T cell growth cytokines cause the superinduction of molecules mediating antigen-induced T lymphocyte death.
TCR stimulation of T lymphocytes that are activated and cycling in the presence of IL-2 leads to programmed cell death. We now show that this effect is at least partly attributable to the ability of IL-2 to dramatically increase the expression of mRNAs encoding ligands and receptors that mediate apoptosis. We also found that cyclosporin was not able to fully inhibit the TCR induction of death molecule mRNAs or TCR-induced apoptosis, although it could completely turn off IL-2 expression. The effect growth cytokines was further explored in T cells derived from mice bearing a homozygous deficiency of the IL-2R alpha-chain. We found that IL-2Ralpha-/- cells were resistant to death if IL-2 was used to induce apoptosis susceptibility, but that large amounts of other T cell growth cytokines, such as IL-4 and IL-7, could induce cell cycle progression and promote TCR-induced apoptosis. However, our findings suggest that autoimmunity and lymphoproliferation in IL-2Ralpha-/- mice can result from the loss of IL-2 stimulated feedback apoptosis and that other growth cytokines are not produced at levels sufficient to compensate for this deficit.
Zheng
L
L
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-1892, USA.
Trageser
C L
CL
Willerford
D M
DM
Lenardo
M J
MJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D053222:Fas Ligand Protein; D007376:Interleukin-2 / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D016572:Cyclosporine