a significant role in the homeostasis of the immune system, because concomitant loss of both Bim and Puma caused a hyperplasia of the lymphoid organ greater than that caused by loss of Bim alone.44 Combined loss of Bim and Puma also promoted spontaneous lymphomagenesis, confirming the tumor suppressor potential of these two proteins.44

3. IMPAIRED APOPTOSIS AND LEUKEMOGENESIS

Apoptosis serves as a barrier against oncogenic transformation. Resistance to apoptosis allows preneoplastic cells to acquire additional mutations and to grow in conditions that should normally signal their death, such as hypoxia.155 Deregulation of apoptosis-related genes has been found in many types of human tumors.156 Bcl-2 was initially identified because of its involvement in oncogenic chromosomal translocation in human follicular lymphoma.157 On its own, Bcl-2 proved to be a rather weak oncogene, but it was shown to dramatically accelerate Myc-induced lymphomagenesis.158 Myc over-expression has been shown to signal proliferation as well as apoptosis, and Bcl-2 is thought to cooperate with Myc by antagonizing its proapoptotic effect.159 Although Myc and Bcl-2 synergize in tumor development, particularly lymphomagenesis, the initiation, development, continued growth, and severity of Eμ-Myc lymphoma do not depend on endogenous Bcl- 2.160 Mice expressing an Mcl-1 transgene in hematolymphoid tissues were found to develop lymphoma with long latency and at high probability (>85% over 2 years). In most cases, the disease was widely disseminated and of clonal B-cell origin. A variety of histologic subtypes were seen, predominantly follicular lymphoma and diffuse large-cell lymphoma.161 Recently, Mcl-1 overexpression has also been shown to dramatically accelerate Myc-driven lymphomagenesis.162 Futher investigations will be required to evaluate the role of endogenous Mcl-1 in this model. A1 has been reported to be required for leukemogenesis mediated by BCR/ABL,163 and Bcl-xL has been implicated in mouse myeloid and T-cell leukemia.164 Because antiapoptotic proteins of the Bcl- 2 family displayed oncogenic potential, it was no surprise when Bim and Puma were found to be tumor suppressors.165,166 Similar to Bcl-2 over-expression, loss of Bim accelerated Myc-driven lymphomagenesis.165 Significantly, mutations inactivating the Bim gene were also described in human mantle cell lymphomas and many Burkitt’s lymphomas.167,168 Silencing of Bim in these tumors was achieved by gene deletion or promoter methylation.168 Downregulation of Puma with shRNAs promoted oncogenic transformation of primary murine

embryonic fibroblasts by the E1A/Ras combination and accelerated Myc-induced lymphomagenesis.166

Recent findings have indicated that Bim is regulated by the miR-17–92 microRNA cluster that is amplified in some human lymphomas.169,170

From a therapeutic point of view, it is rather convenient that deregulation of the apoptotic machinery tends to an increase of the ratio of prosurvival molecules/ proapoptotic BH3-only molecules rather than a destruction of the machine itself (which could be achieved by the loss of Bax and Bak, for example). Many of the commonly used cytotoxic agents work by reversing the skewed ratio in favor of proapoptotic molecules (reviewed in reference 171). For example, the kinase inhibitor imatinib used to counteract the effects of the Bcr/Abl oncogenic protein in chronic myelogenous leukemia kills cells through Bim and Bad,172,173 whereas glucocorticoids used for the treatment of acute lymphocytic leukemia rely on Bim and Puma to kill cells.27,28,171 Because BH3-only proteins antagonize their prosurvival relatives by binding to them through their BH3 α-helical domain, the development of small molecules mimicking the BH3 domain has generated a lot of enthusiasm and hope in the last few years. Several such molecules have been described and are presently tested in the clinic (for review, see Zhang drug resistance updates).174 Of particular interest, a small molecule developed by Abbott Laboratories using a structurebased approach, ABT-737, has been shown to have a very high affinity (nanomolar range) for Bcl-2, Bcl-xL, and Bcl-w.175 ABT-737 proved very efficient at killing cells with low Mcl-1 content, whereas cells with high Mcl-1 content were resistant to the drug. Inhibiting Mcl-1 by over-expression of Noxa in these cells rendered them sensitive to ABT-737, showing that a BH3-mimetic with a limited binding spectrum might be used in combination with conventional drugs to kill cancer cells.176 Understanding the subtleties in the relationships between Bcl-2 family members in the control of life and death in the immune system will be useful to design therapeutic regimes suited to each tumor type.

4. CONCLUSIONS

To become an active part of the immune system, hematopoietic stem cells have to undergo an educational program that will leave most of them dead before reaching their goal. This is the price to pay for the organism to avoid renegade cells taking over the system, leading to its ruin. The Bcl-2 regulated and death receptor pathways are in charge of the elimination of the cells that do not meet the stringent criteria of the system.

Although a lot has been learned about the different signaling mechanisms that decide cell fate at the different checkpoints, some pieces of the puzzle are still missing. How, for example, does a membrane receptor signal death or survival depending on the strength of its interaction for its ligand? There is still much to learn about the mechanisms that control life and death in the immune system, but the work that has been accomplished since the discovery of Bcl-2 has provided valuable insight into the workings of the life/death switches, and strategies based on this knowledge are beginning to emerge.

There is much hope that a better understanding of the mechanisms that orchestrate survival and cell death of immune cells will lead to the development of novel pharmaceutical strategies to prevent inflammation, autoimmune diseases, and cancer.

ACKNOWLEDGMENTS

This work was supported by the NH&MRC (Program Grant, Career Development Award and Project Grant), the Charles and Sylvia Viertel Charitable Foundation and the Australian Research Council. We apologize to the authors who made important contributions to the field but have not been cited as a result of space limitations.

REFERENCES

1.Schneider, P. and J. Tschopp. Apoptosis induced by death receptors. Pharm Acta Helv, 2000. 74(2–3): p. 281–6.

2.Strasser, A., et al. Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J, 1995. 14:

p.6136–47.

3.Zhang, J., et al. Fas-mediated apoptosis and activationinduced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature, 1998. 392: p. 296–300.

4.Kang, T.B., et al. Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol, 2004. 173(5): p. 2976–84.

5.Salmena, L., et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev, 2003. 17: p. 883–95.

6.Yin, X.-M., et al. Bid-deficient mice are resistant to Fasinduced hepatocellular apoptosis. Nature, 1999. 400(6747):

p.886–91.

7.Adams, J.M. and S. Cory. The Bcl-2-regulated apoptosis switch: mechanism and therapeutic potential. Curr Opin Immunol, 2007. 19(5): p. 488–96.

8.Chipuk, J.E. and D.R. Green. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol, 2008. 18(4): p. 157–64.

9.van Delft, M.F. and D.C.S. Huang. How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Research, 2006. 16: p. 203–13.

10.Hughes, P., P. Bouillet, and A. Strasser. Role of Bim and other Bcl-2 family members in autoimmune and degenerative diseases. Curr Dir Autoimmun, 2006. 9: p. 74–94.

11.Strasser, A. The role of BH3-only proteins in the immune system. Nat Rev. Immunol., 2005. 5: p. 189–200.

12.Domen, J., K.L. Gandy, and I.L. Weissman. Systemic overexpression of BCL-2 in the hematopoietic system protects transgenic mice from the consequences of lethal irradiation. Blood, 1998. 91(7): p. 2272–82.

13.Ogilvy, S., et al. Constitutive bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc Natl Acad Sci U S A, 1999. 96(26): p. 14943–8.

14.Domen, J. and I.L. Weissman. Hematopoietic stem cells need two signals to prevent apoptosis; BCL-2 can provide one of these, Kitl/c-Kit signaling the other. J Exp Med, 2000. 192(12): p. 1707–18.

