Activation-induced T cell death occurs at G1A phase of the cell cycle.
Peripheral negative selection of cycling T cells after TCR engagement and deletion of activated T cells after an immune response occur by an apoptotic process termed activation-induced cell death (AICD). The cross-linking of TCR-CD3 complex with anti-CD3 monoclonal antibody led to significant apoptotic cell death in peripheral blood T cells. To further define cell cycle restriction points for triggering AICD in T cells, we evaluated the association between cell cycle progression and death signal transduction. Simultaneous DNA / RNA quantification analysis revealed that T cells entering G1A phase of the cell cycle may acquire sensitivity to AICD. The activation of caspase-3 was induced when T cells entered G1A phase. Up-regulation of cyclin-dependent kinases (Cdk4 and Cdk6) and cyclin D3 was initiated in TCR-stimulated T cells entering G1A phase and expression of these markers steadily increased as T cells progressed from G1A into G1B phase. Interestingly, caspase-3 inhibitors could inhibit the up-regulation of these G1 cell cycle regulators and induce G0 / G1A arrest as well as the inhibition of AICD. On the basis of these results, AICD signals are most likely transduced into TCR-stimulated T cells entering G1A phase. T cells that fail to progress from G1A into G1B phase undergo AICD.
Li
Q S
QS
Department of Pediatrics, Mie University School of Medicine, Tsu, Mie, Japan.
Tanaka
S
S
Kisenge
R R
RR
Toyoda
H
H
Azuma
E
E
Komada
Y
Y
D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D016193:G1 Phase / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology