Cytotoxicity mediated by the Fas ligand (FasL)-activated apoptotic pathway in stem cells.
Whereas it is now clear that human bone marrow stromal cells (BMSCs) can be immunosuppressive and escape cytotoxic lymphocytes (CTLs) in vitro and in vivo, the mechanisms of this phenomenon remain controversial. Here, we test the hypothesis that BMSCs suppress immune responses by Fas-mediated apoptosis of activated lymphocytes and find both Fas and FasL expression by primary BMSCs. Jurkat cells or activated lymphocytes were each killed by BMSCs after 72 h of co-incubation. In comparison, the cytotoxic effect of BMSCs on non-activated lymphocytes and on caspase-8(-/-) Jurkat cells was extremely low. Fas/Fc fusion protein strongly inhibited BMSC-induced lymphocyte apoptosis. Although we detected a high level of Fas expression in BMSCs, stimulation of Fas with anti-Fas antibody did not result in the expected BMSC apoptosis, regardless of concentration, suggesting a disruption of the Fas activation pathway. Thus BMSCs may have an endogenous mechanism to evade Fas-mediated apoptosis. Cumulatively, these data provide a parallel between adult stem/progenitor cells and cancer cells, consistent with the idea that stem/progenitor cells can use FasL to prevent lymphocyte attack by inducing lymphocyte apoptosis during the regeneration of injured tissues.
Mazar
Julia
J
Program on Physical Biology, NICHD, Bethesda, Maryland 20892.
Thomas
Molly
M
Program on Physical Biology, NICHD, Bethesda, Maryland 20892.
Bezrukov
Ludmila
L
Program on Physical Biology, NICHD, Bethesda, Maryland 20892.
Chanturia
Alexander
A
Program on Physical Biology, NICHD, Bethesda, Maryland 20892.
Pekkurnaz
Gulcin
G
Program on Physical Biology, NICHD, Bethesda, Maryland 20892.
Yin
Shurong
S
Program on Physical Biology, NICHD, Bethesda, Maryland 20892.
Kuznetsov
Sergei A
SA
Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
Robey
Pamela G
PG
Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
Zimmerberg
Joshua
J
Program on Physical Biology, NICHD, Bethesda, Maryland 20892.
D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019169:Jurkat Cells; D008214:Lymphocytes / Q000378:metabolism; D008954:Models, Biological; D012313:RNA / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors
D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; D034741:RNA, Small Interfering; D012313:RNA; D053181:Caspase 8