15.Domen, J. and I.L. Weissman. Hematopoietic stem cells and other hematopoietic cells show broad resistance to chemotherapeutic agents in vivo when overexpressing bcl-

2.Exp Hematol, 2003. 31(7): p. 631–9.

16.Veis, D.J., et al. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell, 1993. 75: p. 229–40.

17.Nakayama, K., et al. Targeted disruption of bcl-2α in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci U S A, 1994. 91:

p.3700–4.

18.Kamada, S., et al. bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Res, 1995. 55:

p.354–9.

19.Wojciechowski, S., et al. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis. J Exp Med, 2007. 204(7): p. 1665–75.

20.Motoyama, N., et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x deficient mice. Science, 1995. 267: p. 1506–10.

21.Ma, A., et al. Bclx regulates the survival of double-positive

thymocytes. Proc Natl Acad Sci U S A, 1995. 92(11):

p. 4763–7.

22.Print, C.G., et al. Apoptosis regulator Bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci U S A, 1998. 95: p. 12424–31.

23.Akashi, K., et al. Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood, 2003. 101(2): p. 383–9.

24.Opferman, J., et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science., 2005. 307: p. 1101–4.

25.Dzhagalov, I., A. St. John, and Y.W. He. The Anti-apoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood, 2007. 109(4): p. 1620–6.

26.Chen, L., et al. Differential targeting of pro-survival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell, 2005. 17: p. 393–403.

27.Bouillet, P., et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science, 1999. 286:

p.1735–8.

28.Villunger, A., et al. p53and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa.

Science, 2003. 302: p. 1036–8.

29.Jeffers, J.R., et al. Puma is an essential mediator of p53dependent and -independent apoptotic pathways. Cancer Cell, 2003. 4: p. 321–8.

30.Bouillet, P., et al. Degenerative disorders caused by Bcl-2 deficiency are prevented by loss of its BH3-only antagonist Bim. Dev Cell, 2001. 1(5): p. 645–53.

31.Opferman, J.T., et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature, 2003. 426(6967): p. 671–6.

32.Godfrey, D.I. and A. Zlotnik. Control points in early T-cell development. Immunol Today, 1993. 14(11): p. 547–53.

33.Rodewald, H.-R. and H.J. Fehling. Molecular and cellular events in early thymocyte development. Adv Immunol, 1998. 69: p. 1–112.

34.Capone, M., R.D. Hockett, Jr., and A. Zlotnik. Kinetics of T cell receptor beta, gamma and delta rearrangements during adult thymic development: T cell receptor rearrangements are present in CD44+CD25+ Pro-T thymocytes.

Proc Natl Acad Sci U S A, 1998. 95(21): p. 12522–7.

35.Groettrup, M. and H. von Boehmer. A role for a pre-T- cell receptor in T-cell development. Immunol Today, 1993. 14(12): p. 610–14.

36.von Boehmer, H. Positive selection of lymphocytes. Cell, 1994. 76: p. 219–28.

37.Egerton, M., R. Scollay, and K. Shortman. Kinetics of mature T cell development in the thymus. Proc Natl Acad Sci U S A, 1990. 87: p. 2579–82.

38.Peschon, J.J., et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med, 1994. 180(5): p. 1955–60.

39.von Freeden-Jeffry, U., et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med, 1995. 181(4): p. 1519–26.

40.Maraskovsky, E., et al. Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1 −/− mice. Cell, 1997. 89(7): p. 1011–19.

41.Akashi, K., et al. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell, 1997. 89(7):

p.1033–41.

42.Nakayama, K.-i., et al. Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science, 1993. 261: p. 1584–8.

43.Pellegrini, M., et al. Shut down of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim. Proc Natl Acad Sci U S A, 2003. 100(24): p. 14175–80.

44.Erlacher, M., et al. Puma cooperates with Bim, the ratelimiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J Exp Med, 2006. 203(13): p. 2939–51.

