The Many Roles of FAS Receptor Signaling in the Immune System Andreas Strasser, Philipp J. Jost, Shigekazu Nagata  Immunity  Volume 30, Issue 2, Pages 180-192 (February 2009) DOI: 10.1016/j.immuni.2009.01.001 Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 1 Death Receptor-Induced and Bcl-2-Regulated Apoptosis Signaling This figure shows the two distinct but ultimately converging apoptosis signaling pathways in mammals. One is activated by so-called death receptors, members of the tumor necrosis factor receptor (TNF-R) family with an intracellular death domain, and requires FADD-mediated activation of caspase-8 (shown on the right). Auto-processing of caspase-8 results in a heterotetrameric form of the protein that is able to activate the zymogens of effector caspases, caspase-3 and caspase-7, eventually leading to cleavage of vital proteins within the cell, such as PARP or lamins, or activation of the DNase CAD (caspase-activated DNase) by cleavage of its inhibitor, ICAD (inhibitor of CAD). It is possible that caspase-8 may also proteolyze to a certain extent some of the classical substrates of effector caspases. The BCL-2-regulated pathway (shown on the left) is arbitrated by the complex interplay between pro- and antiapoptotic members of the BCL-2 protein family and involves mitochondrial outer membrane permeabilization (MOMP). MOMP results in release of cytochrome C from the intermembrane space of the mitochondria into the cytosol to initiate apoptosome formation resulting in APAF-1-mediated activation of the “initiator” caspase, caspase-9, further leading to proteolytic activation of the downstream effector caspases, caspase-3 and caspase-7. Abbreviations: BH3-only, BCL-2 homology domain 3 only protein; MOMP, mitochondrial outer membrane permeabilization; Cyt. C, cytochrome C; ICAD, Inhibitor of caspase activated DNase (CAD); PARP, Poly (ADP-ribose) polymerase. Immunity 2009 30, 180-192DOI: (10.1016/j.immuni.2009.01.001) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 2 Fas-Mediated Death Receptor Signaling and Bcl-2-Regulated Apoptosis Signaling in the Killing of Activated T and B Lymphocytes This figure shows the mechanisms that control FASL-FAS-induced apoptosis and BIM-dependent BCL-2-regulated apoptosis in activated T and B cells during shutdown of acute or chronic immune responses. During shutdown of an acute T cell immune response (left side, top), the reduction in the concentrations of cytokines, such as IL-2 and IL-7, leads to a reduction in PI3K and AKT. This causes activation of the transcription factor FOXO3A, which promotes transcriptional induction of the proapoptotic BH3-only protein BIM and consequently activation of the BCL-2-regulated apoptotic pathway. Furthermore, reduced antigen concentration leads to diminished TCR stimulation and consequently reduced activation of the REL-NF-κB and NF-AT transcription factors, which are known to promote expression of prosurvival proteins, such as BCL-2 or BCL-XL. As in shutdown of acute T cell immune responses, during shutdown of a chronic T cell response (left side, bottom), the availability of growth factors is also reduced, leading to the activation of BIM and initiation of the BCL-2-regulated apoptotic pathway as described above. In addition, repeated TCR ligation triggers FASL expression on T cells leading to autocrine and/or paracrine stimulation of FAS, caspase-8 activation, activation of effector caspases, and consequently apoptosis as shown in Figure 1. During shutdown of a B cell immune response (left side), FAS is induced on B cells and can be activated by FASL presented on T helper cells. This leads to B cell apoptosis when CD40 signaling is diminished because of reduced expression of CD40L on T helper cells, because this causes a reduction in the activity of the REL/NF-κB and NF-AT transcription factors, which normally promote expression of prosurvival proteins, such as c-FLIP. In addition, a reduction in the concentration of growth factors can lead to BIM upregulation as described above. Abbreviations: γc Receptors, common gamma chain containing cytokine receptors (e.g., receptors for IL-2, IL-4, IL-7, IL-15); DISC, death-inducing signaling complex; GF-Rec., growth factor receptors; TCR, T cell antigen receptor; PI3K, phosphoinositide 3-kinases; BCR, B cell antigen receptor; C8, caspase 8. Immunity 2009 30, 180-192DOI: (10.1016/j.immuni.2009.01.001) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 3 Nonapoptotic Signaling by Components of the Death Receptor Pathway This figure shows the two distinct modes of caspase-8 activation: the well-known death receptor apoptotic pathway involving caspase-8 autoprocessing (shown on the left) followed by either direct activation of effector caspases or proteolytc activation of the BH3-only protein BID to activate the BCL-2-regulated apoptotic pathway (see also Figure 1). The caspase-8-related protein c-FLIP mainly acts as a catalytically inactive caspase-8 substitute competing for the binding to FADD, thereby limiting recruitment and activation of caspase-8 and thus blocking apoptosis initiation. However, c-FLIP has also been shown to promote caspase-8 recruitment and activation in certain circumstances. The right side illustrates the presently only poorly understood pathway by which FADD and caspase-8 promote cellular activation, proliferation, and differentiation without the need of self-processing. For this pathway, neither the upstream activators (death receptors?) nor the substrates of caspase-8 are identified. Abbreviations: DISC, death-inducing signaling complex; MOMP, mitochondrial outer membrane permeabilization; Cyt. C, cytochrome C; c-FLIP, cellular form of FADD-like IL-1β-converting enzyme-inhibitory protein; casp-8, caspase-8. Immunity 2009 30, 180-192DOI: (10.1016/j.immuni.2009.01.001) Copyright © 2009 Elsevier Inc. Terms and Conditions