C-FLIP Protects Mature T Lymphocytes from TCR-mediated Killing

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2008 Oct 4

PMID 18832693

Citations 19

Authors

Nu Zhang

Kaycie Hopkins

You-Wen He

Affiliations

Soon will be listed here.

Abstract

Although c-FLIP has been identified as an important player in the extrinsic (death receptor-induced) apoptosis pathway, its endogenous function in mature T lymphocytes remains undefined. c-FLIP may inhibit or promote T cell death as previous data demonstrate that the c-FLIP(L) isoform can promote or inhibit caspase 8 activation while the c-FLIP(S) isoform promotes or inhibits T cell death when overexpressed. Although the c-FLIP(R) isoform inhibits cell death in cell lines, its function in T cells remains unknown. To investigate the function of c-FLIP in mature T cells, we have generated several genetic mouse models with c-FLIP or its individual isoforms deleted in mature T cells. Surprisingly, we found that c-FLIP protects mature T cells not only from apoptosis induced by the death receptors Fas and TNFR but also from TCR-mediated and spontaneous apoptosis. Thus, c-FLIP plays an essential role in protecting mature T cells from a death signal induced through the TCR itself and is required for naive T cell survival. Our results demonstrate that c-FLIP functions beyond the extrinsic death pathway.

Citing Articles

RNA-Seq Reveals Transcriptome Changes Following Zika Virus Infection in Fetal Brains in Knockdown Mice.

Xie T, Chen Q, Li N, Zhang S, Zhu L, Bai S Viruses. 2024; 16(11).

PMID: 39599827 PMC: 11599063. DOI: 10.3390/v16111712.

BTN3A: A Promising Immune Checkpoint for Cancer Prognosis and Treatment.

Kone A, Ssi S, Sahraoui S, Badou A Int J Mol Sci. 2022; 23(21).

PMID: 36362212 PMC: 9653866. DOI: 10.3390/ijms232113424.

Anti-Apoptotic c-FLIP Reduces the Anti-Tumour Activity of Chimeric Antigen Receptor T Cells.

Tan G, Poudel A, Ali Hosseini Rad S, McLellan A Cancers (Basel). 2022; 14(19).

PMID: 36230780 PMC: 9564159. DOI: 10.3390/cancers14194854.

LUBAC Suppresses IL-21-Induced Apoptosis in CD40-Activated Murine B Cells and Promotes Germinal Center B Cell Survival and the T-Dependent Antibody Response.

Wang J, Li T, Zan H, Rivera C, Yan H, Xu Z Front Immunol. 2021; 12:658048.

PMID: 33953720 PMC: 8089397. DOI: 10.3389/fimmu.2021.658048.

ZAP-70 Regulates Autoimmune Arthritis via Alterations in T Cell Activation and Apoptosis.

Kugyelka R, Prenek L, Olasz K, Kohl Z, Botz B, Glant T Cells. 2019; 8(5).

PMID: 31137740 PMC: 6562615. DOI: 10.3390/cells8050504.

References

Kennedy N, Kataoka T, Tschopp J, Budd R . Caspase activation is required for T cell proliferation. J Exp Med. 1999; 190(12):1891-6. PMC: 2195711. DOI: 10.1084/jem.190.12.1891. View

Alam A, Cohen L, Aouad S, Sekaly R . Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J Exp Med. 1999; 190(12):1879-90. PMC: 2195712. DOI: 10.1084/jem.190.12.1879. View

Thome M, Tschopp J . Regulation of lymphocyte proliferation and death by FLIP. Nat Rev Immunol. 2002; 1(1):50-8. DOI: 10.1038/35095508. View

Chang D, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart B, Yaish-Ohad S . c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 2002; 21(14):3704-14. PMC: 125398. DOI: 10.1093/emboj/cdf356. View

Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson D . The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem. 2002; 277(47):45162-71. DOI: 10.1074/jbc.M206882200. View

Sparwasser T, Gong S, Li J, Eberl G . General method for the modification of different BAC types and the rapid generation of BAC transgenic mice. Genesis. 2004; 38(1):39-50. DOI: 10.1002/gene.10249. View

Wu W, Rinaldi L, Fortner K, Russell J, Tschopp J, Irvin C . Cellular FLIP long form-transgenic mice manifest a Th2 cytokine bias and enhanced allergic airway inflammation. J Immunol. 2004; 172(8):4724-32. DOI: 10.4049/jimmunol.172.8.4724. View

Boatright K, Deis C, Denault J, Sutherlin D, Salvesen G . Activation of caspases-8 and -10 by FLIP(L). Biochem J. 2004; 382(Pt 2):651-7. PMC: 1133822. DOI: 10.1042/BJ20040809. View

Russell J, Wang R . Autoimmune gld mutation uncouples suicide and cytokine/proliferation pathways in activated, mature T cells. Eur J Immunol. 1993; 23(9):2379-82. DOI: 10.1002/eji.1830230951. View

10.

Alderson M, Tough T, Braddy S, Falk B, Schooley K, Goodwin R . Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995; 181(1):71-7. PMC: 2191813. DOI: 10.1084/jem.181.1.71. View

11.

Dhein J, Walczak H, Baumler C, Debatin K, Krammer P . Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature. 1995; 373(6513):438-41. DOI: 10.1038/373438a0. View

12.

Brunner T, Mogil R, LaFace D, Yoo N, Mahboubi A, Echeverri F . Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995; 373(6513):441-4. DOI: 10.1038/373441a0. View

13.

Ju S, Panka D, Cui H, Ettinger R, El-Khatib M, Sherr D . Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995; 373(6513):444-8. DOI: 10.1038/373444a0. View

14.

Mixter P, Russell J, Budd R . Delayed kinetics of T lymphocyte anergy and deletion in lpr mice. J Autoimmun. 1994; 7(6):697-710. DOI: 10.1006/jaut.1994.1055. View

15.

Zheng L, Fisher G, Miller R, Peschon J, Lynch D, Lenardo M . Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995; 377(6547):348-51. DOI: 10.1038/377348a0. View

16.

Sytwu H, Liblau R, McDevitt H . The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice. Immunity. 1996; 5(1):17-30. DOI: 10.1016/s1074-7613(00)80306-4. View

17.

Speiser D, Sebzda E, Ohteki T, Bachmann M, Pfeffer K, Mak T . Tumor necrosis factor receptor p55 mediates deletion of peripheral cytotoxic T lymphocytes in vivo. Eur J Immunol. 1996; 26(12):3055-60. DOI: 10.1002/eji.1830261235. View

18.

Shu H, Halpin D, Goeddel D . Casper is a FADD- and caspase-related inducer of apoptosis. Immunity. 1997; 6(6):751-63. DOI: 10.1016/s1074-7613(00)80450-1. View

19.

Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V . Inhibition of death receptor signals by cellular FLIP. Nature. 1997; 388(6638):190-5. DOI: 10.1038/40657. View

20.

Hu S, Vincenz C, Ni J, Gentz R, Dixit V . I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. J Biol Chem. 1997; 272(28):17255-7. DOI: 10.1074/jbc.272.28.17255. View