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Regulation of lymphocyte proliferation and death by flip

Key Points

  • Lymphocyte homeostasis requires a balance between lymphocyte proliferation induced by antigen-receptor stimulation and co-stimulation, and lymphocyte death, induced by pro-apoptotic signals from death receptors of the tumour-necrosis-factor-receptor family, but also by the limited availability of cytokines.

  • T-cell stimulation results in increased expression of the death receptor, Fas, and its ligand, FasL, which leads to apoptotic elimination of activated T cells, a process that is called activation-induced cell death (AICD). Humans and mice that lack functional Fas or FasL develop autoimmune lymphoproliferative disorders.

  • Death receptors such as Fas induce apoptosis through the recruitment and activation of proteolytic enzymes called caspases. An initiator caspase (caspase-8) is directly recruited to the receptor, and subsequently activates cytoplasmic 'effector' caspases.

  • The activation of the receptor-proximal caspase, caspase-8, is specifically regulated by the anti-apoptotic protein, FLICE/FLIP; also known as caspase-8 inhibitory protein). Owing to its structural homology with the initiator caspase-8, FLIP interferes with the recruitment and activation of caspase-8 by the death receptor.

  • FLIP expression is tightly regulated in lymphocytes and might, therefore, contribute to the control of lymphocyte activation and death. The initial upregulation of FLIP levels after T-cell activation correlates with the early resistance of activated T cells to Fas-mediated apoptosis; however, whether subsequent downregulation of FLIP sensitizes the cells to AICD is still a matter of debate.

  • Disregulated expression of FLIP might have a role in the development of autoimmune diseases, tumour progression and cardiovascular disorders.


Lymphocyte homeostasis is a balance between lymphocyte proliferation and lymphocyte death. Tight control of apoptosis is essential for immune function, because its altered regulation can result in cancer and autoimmunity. Signals from members of the tumour-necrosis-factor receptor (TNF-R) family, such as Fas and TNF-R1, activate the caspase cascade and result in lymphocyte death by apoptosis. Anti-apoptotic proteins, such as FLIP (also known as FLICE/caspase-8 inhibitory protein) have recently been identified. FLIP expression is tightly regulated in T cells and might be involved in the control of both T-cell activation and death. Abnormal expression of FLIP might have a role not only in autoimmune diseases, but also in tumour development and cardiovascular disorders.

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Figure 1: Apoptotic pathways activated by cytolytic T cells.
Figure 2: Molecular structure of viral and cellular FLIPs.
Figure 3: Death-receptor signalling in the absence or presence of FLIP.
Figure 4: Activation-induced cell death of T cells.
Figure 5: Regulation of death-receptor-induced gene expression by FLIP.


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We wish to apologize to those colleagues whose work has not been discussed due to space restrictions. J.T. acknowledges support from the Swiss National Foundation

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List of apoptosis regulators



Family of cytosolic proteases that contain a cysteine residue within the active site, and which cleave their substrate after an aspartic acid residue. They can be divided into inflammatory caspases (-1, -4, -5 and -11), which cleave and activate pro-inflammatory cytokines, and pro-apoptotic caspases, which cleave and activate pro-apoptotic substrates. Pro-apoptotic caspases comprise initiator caspases (-2, -8 and -9), which, in turn, cleave and activate effector caspases (-3, -6 and -7).


(AICD). Apoptotic cell death of activated lymphocytes. Ensures the rapid elimination of effector cells after their antigen-dependent clonal expansion. Defects in AICD result in lymphoproliferative diseases associated with autoimmune disorders.


(IAP). A class of proteins (IAP, XIAP, NAIP) that contain a BIR domain, which can act as an intracellular caspase inhibitor.


(RIP). A family of serine/threonine kinases with homologous kinase domains. RIP-1 is recruited to TNF-R1 and mediates TNF-induced activation of JNK and NF-κB transcriptional pathways. RIP-2 (CARDIAK/RICK) binds to caspase-1 and activates NF-κB.


(TRAF). A family of conserved scaffold proteins that link receptors of the TNF receptor family to signalling pathways, such as activation of the transcription factors NF-κB (via IKKs) and activator protein-1 (via MAPKs).


(Nuclear factor κB). A family of transcription factors important for pro-inflammatory and anti-apoptotic responses. They are activated by the phosphorylation and subsequent ubiquitin-dependent proteolytic degradation of their respective inhibitors, called inhibitor of κB (IκB). Phosphorylation of IκB occurs through tissue-specific kinases, IκB kinase-1 and -2 (IKK-1 and -2).


Optimal signalling through the T-cell receptor complex requires accessory cell-surface molecules, such as CD28 or lymphocyte-function-associated antigen 1 (LFA-1). Signals delivered from these molecules contribute to enhance the immune response. In the absence of these co-stimulatory signals, naive T cells become unresponsive to a subsequent challenge with antigen.

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Thome, M., Tschopp, J. Regulation of lymphocyte proliferation and death by flip. Nat Rev Immunol 1, 50–58 (2001).

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