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cFLIP regulation of lymphocyte activation and development

Key Points

  • Cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) is an enzymatically inert homologue of caspase-8 that competes with caspase-8 for recruitment to the death-inducing signalling complex (DISC).

  • Paradoxically, cFLIP can also heterodimerize with caspase-8, which results in activation of the full-length caspase-8 protein.

  • Caspase-8 activity is necessary to initiate the activation of nuclear factor-κB (NF-κB) and to promote proliferation of T cells, and possibly other cell types. Increased expression of cFLIP can augment caspase-8 activity following T-cell receptor (TCR) ligation on T cells. This results in both increased proliferation, and also, ultimately, increased cell death.

  • cFLIP can associate with adaptor proteins such as tumour-necrosis-factor-receptor-associated factor 2 (TRAF2) that link to the NF-κB pathway. Therefore, increased expression of cFLIP might augment NF-κB activity in some situations, but it has also been reported to decrease NF-κB signalling following CD95 (also known as FAS) stimulation. The explanation for these disparate results is not certain at present.

  • T cells lacking cFLIP manifest decreased proliferation and survival. This might be related to decreased production of and response to interleukin-2 (IL-2) by the cFLIP-deficient T cells.

  • cFLIP might be crucial to effector function in many other cell types; for example, myeloid dendritic cells, which express high levels of cFLIP, are resistant to FAS-mediated cell death, and produce large amounts of several cytokines and mediate upregulation of CD80 and CD86 in response to CD95 ligation.


Cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) was originally identified as an inhibitor of death-receptor signalling through competition with caspase-8 for recruitment to FAS-associated via death domain (FADD). More recently, it has been determined that both cFLIP and caspase-8 are required for the survival and proliferation of T cells following T-cell-receptor stimulation. This paradoxical finding launched new investigations of how these molecules might connect with signalling pathways that link to cell survival and growth following antigen-receptor activation. As discussed in this Review, insight gained from these studies indicates that cFLIP and caspase-8 form a heterodimer that ultimately links T-cell-receptor signalling to activation of nuclear factor-κB through a complex that includes B-cell lymphoma 10 (BCL-10), mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1) and receptor-interacting protein 1 (RIP1).

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Figure 1: Regulation of CD95 and T-cell-receptor-mediated signalling by caspase-8 and cFLIP.
Figure 2: Molecular structure of viral and cFLIP.
Figure 3: cFLIP modulates activation of caspase-8 and nuclear factor-κB.


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This work was supported by funding from the National Institutes of Health, the Swiss National Science Foundation, the National Cancer Institute of Canada, and the Canadian Institutes of Health Research.

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Death domain

A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.

Death-effector domain

(DED). A domain that is found in certain initiator caspases (for example, mammalian caspase-8) and their adaptor protein (for example, FAS-associated via death domain (FADD)). This domain mediates protein–protein interactions.

Gln-Ala-Cys-X-Gly motif

A cysteine-containing sequence that is found at the enzymatic site of caspases.

His-Gly motif

A crucial histidine sequence at the enzymatic site that is conserved in caspases.

Death-inducing signalling complex

(DISC). This complex forms after death-receptor ligation. In the case of CD95, the DISC rapidly recruits FAS-associated via death domain (FADD) through the mutual death-effector domains of CD95 and FADD, followed by caspase-8 and/or cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) recruitment by death-effector domains.

Jurkat T cell

A human leukaemic T-cell line used to study several aspects of T-cell biology and signalling, in particular signal-transduction events initiated by the T-cell receptor.

Complementation of Rag1−/− blastocysts

A method for generating lymphocytes deficient in molecules whose absence is lethal in mice. Blastocysts from a gene-knockout mouse are fused with those from Rag1−/− mice. Because Rag1−/− cells cannot give rise to lymphocytes (as their antigen-receptor genes cannot rearrange), lymphocytes that develop from these fusions will occur only from the gene-knockout cells.


An inhibitor of protein kinase C and certain G-protein-coupled receptor kinases.


An inhibitor of protein synthesis.

Autoimmune lymphoproliferative syndrome

(ALPS). A systemic lupus erythematosus (SLE)-like condition that is seen in patients bearing mutations in CD95.

BH3-only family

Members of the B-cell lymphoma (BCL-2) family that contain only the BCL-2 homology domain 3 (BH3). BH3-only members are pro-apoptotic.

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Budd, R., Yeh, WC. & Tschopp, J. cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol 6, 196–204 (2006).

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