza
Guillermo
G
Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, NG6 2V4, London, ON, Canada.
Salojin
Konstantin
K
Yang
Wen
W
Zhang
Jian
J
Gill
Bruce
B
Mi
Qing-Sheng
QS
Gao
Jian-Xin
JX
Meagher
Craig
C
Cameron
Mark
M
Delovitch
Terry L
TL
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004789:Enzyme Activation; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013047:Specific Pathogen-Free Organisms
D015703:Antigens, CD; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases