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  • Review Article
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CD95, BIM and T cell homeostasis

Nature Reviews Immunology volume 9, pages 514–519 (2009)Cite this article

Key Points

  • When activated by a cognate antigen, T cells proliferate and become effector cells to eliminate the source of the antigen.

  • After clearance of the antigen, these now useless T cells must be cleared to prevent autoimmunity.

  • Death following restimulation of the T cell receptor (TCR), as occurs during activation-induced cell death, is known to depend on the CD95–CD95 ligand pathway. This has long been considered a good model for the study of the contraction of T cell immune responses.

  • BCL-2-interacting mediator of cell death (BIM), a BCL-2-homology-domain-3-only protein of the B cell lymphoma 2 (BCL-2) family, was found to be necessary in vivo for the termination of acute immune responses.

  • Studies of mice lacking both CD95 and BIM have now shown that both proteins cooperate in the shutdown of immune responses.

  • We propose that the intensity of the signal through the TCR dictates which pathway will be activated to terminate the immune response.

Abstract

The relative importance of the intrinsic and extrinsic apoptotic pathways in the control of haematopoietic cell homeostasis has been a matter of debate for many years. Cell death is omnipresent in this cellular compartment and ensures the removal of cells that are not properly equipped to assume their function as well as those that have assumed function but are no longer required. In this Review we focus on the roles of CD95 (also known as FAS) and BCL-2-interacting mediator of cell death (BIM), two major regulators of apoptosis in T cell homeostasis, with a particular emphasis on their cooperation in the shutdown of T cell responses.

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Figure 1: Quality checkpoints and death during T cell development and function.
Figure 2: Extrinsic and intrinsic pathways leading to apoptosis.
Figure 3: The three phases of a T cell response to an acute infection.
Figure 4: Differential responses may be driven by signals of different strength through the T cell receptor.

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Acknowledgements

We thank A. Strasser, J. M. Adams, S. Cory and all our close colleagues for fruitful discussions and support. We apologize to our colleagues whose work has been referred to only indirectly through reviews. Our work is supported by grants and fellowships from The National Health and Medical Research Council of Australia, the Leukemia and Lymphoma Society, the Australian Research Council, the Cancer Council Victoria (Australia) and the Charles and Sylvia Viertel Charitable foundation.

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Authors and Affiliations

  1. Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, 3050, Parkville, Victoria, Australia

    Philippe Bouillet & Lorraine A. O'Reilly

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  1. Philippe Bouillet
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Correspondence to Philippe Bouillet.

Glossary

Death-inducing signalling complex

A caspase 8 activation platform downstream of CD95.

Apoptosome

A protein complex that activates initiator caspase 9 and is composed of apoptotic protease-activating factor 1, cytochrome c and ATP. Its formation is triggered by the release of cytochrome c from the mitochondria.

Autoimmune lymphoproliferative syndrome

A form of lymphoproliferative disorder that is often the result of mutations of the death receptor CD95 or its ligand.

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Bouillet, P., O'Reilly, L. CD95, BIM and T cell homeostasis. Nat Rev Immunol 9, 514–519 (2009). https://doi.org/10.1038/nri2570

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