Cell cycle phase-specific survival of CD95 ligand-challenged Jurkat cells: upregulation of heat-shock response.
An important means of regulating T-cell function occurs via physical deletion (cytolysis) of unnecessary/unwanted T cells. Among cytolytic pathways, CD95 (Fas)-based killing plays a prominent role. Although activation of T cells results in rapid upregulation of surface CD95 expression, sensitivity to CD95-based killing lags behind. To assess determinants of resistance to CD95-based killing, we used Jurkat cells as a model. Analysis of the 10% survivors of a LD(90) dose of CD95 ligand (CD95L) at 24 h demonstrated them to arise preferentially from the S + G2/M phases of the cell cycle and to remain clustered in S + G2/M without undergoing cell division. Protein immunoblot, immunocytochemistry, and RT-PCR analyses demonstrated that hsp72 was markedly upregulated in CD95L survivors within hours of CD95L challenge, indicative of a heat-shock response. Indeed, exposure of Jurkat cells to bona fide heat shock did markedly upregulate hsp72 and, upon subsequent CD95L challenge, did greatly enhance cell survival with persistent clustering to S + G2/M. These findings collectively suggest that in response to a CD95L insult, development of a heat-shock response above some critical threshold level can protect against lethality. This raises the possibility that exaggerated and/or protracted heat-shock responses under in vivo conditions may favor the survival of T cells (including autoaggressive T cells) that otherwise would be destined to die via a CD95-based pathway.
Parr
T B
TB
Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine, University of California, Los Angeles, 90033, USA.
Hofman
F M
FM
Kiener
P A
PA
Stohl
W
W
D017209:Apoptosis; D002470:Cell Survival; D053222:Fas Ligand Protein; D016195:G2 Phase; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018869:Heat-Shock Response; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008938:Mitosis; D012333:RNA, Messenger / Q000096:biosynthesis; D016196:S Phase; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger