Molecular Mechanisms of Apoptosis in Naive and Memory Human T-Cell Subsets

Effect of Age
Living reference work entry

Abstract

There are multiple ways for cells to die, including necrosis and apoptosis. Apoptosis or programmed cell death or suicidal cell death is a physiological form of cell death, which is critical in cellular homeostasis. Apoptosis occurs in almost all cell types in the body and begins as early as eight-cell embryo stage and continues throughout the lifespan of the organism, albeit at different rate. There are multiple roads to apoptotic cell death, including extrinsic or death receptor-mediated and intrinsic, which may be mediated via mitochondrial pathway and the endoplasmic reticulum (ER) pathways. Most of apoptotic cell deaths are mediated by serine proteases, the caspases, which cleave a number of target substrates, including enzymes, transcription factors, and structural proteins. However, apoptosis may also be mediated by caspase-independent pathways. In this review, we will discuss molecular signaling and regulation of death receptor pathways, particularly CD95- and TNFR-mediated apoptosis and mitochondrial and ER stress pathways of apoptosis in naïve and various memory subsets of T cells, and changes during human aging.

Keywords

CD95 Caspases NF-kB FLIP TNF receptors Mitochondria ER stress 

References

  1. Aggarwal S, Gupta S (1998) Increased apoptosis of T cell subsets in aging humans: altered expression of Fas (CD95), Fas ligand, Bcl-2, and Bax. J Immunol 160:1627–1637PubMedPubMedCentralGoogle Scholar
  2. Aggarwal S, Gupta S (1999) Increased activity of caspase-3 and caspase-8 during Fas-mediated apoptosis in lymphocytes from aging humans. Clin Exp Immunol 117:285–290PubMedPubMedCentralCrossRefGoogle Scholar
  3. Aggarwal S, Gollapudi S, Gupta S (1999) Increased TNF-α-induced apoptosis in lymphocytes from aged humans: changes in TNF-α receptor expression and activation of caspases. J Immunol 162:2154–2161PubMedPubMedCentralGoogle Scholar
  4. Alpdogan O, Van Den Brink MRM (2005) IL-7 and IL-15: therapeutic cytokines for immunodeficiency. Trends Immunol 26:56–64PubMedCrossRefPubMedCentralGoogle Scholar
  5. Ashkanazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308CrossRefGoogle Scholar
  6. Bandres E, Merino J, Vazquez S et al (2000) The increase of IFN-γ production through aging correlates with the expanded CD8+CD28-CD57+ subpopulation. Clin Immunol 96:230–235PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bellomo G, Parotti M, Taddei F et al (1992) Tumor necrosis factor-α induces apoptosis in mammary adenocarcinoma cells by an increase in intranuclear free calcium concentration and DNA fragmentation. Cancer Res 52:1342–1346PubMedPubMedCentralGoogle Scholar
  8. Brzezinska A, Magalska A, Szybinska A et al (2004) Proliferation and apoptosis of human CD8+CD28+ and CD8+CD28- lymphocytes during aging. Exp Gerontol 39:539–544PubMedCrossRefPubMedCentralGoogle Scholar
  9. Chang DW, Xing Z, Capacio VL et al (2003) Interdimer processing mechanism of procaspase-8 activation. EMBO 22:4132–4142CrossRefGoogle Scholar
  10. Chen C, Edelstein LC, Gelinas C (2000) The Rel/NF-κB family directly activates expression of the apoptotic inhibitor Bcl-x (L). Mol Cell Biol 20:2687–2695PubMedPubMedCentralCrossRefGoogle Scholar
  11. De Smaele E, Zazzeroni F, Papa S et al (2001) Induction of gadd45α by NF-κB downregulates proapoptotic JNK signaling. Nature 414:308–313PubMedCrossRefPubMedCentralGoogle Scholar
  12. Declercz W, Denecker G, Fiers W et al (1998) Cooperation of both TNF receptors in inducing apoptosis: involvement of the TNF receptor-associated factor binding domain of the TNF receptor 75. J Immunol 161:390–399Google Scholar
  13. Dohrman A, Kataoka T, Cuenin S et al (2005) Cellular FLIP (long form) regulates CD8+ T cell activation through caspase-8-dependent NF-κB activation. J Immunol 174:5270–5278PubMedCrossRefPubMedCentralGoogle Scholar
  14. Draper DW, Harris VG, Culver CA et al (2004) Calcium and its role in nuclear translocation and activation of cytosolic phospholipase A2 in cells rendered sensitive to TNF-induced apoptosis by cycloheximide. J Immunol 172:2416–2423PubMedCrossRefPubMedCentralGoogle Scholar
  15. Effros RB, Boucher N, Porter V et al (1994) Decline in CD28 +T cells in centenarians and in long-term T cell cultures: a possible cause of both in vivo and in vitro immunosenescence. Exp Gerontol 29:601–609PubMedCrossRefPubMedCentralGoogle Scholar
  16. Fagnoni FF, Vescovini R, Paserri G et al (2002) Shortage of circulating naïve CD8+ T cells provides new insights on immunodeficiency in aging. Blood 95:2860–2868Google Scholar
  17. Fernandez A, Kiefer J, Fosdick L et al (1995) Oxygen radical production and thiol depletion are required for Ca++ -mediated endogenous endonucleases activation in apoptotic thymocytes. J Immunol 155:5133–5139PubMedPubMedCentralGoogle Scholar
  18. Ferri KF, Kroemer G (2001) Organelle-specific initiation of cell death pathways. Nat Cell Biol 3:E255–E263PubMedCrossRefPubMedCentralGoogle Scholar
  19. Ghosh S, Karin M (2002) Missing pieces in the NF-kB puzzle. Cell 109:S81–S96PubMedCrossRefPubMedCentralGoogle Scholar
  20. Golks A, Brenner D, Krammer PH et al (2005a) The c-FLIP NH2 terminus (p22-FLIP) induces NF-κB activation. J Exp Med 203:1295–1305CrossRefGoogle Scholar
  21. Golks A, Brenner D, Fritsch C et al (2005b) cFLIP R a new regulator of death receptor-induced apoptosis. J Biol Chem 280:14507–14513PubMedCrossRefPubMedCentralGoogle Scholar
  22. Grayson JM, Harrington LE, Lanier JG et al (2002) Differential sensitivity of naïve and memory CD8+ T cells to apoptosis in vivo. J Immunol 169:3760–3770PubMedCrossRefPubMedCentralGoogle Scholar
  23. Green DR, Evan GI (2002) A matter of life and death. Cancer Cell 1:19–30PubMedCrossRefPubMedCentralGoogle Scholar
  24. Gupta S (2000a) Molecular steps of death receptor and mitochondrial pathways of apoptosis. Life Sci 69:2957–2964CrossRefGoogle Scholar
  25. Gupta S (2000b) Molecular and biochemical pathways of apoptosis in lymphocytes from aged humans. Vaccine 18:1596–1601PubMedCrossRefPubMedCentralGoogle Scholar
  26. Gupta S (2001) Molecular steps of TNF receptor-mediated apoptosis. Curr Mol Med 1:299–306CrossRefGoogle Scholar
  27. Gupta S (2002a) Decision between life and death during TNF-induced signaling. J Clin Immunol 22:270–278CrossRefGoogle Scholar
  28. Gupta S (2002b) Tumor necrosis factor-a-induced apoptosis in T cells from aged humans: a role of TNFR-I and downstream signaling molecules. Exp Gerontol 37:293–299PubMedCrossRefPubMedCentralGoogle Scholar
  29. Gupta S (2003) Molecular signaling in death receptor and mitochondrial pathways of apoptosis. Int J Oncol 22:15–20PubMedPubMedCentralGoogle Scholar
  30. Gupta S (2005a) Death of lymphocytes: a clue to immune deficiency in human aging. Discov Med 5:298–302PubMedGoogle Scholar
  31. Gupta S (2005b) Molecular mechanisms of apoptosis in the cells of the immune system in human aging. Immunol Rev 205:114–129PubMedCrossRefGoogle Scholar