45.Habu, S., et al. Correlation of T cell receptor gene rearrangements to T cell surface antigen expression and to serum immunoglobulin level in scid mice. Eur J Immunol, 1987. 17(10): p. 1467–71.

46.Shores, E.W., et al. T cell receptor-negative thymocytes from SCID mice can be induced to enter the CD4/CD8 differentiation pathway. Eur J Immunol, 1990. 20(1): p. 69–77.

47.Mombaerts, P., et al. Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages. Nature, 1992. 360: p. 225–31.

48.Shinkai, Y., et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangements. Cell, 1992. 68: p. 855–67.

49.Malissen, M., et al. Altered T cell development in mice with a targeted mutation of the CD3-ε gene. EMBO J, 1995. 14(19): p. 4641–53.

50.Fehling, H.J., et al. Crucial role of the pre-T-cell receptor alpha gene in development of alpha-beta but not gammadelta T cells. Nature, 1995. 375: p. 795–8.

51.Strasser, A., et al. bcl-2 expression promotes B but not T lymphoid development in scid mice. Nature, 1994. 368: p. 457–60.

52.Newton, K., A.W. Harris, and A. Strasser. FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor. EMBO J, 2000. 19: p. 931–41.

53.Guo, J., et al. Regulation of the TCRα repertoire by the survival window of CD4+CD8+ thymocytes. Nat Immunol, 2002. 3(5): p. 469–76.

54.Mandal, M., et al. The BCL2A1 gene as a pre-T cell receptor-induced regulator of thymocyte survival. J Exp Med, 2005. 201(4): p. 603–14.

55.Strasser, A., et al. Positive and negative selection of T cells in T cell receptor transgenic mice expressing a bcl-2 transgene. Proc Natl Acad Sci U S A, 1994. 91: p. 1376–80.

56.Newton, K., et al. A dominant interfering mutant of FADD/Mort1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes.

EMBO J, 1998. 17(3): p. 706–18.

57.Linette, G.P., et al. Bcl-2 is upregulated at the CD4+CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity, 1994. 1: p. 197–205.

58.Groves, T., et al. TCR engagement of CD4+CD8+ thymocytes in vitro induces early aspects of positive selection, but not apoptosis. J Immunol, 1997. 158: p. 65–75.

59.Singer, G.G. and A.K. Abbas. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity, 1994. 1: p. 365– 71.

60.Lamhamedi-Cherradi, S.E., et al. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL- /- mice. Nat Immunol, 2003. 4(3): p. 255–60.

61.Corazza, N., et al. TRAIL and immunity: more than a license to kill tumor cells. Cell Death Differ, 2004. 11 Suppl

2:p. S122–5.

62.Cretney, E., et al. Normal thymocyte negative selection in TRAIL-deficient mice. J Exp Med, 2003. 198(3): p. 491–6.

63.Cretney, E., et al. No requirement for TRAIL in intrathymic negative selection. Int Immunol, 2008. 20(2): p. 267–76.

64.Bouillet, P., et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature, 2002. 415: p. 922–6.

65.von Boehmer, H. Developmental biology of T cells in T cell-receptor transgenic mice. Ann Rev Immunol, 1990. 8: p. 531–56.

66.Cante-Barrett, K., et al. Thymocyte negative selection is mediated by protein kinase C- and Ca2+-dependent transcriptional induction of bim of cell death. J Immunol, 2006. 176(4): p. 2299–306.

67.Lindsten, T., et al. The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol Cell, 2000. 6(6): p. 1389–99.

68.Rathmell, J.C., et al. Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat Immunol, 2002. 3(10): p. 932–9.

69.Villunger, A., et al. Negative selection of semimature CD4(+)8(-)HSA+ thymocytes requires the BH3-only protein Bim but is independent of death receptor signaling.

Proc Natl Acad Sci U S A, 2004. 101(18): p. 7052–7.

