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Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Dotti, Gianpietro Savoldo, Barbara Pule, Martin A. Straathof, Karin C. M. Biagi, Ettore Yvon, Eric S. Vigouroux, Stéphane Rooney, Cliona M. |
| Copyright Year | 2005 |
| Abstract | Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Fas(low) and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.bloodjournal.org/content/bloodjournal/early/2005/02/15/blood-2004-08-3337.full.pdf?sso-checked=true |
| Alternate Webpage(s) | http://discovery.ucl.ac.uk/7068/1/7068.pdf |
| Alternate Webpage(s) | http://www.bloodjournal.org/content/bloodjournal/105/12/4677.full.pdf?sso-checked=true |
| PubMed reference number | 15713795v1 |
| Volume Number | 105 |
| Issue Number | 12 |
| Journal | Blood |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Cessation of life Epstein-Barr Virus Fatty-acid synthase Fetal Alcohol Syndrome Helper-Inducer T-Lymphocyte Infiltration Ligands Nasopharyngeal carcinoma Nasopharynx Non-Small Cell Lung Carcinoma Pituitary Neoplasms Poly(ADP-ribose) Polymerases RNA RNA, Small Interfering Ribose autologous Epstein-Barr virus-specific cytotoxic T lymphocytes (cell) stage IV childhood Hodgkin's lymphoma transduction |
| Content Type | Text |
| Resource Type | Article |