  32. Gupta S, Gollapudi S (2006a) Molecular mechanisms of TNF-α-induced apoptosis in naïve and memory T cell subsets. Autoimmun Rev 5:264–268PubMedCrossRefGoogle Scholar
  33. Gupta S, Gollapudi S (2006b) TNF-α-induced apoptosis in human naïve and memory CD8+ T cells in aged humans. Exp Gerontol 41:69–77PubMedCrossRefGoogle Scholar
  34. Gupta S, Gupta A (2007) Death of memory T cell subsets in humans: changes during aging. Expert Rev Clin Immunol 3:637–645PubMedCrossRefGoogle Scholar
  35. Gupta S, Hacki J, Egger L, Monney L et al (2000) Apoptotic cross talk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19:2286–2295CrossRefGoogle Scholar
  36. Gupta S, Chiplunkar S, Kim C et al (2003) Effect of age on molecular signaling of TNF-α-induced apoptosis in human lymphocytes. Mech Ageing Dev 124:503–509PubMedCrossRefGoogle Scholar
  37. Gupta S, Bi R, Su K et al (2004) Characterization of naïve, memory, and effector CD8+ T cells: effect of age. Exp Gerontol 39:545–550PubMedCrossRefPubMedCentralGoogle Scholar
  38. Gupta S, Bi R, Kim C et al (2005) A role of NF-κB signaling pathway in increased tumor necrosis factor-α-induced apoptosis of lymphocytes in aged humans. Cell Death Differ 12:177–183PubMedCrossRefPubMedCentralGoogle Scholar
  39. Gupta S, Bi R, Gollapudi S (2006) Differential sensitivity of naïve and memory subsets of human CD8+ T cells to TNF-α-induced apoptosis. J Clin Immunol 26:193–203PubMedCrossRefPubMedCentralGoogle Scholar
  40. Gupta S, Young T, Yel L et al (2007) Differential sensitivity of naïve and subsets of memory CD4+ and CD8+ T cells to hydrogen peroxide-induced-apoptosis. Genes Immun 8:1–10CrossRefGoogle Scholar
  41. Gupta S, Bi R, Su H et al (2008) CD95-mediated apoptosis in naïve, and central and effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp Gerontol 43:266–274PubMedCrossRefGoogle Scholar
  42. Gupta S, Agrawal S, Su H, Gollapudi S (2018) Molecular changes associated with of TNF-α-induced apoptosis in naïve (TN) and central memory (TCM) CD8+ T cells in aging. Ageing Immun 15:2.  https://doi.org/10.1186/s12979-017-0109-0CrossRefGoogle Scholar
  43. Hacki J, Egger L, Monney L et al (2000) Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19:2286–2295PubMedCrossRefPubMedCentralGoogle Scholar
  44. Haridas V, Darnay BG, Natrajan K et al (1998) Overexpression of the p80 TNFR leads to TNF-dependent apoptosis, nuclear factor-kappa B activation. J Immunol 160:3152–3162PubMedPubMedCentralGoogle Scholar
  45. Hegde R, Srinivasula SM, Zhang Z et al (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 277:432–438PubMedCrossRefPubMedCentralGoogle Scholar
  46. Herndon FJ, Hsu HC, Mountz JD (1997) Increased apoptosis of CD45RO- T cells with aging. Mech Ageing Dev 194:123–134CrossRefGoogle Scholar
  47. Heyninck K, Beyaert R (2005) A20 inhibits NF-kB activation by dual ubiquitin-editing functions. Trends Biochem Sci 30:1–4PubMedCrossRefPubMedCentralGoogle Scholar
  48. Hsu H, Shu HB, Pan MG et al (1996) TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1signal transduction pathways. Cell 84:299–308CrossRefGoogle Scholar
  49. Igney FH, Krammer PH (2002) Immune escape of tumors: apoptosis resistance and counterattack. J Leukoc Biol 71:907–920PubMedPubMedCentralGoogle Scholar
  50. Iwai K, Miyawaki T, Takizawa T et al (1994) Differential expression of bcl-2 and susceptibility toanti-Fas-mediated death in peripheral blood lymphocytes, monocytes and neutrophils. Blood 84:1201–1208PubMedPubMedCentralGoogle Scholar