70.Hara, H., et al. The apoptotic protease-activating factor 1- mediated pathway of apoptosis is dispensable for negative selection of thymocytes. J Immunol, 2002. 168(5): p. 2288– 95.

71.Chautan, M., et al. Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr Biol, 1999. 9: p. 967–70.

72.Sentman, C.L., et al. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell, 1991.

67:p. 879–88.

73.Liu, Z.-G., et al. Apoptotic signals delivered through the T- cell receptor of a T-cell hybrid require the immediate-early gene nur77. Nature, 1994. 367: p. 281–4.

74.Woronicz, J.D., et al. Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature, 1994. 367: p. 277–81.

75.Cheng, L.E.-C., et al. Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis.

EMBO J, 1997. 16(8): p. 1865–75.

76.Kuang, A.A., D. Cado, and A. Winoto. Nur77 transcription activity correlates with its apoptotic function in vivo. Eur J Immunol, 1999. 29(11): p. 3722–8.

77.Lee, S.L., et al. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science, 1995. 269(5223): p. 532–5.

78.Ponnio, T., et al. The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear. Mol Cell Biol, 2002. 22(3): p. 935–45.

79.Calnan, B.J., et al. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity, 1995. 3(3): p. 273–82.

80.Zhou, T., et al. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J Exp Med, 1996. 183: p. 1879–92.

81.Rajpal, A., et al. Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor. EMBO J, 2003. 22(24): p. 6526–36.

82.Ley, R., et al. Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem, 2003. 278(21): p. 18811–16.

83.Ewings, K.E., et al. ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and BclxL. EMBO J, 2007. 26(12): p. 2856–67.

84.Lei, K. and R.J. Davis. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A, 2003. 100: p. 2432–7.

85.Rincon,´ M., et al. The JNK pathway regulates the In vivo deletion of immature CD4+CD8+ thymocytes. J Exp Med, 1998. 188(10): p. 1817–30.

86.Sugawara, T., et al. Differential roles of ERK and p38 MAP kinase pathways in positive and negative selection of T lymphocytes. Immunity, 1998. 9(4): p. 565–74.

87.Werlen, G., B. Hausmann, and E. Palmer. A motif in the αT- cell receptor controls positive selection by modulating ERK activity. Nature, 2000. 406(6794): p. 422–6.

88.Hubner, A., et al. Multisite phosphorylation regulates bim stability and apoptotic activity. Mol Cell, 2008. 30(4): p. 415–25.

89.Sohn, S.J., G.M. Lewis, and A. Winoto. Non-redundant function of the MEK5-ERK5 pathway in thymocyte apoptosis. EMBO J, 2008. 27: p. 1896–906.

90.Lin, B., et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell, 2004. 116(4): p. 527–40.

91.Luciano, F., et al. Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. Blood, 2007. 109(9): p. 3849–55.

92.Thompson, J. and A. Winoto. During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain. J Exp Med, 2008. 205: p. 1029–36.

93.Kurts, C., et al. The peripheral deletion of autoreactive CD8+ T cells induced by cross-presentation of selfantigens involves signaling through CD95 (Fas, Apo-1).

J Exp Med, 1998. 188(2): p. 415–20.

94.Davey, G.M., et al. Peripheral deletion of autoreactive CD8 T cells by cross presentation of self-antigen occurs by a Bcl- 2-inhibitable pathway mediated by Bim. J Exp Med, 2002. 196(7): p. 947–55.

95.Redmond, W.L., et al. The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen. J Immunol, 2008. 180: p. 5275–82.

96.Hernandez, J., et al. Phenotypic and functional analysis of CD8+ T cells undergoing peripheral deletion in response to cross-presentation of self-antigen. J Exp Med, 2001. 194(6): p. 707–717.

97.Van Parijs, L., D.A. Peterson, and A.K. Abbas. The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens. Immunity, 1998. 8(2):

p.265–74.

