Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes.
Activation-induced cell death (AICD) is involved in peripheral tolerance by controlling the expansion of repeatedly stimulated T cells via an apoptotic Fas (CD95; APO-1)-dependent pathway. The TNFRSF-6 gene encoding Fas is mutated in children suffering from autoimmune lymphoproliferative syndrome (ALPS), which is characterized by lymphoproliferation and autoimmunity. We examined AICD in Fas-deficient T cells from ALPS patients. We showed that primary activated Fas-deficient T cells die by apoptosis after repeated T cell antigen receptor (TCR) stimulation despite resistance to Fas-mediated cell death. This Fas-independent AICD was found to be mediated through a cytotoxic granules-dependent pathway. Cytotoxic granules-mediated AICD was also detected in normal T lymphocytes though to a lesser extent. As expected, the cytotoxic granules-dependent AICD was abolished in T cells from Rab27a- or perforin-deficient patients who exhibited defective granules-dependent cytotoxicity. Supporting an in vivo relevance of the cytotoxic granules-dependent AICD in ALPS patients, we detected an increased number of circulating T lymphocytes expressing granzymes A and B. Altogether, these data indicated that the cytotoxic granules-dependent cell death in ALPS may compensate for Fas deficiency in T lymphocytes. Furthermore, they identified a novel AICD pathway as a unique alternative to Fas apoptosis in human peripheral T lymphocytes.
Mateo
Véronique
V
INSERM, U768, Paris, France.
Ménager
Michael
M
de Saint-Basile
Geneviève
G
Stolzenberg
Marie-Claude
MC
Roquelaure
Bertrand
B
André
Nicolas
N
Florkin
Benoit
B
le Deist
Françoise
F
Picard
Capucine
C
Fischer
Alain
A
Rieux-Laucat
Frédéric
F
D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology; D016022:Case-Control Studies; D016923:Cell Death; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D009154:Mutation; D054353:Perforin / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology*; D019014:fas Receptor / Q000172:deficiency* / Q000235:genetics
D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D054353:Perforin