  51. Karin M, Lin A (2002) NF-κB at the crossroads of life and death. Nat Immunol 3:221–227PubMedCrossRefPubMedCentralGoogle Scholar
  52. Kataoka T, Tschopp J (2004) N-terminal fragment of c-FLIP, process by caspase-8 specifically interacts with TRAF2 and induces activation of the NF-κB. Mol Cell Biol 24:2627–2636PubMedPubMedCentralCrossRefGoogle Scholar
  53. Kataoka T, Budd RC, Holler N et al (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science 291:2413–2417CrossRefGoogle Scholar
  54. Kaufman RJ (2002) Orchestrating the unfolded protein response in health and disease. J Clin Invest 110:1389–1298PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kischkel FC, Lawrence DA, Tinel A et al (2001) Death receptor recruitment of endogenous caspase- 10 and apoptosis initiation in the absence of caspase-8. J Biol Chem 276:46639–46646PubMedCrossRefPubMedCentralGoogle Scholar
  56. Kong SK, Fung KP, Choi YM et al (1997) Slow increase in intranuclear and cytosolic free Ca++ concentrations in L929 cells is important in tumor necrosis factor-α-mediated cell death. Oncology 54:55–62PubMedCrossRefPubMedCentralGoogle Scholar
  57. Krammer PH, Arnold R, Lavrik I (2007) Life and death in peripheral T cells. Nat Rev Immunol 7:532–542PubMedCrossRefPubMedCentralGoogle Scholar
  58. Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6:513–519PubMedCrossRefPubMedCentralGoogle Scholar
  59. Lam M, Dubyak G, Chen L et al (1994) Evidence that Bcl-2 can inhibit apoptosis induced by regulating endoplasmic reticulum-associated fluxes. Proc Nat Acad Sci USA 91:6569–6573PubMedPubMedCentralCrossRefGoogle Scholar
  60. Larvik I, Golks A, Krammer PH (2005) Death receptor signaling. J Cell Sci 118:265–267CrossRefGoogle Scholar
  61. Lechner H, Amort M, Steger MM et al (1996) Regulation of CD95 (Apo-1) expression and the induction of apoptosis of human T cells: changes in old age. Int Arch Allergy Immunol 110:238–243PubMedCrossRefPubMedCentralGoogle Scholar
  62. Lee ST, Hoeflich KP, Wasfy GW et al (1999) Bcl-2 targeted to the endoplasmic reticulum can inhibit apoptosis induced by Myc but not etoposide in rat-1 fibroblasts. Oncogene 18:3520–3528PubMedCrossRefPubMedCentralGoogle Scholar
  63. Li LY, Luo X, Wang X (2001) Endonuclease G is an apoptotic DNAase when released from mitochondria. Nature 412:95–99PubMedCrossRefPubMedCentralGoogle Scholar
  64. Liston P, Roy N, Tamai K et al (1996) Suppression of apoptosis in mammalian cells by NIAP and a related family of IAP genes. Nature 379:349–353PubMedPubMedCentralCrossRefGoogle Scholar
  65. Locksley RM, Kileen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501PubMedCrossRefPubMedCentralGoogle Scholar
  66. Loeffler M, Daugas E, Susin SA et al (2001) Dominant cell death induced by extramitochondrially targeted apoptosis-inducing factor. FASEB J 15:758–767PubMedCrossRefPubMedCentralGoogle Scholar
  67. Lorenzo HK, Susin SA, Penninger J et al (1999) Apoptosis inducing factor (AIF): a physiologically old, caspases-independent effector of cell death. Cell Death Diff 6:516–524CrossRefGoogle Scholar
  68. Martinou J-C, Green DR (2001) Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2:63–67PubMedCrossRefPubMedCentralGoogle Scholar
  69. Miyawaki T, Uehara T, Nabu R et al (1992) Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol 49:3753–3758Google Scholar
  70. Monteiro J, Baltiwala F, Ostrer H et al (1996) Shortened telomeres in clonally expanded CD28- CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J Immunol 156:3587PubMedPubMedCentralGoogle Scholar