98.Vella, A., et al. Interleukin 4 (IL-4) or IL-7 prevents the death of resting T cells: Stat6 is probably not required for the effect of IL-4. J Exp Med, 1997. 186(2): p. 325– 30.

99.Vella, A.T., et al. Cytokine-induced survival of activated T cells in vitro and in vivo. Proc Natl Acad Sci U S A, 1998. 95:

p.3810–15.

100.Li, X.C., et al. IL-15 and IL-2: a matter of life and death for T cells in vivo. Nat Med, 2001. 7(1): p. 114–18.

101.Strasser, A., A.W. Harris, and S. Cory. Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship.

Cell, 1991. 67: p. 889–99.

102.Sprent, J. and D.F. Tough. T cell death and memory. Science, 2001. 293(5528): p. 245–8.

103.Brunner, T., et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature, 1995. 373: p. 441–4.

104.Dhein, J., et al. Autocrine T-cell suicide mediated by APO- 1/(Fas/CD95). Nature, 1995. 373: p. 438–41.

105.Russell, J.H. and R. Wang. Autoimmune gld mutation uncouples suicide and cytokine/proliferation pathways in activated, mature T cells. Eur J Immunol, 1993. 23: p. 2379– 82.

106.Mogil, R.J., et al. Fas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo. Int Immunol, 1995. 7(9): p. 1451–8.

107.Van Parijs, L., A. Ibraghimov, and A.K. Abbas. The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. Immunity, 1996. 4: p. 321–8.

108.Strasser, A., et al. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci U S A, 1991. 88: p. 8661–5.

109.Hildeman, D.A., et al. Activated T cell death in vivo mediated by pro-apoptotic Bcl-2 family member, Bim. Immunity, 2002. 16: p. 759–67.

110.Watanabe-Fukunaga, R., et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature, 1992. 356: p. 314–17.

111.Rieux-Laucat, F., et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.

Science, 1995. 268: p. 1347–9.

112.Hughes, P.D., et al. Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity, 2008. 28(2): p. 197– 205.

113.Weant, A.E., et al. Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8+ T cell contraction. Immunity, 2008. 28(2): p. 218–30.

114.Hutcheson, J., et al. Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Immunity, 2008. 28(2): p. 206–17.

115.Krammer, P.H. CD95’s deadly mission in the immune system. Nature, 2000. 407(6805): p. 789–95.

116.Vabulas, R., et al. Rapid clearance of the bacterial superantigen staphylococcal enterotoxin B in vivo. Infect Immun, 1996. 64(11): p. 4567–73.

117.Kallies, A. Distinct regulation of effector and memory T-cell differentiation. Immunol Cell Biol, 2008. 86(4): p. 325–32.

118.Sprent, J., et al. T cell homeostasis. Immunol Cell Biol, 2008. 86(4): p. 312–19.

119.Maris, C.H., et al. A transgenic mouse model genetically tags all activated CD8 T cells. J Immunol, 2003. 171(5):

p.2393–401.

120.Lauvau, G., et al. Priming of memory but not effector CD8 T cells by a killed bacterial vaccine. Science, 2001. 294(5547):

p.1735–9.

121.Kaech, S.M., et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol, 2003. 4(12):

p.1191–8.

122.Sun, J.C., S.M. Lehar, and M.J. Bevan. Augmented IL-7 signaling during viral infection drives greater expansion of effector T cells but does not enhance memory. J Immunol, 2006. 177(7): p. 4458–63.

123.Hand, T.W., M. Morre, and S.M. Kaech. Expression of IL-7 receptor alpha is necessary but not sufficient for the formation of memory CD8 T cells during viral infection. Proc Natl Acad Sci U S A, 2007. 104(28): p. 11730–5.

124.Klonowski, K.D., et al. Cutting edge: IL-7-independent regulation of IL-7 receptor alpha expression and memory CD8 T cell development. J Immunol, 2006. 177(7): p. 4247–51.

