CD95, BIM and T cell homeostasis

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. Cell death has a vital role in maintaining homeostasis in the T cell pool. However, the specific roles of BIM and CD95 in the contraction phase of T cell responses has been controversial. Recent studies show that BIM and CD95 have complementary roles in this process. 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.