  71. Nakagawa T et al (2000) Caspase-12 mediated endoplasmic reticulum-specific apoptosis and cytotoxicity by amyloid β. Nature 403:98–103PubMedCrossRefPubMedCentralGoogle Scholar
  72. Natoli G, Costanzo A, Ianni A et al (1997) Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF-2-dependent pathway. Science 275:200–203PubMedCrossRefPubMedCentralGoogle Scholar
  73. Ng FW et al (1997) p28BAP31, a Bcl-2/Bcl-xL and procaspase-8 associated protein in the endoplasmic reticulum. J Cell Biol 139:327–328PubMedPubMedCentralCrossRefGoogle Scholar
  74. Nociari MM, Telford W, Russo C (1999) Postthymic development of CD28-CD8+ T cell subset: age-associated expansion and shift from memory to naïve phenotype. J Immunol 162:3327–3335PubMedPubMedCentralGoogle Scholar
  75. Nutt LK et al (2002) BAX and BAK promote apoptosis by regulating endoplasmic reticular and mitochondrial Ca++ stores. J Biol Chem 277:9219–9225PubMedCrossRefPubMedCentralGoogle Scholar
  76. Opipari AW Jr, Hu HM, Yabkowitz R et al (1992) The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity. J Biol Chem 267:12424–12427PubMedPubMedCentralGoogle Scholar
  77. Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4:552–564PubMedCrossRefPubMedCentralGoogle Scholar
  78. Pahlavani M, Harris MD (1996) The age-related changes in DNA binding activity of AP-1, NF-κB, and Oct-1 transcription factors in lymphocytes from rats. Age 19:45–54CrossRefGoogle Scholar
  79. Phelouzat MA, Arbogast A, Laforge T et al (1996) Excessive apoptosis of mature T lymphocytes is a characteristic feature of human immune senescence. Mech Ageing Dev 88:25–38PubMedCrossRefPubMedCentralGoogle Scholar
  80. Phelouzat MA, Laforge T, Abrogast A et al (1997) Susceptibility to apoptosis of T lymphocytes from elderly humans is associated with increased in vivo expression of functional fas receptors. Mech Ageing Dev 96:35–46PubMedCrossRefPubMedCentralGoogle Scholar
  81. Pimentel-Muinos FX, Seed B (1999) Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity 11:783–793PubMedCrossRefPubMedCentralGoogle Scholar
  82. Ponnappan U, Zhong M, Trebilcock GU (1999) Decreased proteasome-mediated degradation in T cells from the elderly: a role in immune senescence. Cell Immunol 192:167–174PubMedCrossRefPubMedCentralGoogle Scholar
  83. Posnett DN, Sinha R, Kabak S et al (1994) Clonal populations of T cells in normal elderly humans: the cell equivalent to “benign monoclonal gammopathy”. J Exp Med 179:609–618PubMedCrossRefPubMedCentralGoogle Scholar
  84. Reed JC (1997) Double identity for protein of Bcl-2 family. Nature 387:773–778PubMedCrossRefPubMedCentralGoogle Scholar
  85. Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22:745–763PubMedCrossRefPubMedCentralGoogle Scholar
  86. Salvesen GS, Duckett CS (2004) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3:401–410CrossRefGoogle Scholar
  87. Saurwein-Teissl M, Lung TL, Marx F et al (2002) Lack of antibody production following immunization in old age: association with CD8+CD28- T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol 168:5893–5899PubMedCrossRefPubMedCentralGoogle Scholar
  88. Scaffidi C, Fulda S, Srinivasan A et al (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687PubMedPubMedCentralCrossRefGoogle Scholar
  89. Schluns KS, Lefrancois L (2003) Cytokine control of memory T cell development and survival. Nat Rev Immunol 3:269–279PubMedCrossRefPubMedCentralGoogle Scholar
  90. Scorrano L, Oakes SA, Opferman JT et al (2003) BAX and BAX regulation of endoplasmic reticulum Ca++: a control point for apoptosis. Science 300:135–139PubMedCrossRefPubMedCentralGoogle Scholar
