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Introduction Cytotoxic Granule Contents Inhibitors of Apoptosis

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Introduction Cytotoxic Granule Contents Inhibitors of Apoptosis MCP-3 RANTES Phagocytosis IL-15 MCP-1 IL-8 Endo G Eotaxin HSP90 Bcl-2 AIF Bcl-2 APAF- 1 CARD DNA Fragmentation Bcl-x L Chromatin condensation BIM Bcl-2 Mitochondrion HSP27 CARD BAK IP-10 Dynein Procaspase-9 BAK Cytochrome c Sugar Survivin Survivin BAK Residues AT P HSP70 Bax Microtubules Microtubules Bcl-2 Phagocyte Recognition TSP-1 Bax TSP-1 binding site tBID Phosphatidylserine ABC1 CAD DNA nick s Apoptosome BID ICAD Core Histone Histone H1 IAPs NM23-H1 Procaspase-3/7 FLIP Nucleus CAD Procaspase-8/10 L4-100 kDa (viral) ICAM-1 (viral) SMAC / ICAD Diablo Set Complex Nuclear lamins Fas Granzyme B SET HMG-2 CrmA Granzyme B APE (viral) HtrA2 / OMI pp32 Fas ligand NM23-H1 FADD US3 (viral) TRADD Cytolytic granule Perforin Perforin pore Endosome Caspase-3/7 CD3 ZAP-70 MHC I Granzyme A Golgi MTOC Antigen Set Complex PKC q Lck CD8 HMG-2 q Lck SET Granzyme A APE NDUFS1 (p75 Subunit of pp32 ICAM-1 BID ICAM-1 Respiratory Complex I) NM23-H1 IL-12 tBID Endoplasmic Reticulum Bax Bax Bax Cytochrome c E1B 19K (viral) Mcl-1 Microtubules BIM Nucleus BIM DYm ≠ROS Cytotoxic T Cell IL-18 IL-6 Influenza A Virus T Cell-mediated Cytotoxicity Introduction Cytotoxic Granule Contents Bcl-2 Family Members Cytotoxic T lymphocytes (CTLs) are an essential part of the adaptive immune response to PROTEIN FUNCTION ANTI-APOPTOTIC STRUCTURE BH3-ONLY STRUCTURE viral infection. They can elicit apoptosis in the target cell either through the release of cy- Calreticulin Binds Perforin and may inhibit Perforin-mediated damage to the eff ector cell A1 Bad tolytic granules, or through the ligation of TNF superfamily death receptors. CTLs recognize Appears on the cell surface following degranulation and may off er protection from MHC I-associated antigen on target cells via a T cell receptor (TCR) complex that includes Cathepsin B Perforin-mediated self-destruction Bcl-2 BID TCR, CD3, and CD8. Antigen recognition stimulates signaling cascades that reorient the Cathepsin C Processes Granzyme pro-enzymes Bcl-b Bik/Nbk Golgi and the microtubule-organizing center (MTOC) toward the target cell and cytolytic Chemokines: RANTES/CCL5, IP-10/CXCL10, Small proteins capable of mediating chemotaxis and/or cell activation granules move toward the membrane for docking and release. The immunological synapse and MIP-1α/CCL3 Bcl-w BIM Fas Ligand/TNFSF6 Potent apoptosis-inducing TNF superfamily member formed between a CTL and its target is stabilized by adhesion molecules including Bcl-xES BLK α β /LFA-1 and ICAM-1. Key components of the granules include the Granzyme proteases Human membrane perturbing microbicidal protein that can initiate Cytochrome c L 2 Granulysin Bcl-x Bmf and the membrane-perturbing protein Perforin. Classically, Perforin was thought to form release and apoptosis L pores in the target cell plasma membrane for passive diff usion of cytolytic molecules. More Granzymes: A, B, C, D, E, F, G, H, K, and M Serine proteases with roles in Caspase-dependent and -independent apoptosis Boo/DIVA BNIP3 + likely, the mechanism involves endocytosis and subsequent Perforin-mediated release from H ATPase Granule acidifi cation Mcl-1 Hrk/DP5 the endosomes. Membrane perturbing protein important for Granzyme entry into target Perforin cell cytoplasm NR-13 Noxa Granzymes A and B, and TNF superfamily receptors initiate cascades of intracellular events Serglycin Proteoglycan that non-covalently binds Granzymes PUMA that ultimately result in destruction of the target cell. Granzyme A targets components PRO-APOPTOTIC STRUCTURE of the multi-molecular SET complex, freeing NM23-H1 to cause single stranded DNA nicks. Spike BAK Other Granzyme A substrates include the nuclear Lamins and core and H1 histones. Gran- DOMAIN KEY zyme B cleaves the pro-apoptotic Bcl-2 family member BID (tBID) and initiates Bax/BAK- Inhibitors of Apoptosis (IAPs) Bax mediated release of mitochondrial Cytochrome c. BID cleavage and Cytochrome c release IAPs STRUCTURE TARGET Bcl-rambo BH4 BH3 BH1 BH2 TM also result from Caspase-8/10 activation following death receptor ligation. Mediators of DNA Apollon/BRUCE Caspase-3, -9 Bcl-x degradation including AIF and Endo G, and inhibitors of the IAP family, SMAC/Diablo and S HtrA2/Omi may also be released from the mitochondria. Cytosolic Cytochrome c binds cIAP-1 Caspase-3, -7, -9 BOK/Mtd APAF-1 and Procaspase-9 is recruited/activated, thus forming the apoptosome complex. The cIAP-2 Caspase-3, -7, -9 eff ector Procaspases-3 and -7 are potential substrates for Caspase-9, Caspase-8/10, and NOTE: This poster conveys a general overview of selected aspects of T cell-mediated cytotoxicity and should not be considered comprehensive nor defi nitive. The details of the Granzyme B. Activated eff ector Caspases and/or Granzyme B target ICAD and release the ILP-2 Caspase-9 process are understood to be subject to interpretation. © R&D Systems, Inc. 2005 endonuclease CAD from repression. They may also cleave anti-apoptotic Bcl-2 family mem- Livin/KIAP/ML-IAP Caspase-3, -7, -9 ber Mcl-1, releasing sequestered pro-apoptotic BIM. Apoptosis cascades are susceptible to NAIP Caspase-3, -7, -9 regulation by several anti-apoptotic factors including Bcl-2 family members, heat shock pro- teins (HSP), and several viral proteins. The cellular response to viral infection also includes Survivin Caspase-3, -7, -9 the secretion of an array of antiviral and immunoregulatory cytokines and chemokines. XIAP Caspase-3, -7, -9 DOMAIN KEY BIR CARD RING UBC PM103_Tcell_APR R&D Systems, Inc., 1-800-343-7475, www.RnDSystems.com.
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