Activation of T-cells through an antigen-independent alternative pathway induces precocious sensitivity to Fas-induced apoptosis.
Autoreactive T-cells can be activated inadvertently during immune responses through antigen-independent pathways. It has been suggested that Fas/Fas ligand interactions may play a role in eliminating these cells, but the extent that cells activated through such alternative pathways are sensitive to Fas-induced apoptosis has not been extensively evaluated. Proliferation of peripheral blood T-cells from normal individuals activated for 4 days with PHA or PMA + ionophore was not influenced by the presence of anti-Fas antibody. When the same cells were activated with soluble factors produced by previously activated T-cells (lymphostimulatory activity), anti-Fas antibodies inhibited thymidine incorporation by 74+/-4%. The presence of typical morphological changes and oligonucleosomal fragmentation of DNA indicated that the reduced proliferation resulted from apoptotic death of the lymphoblasts. Fas-sensitivity of T-cells activated by lymphostimulatory activity was first detectable 4 days after activation, and at 5 days the majority of lymphoblasts had become sensitive to Fas, whereas no evidence of sensitivity to Fas was observed for lymphoblasts generated by PHA or PMA + ionophore during the first 5 days of culture. Incubation of cells activated with PHA or PMA+ ionophore in the presence of IL-2 at concentrations 10-fold higher than that present in lymphostimulatory activity did not induce early sensitivity to Fas, indicating that exposure to IL-2 could not explain the precocious development of sensitivity to Fas seen following activation by lymphostimulatory activity. These studies demonstrate that T-cells activated through an antigen-independent 'alternative' pathway develop precocious sensitivity to Fas-induced apoptosis, which may be important in permitting the elimination of autoreactive bystander cells activated in the course of immune responses.
Bonay
M
M
INSERM U.82, Faculté de Médecine Xavier Bichat, Paris, France.
Bouchonnet
F
F
Lecossier
D
D
Boumsell
L
L
Soler
P
P
Grodet
A
A
Robertson
M J
MJ
Hance
A J
AJ
D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D000941:Antigens / Q000276:immunology; D017209:Apoptosis; D000001:Calcimycin / Q000494:pharmacology; D002455:Cell Division; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation; D010835:Phytohemagglutinins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000941:Antigens; D007376:Interleukin-2; D010835:Phytohemagglutinins; D019014:fas Receptor; D000001:Calcimycin; D013755:Tetradecanoylphorbol Acetate