  91. Screaton G, Xu X-N (2000) T cell life and death signaling via TNF-receptor family members. Curr Opin Immunol 12:316–3222PubMedCrossRefPubMedCentralGoogle Scholar
  92. Shinohara S, Sawada T, Nishioka Y et al (1995) Differential expression of Fas and Bcl-2 protein on CD4+ T cells, CD8+ T cells and monocytes. Cell Immunol 163:303–308PubMedCrossRefPubMedCentralGoogle Scholar
  93. Sprick MR, Rieser E, Stahl H et al (2002) Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signaling complexes in FADD-dependent manner but cannot functionally substitute caspase-8. EMBO J 21:4520–4530PubMedPubMedCentralCrossRefGoogle Scholar
  94. Suzuki Y, Imai Y, Nakayama H et al (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8:613–621PubMedCrossRefPubMedCentralGoogle Scholar
  95. Tang G, Minemoto Y, Dibling B et al (2001) Inhibition of JNK activation through NF-κB target genes. Nature 414:313–317PubMedCrossRefPubMedCentralGoogle Scholar
  96. Tartaglia L, Pennica D, Goddel DV (1993) Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the p55-kDa TNF receptor. J Biol Chem 268: 18542–18548PubMedPubMedCentralGoogle Scholar
  97. Thomas B, Grell M, Pfizenmaier K et al (1990) Identification of a 60-kDa tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J Exp Med 172:019–1023CrossRefGoogle Scholar
  98. Thome M, Tschopp J (2001) Regulation of lymphocyte proliferation and death by flip. Nat Rev Immunol 1:50–58PubMedCrossRefPubMedCentralGoogle Scholar
  99. Tomiyama H, Matsuda T, Takiguchi M (2002) Differentiation of CD8+ T cells from a memory to memory/effector phenotype. J Immunol 168:5538–5550PubMedCrossRefPubMedCentralGoogle Scholar
  100. Trebilcock GU, Ponnappan U (1996) Evidence for lowered induction of nuclear factor kappa B in activated human T lymphocytes during aging. Gerontology 42:137–146PubMedCrossRefGoogle Scholar
  101. Vandenabeele P, Declercq W, Vanhaesebroeck B et al (1995) Both TNF receptors are required for TNF-mediated induction of apoptosis in PC60 cells. J Immunol 154:2904–2913PubMedGoogle Scholar
  102. Weiss T, Grell M, Siekienski K et al (1998) TNFR80-dependent enhancement of TNFR60-induced cell death is mediated by TNFR-associated factor 2 and is specific for TNFR60. J Immunol 161:3136–3142PubMedPubMedCentralGoogle Scholar
  103. Weninger W, Crowley MA, Manjunath N (2001) Migratory properties of naïve, effector, and memoryCD8 (+) T cells. J Exp Med 194:953–966PubMedPubMedCentralCrossRefGoogle Scholar
  104. Whisler RL, Beiqing L, Chen M (1996) Age-related decreases in IL-2 production by human T cells are associated with impaired activation of nuclear transcriptional factors AP-1 and NF-AT. Cell Immunol 169:185–195PubMedCrossRefPubMedCentralGoogle Scholar
  105. Yoshino K, Kondo E, Cao L et al (1994) Inverse expression of Bcl-2 protein and Fas antigen in lymphoblasts in peripheral nodes and activated peripheral blood T and B lymphocytes. Blood 83:1856–1861PubMedGoogle Scholar
  106. Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how pandora’s box opens. Nat Rev Mol Cell Biol 2:67–71PubMedCrossRefGoogle Scholar
  107. Zhu W, Cowie A, Wasfy GW et al (1996) Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types. EMBO J 15:4130–4414PubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Basic and Clinical ImmunologyUniversity of California at IrvineIrvineUSA
  2. 2.Allergy & ImmunologyHoag Medical GroupNewport BeachUSA

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