125.Williams, M.A., et al. Developing and maintaining protective CD8+ memory T cells. Immunol Rev, 2006. 211: p. 146– 53.

126.Bachmann, M.F., et al. Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur J Immunol, 2007. 37(6): p. 1502–12.

127.Joshi, N.S., et al. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity, 2007. 27(2): p. 281–95.

128.Marsden, V. and A. Strasser. Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. Ann Rev of Immunol, 2003. 21: p. 71–105.

129.Mombaerts, P., et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell, 1992. 68(5): p. 869–77.

130.Tarlinton, D.M., L.M. Corcoran, and A. Strasser. Continued differentiation during B lymphopoiesis requires signals in addition to cell survival. Int Immunol, 1997. 9(10): p. 1481– 94.

131.Fang, W., et al. Self-reactive B lymphocytes overexpressing Bcl-xL escape negative selection and are tolerized by clonal anergy and receptor editing. Immunity, 1998. 9(1): p. 35– 45.

132.Pellegrini, M., et al. Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice. J Exp Med, 2004. 200(9): p. 1189–95.

133.Oliver, P.M., et al. Loss of bim allows precursor B cell survival but not precursor B cell differentiation in the absence of interleukin 7. J Exp Med, 2004. 200(9): p. 1179–87.

134.Mackay, F., P.A. Silveira, and R. Brink. B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr Opin Immunol, 2007. 19(3): p. 327–36.

135.Schiemann, B. et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001. 16: p. 2011-2014.

136.Mackay, F., et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med, 1999. 190(11): p. 1697–710.

137.Thompson, J.S., et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science, 2001. 293(5537): p. 2108–11.

138.Lam, K.P., R. Kuhn, and K. Rajewsky. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell, 1997. 90(6): p. 1073–83.

139.Tiegs, S.L., D.M. Russell, and D. Nemazee. Receptor editing in self-reactive bone marrow B cells. J Exp Med, 1993. 177(4): p. 1009–20.

140.Hartley, S.B., et al. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell, 1993. 72: p. 325–35.

141.Shokat, K.M. and C.C. Goodnow. Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature, 1995. 375(6529): p. 334–8.

142.Pulendran, B., et al. Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature, 1995. 375(6529): p. 331–4.

143.Rathmell, J.C. and C.C. Goodnow. Effects of the lpr mutation on elimination and inactivation of self-reactive B cells.

J Immunol, 1994. 153: p. 2831–42.

144.Rubio, C.F., et al. Analysis of central B cell tolerance in autoimmune-prone MRL/lpr mice bearing autoantibody transgenes. J Immunol, 1996. 157(1): p. 65–71.

145.Yoshida, T., et al. Rapid B cell apoptosis induced by antigen receptor ligation does not require fas (CD95/APO-1), the adaptor protein FADD/MORT1 or CrmAsensitive caspases but is defective in both MRL-+/+ and MRL-lpr/lpr mice. Int Immunol, 2000. 12(4): p. 517–26.

146.Nisitani, S., et al. The bcl-2 gene product inhibits clonal deletion of self-reactive B lymphocytes in the periphery but not in the bone marrow. J Exp Med, 1993. 178: p. 1247–54.

147.Enders, A., et al. Loss of the pro-apoptotic BH3-only Bcl- 2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreative B cells. J Exp Med, 2003. 198: p. 1119–26.

148.Smith, S.H. and M.P. Cancro. Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and

their immediate progenitors. J Immunol, 2003. 170(12):

p.5820–3.

149.Yan, M., et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B-cell deficiency. Curr Biol, 2001. 11(19): p. 1547– 52.

150.Schiemann, B., et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science, 2001. 16: p. 2111–14.

151.Yan, M., et al. Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol, 2001. 2(7): p. 638– 43.

152.Smith, K.G.C., et al. BCL-2 increases memory B cell recruitment but does not perturb selection in germinal centers.

Immunity, 1994. 1: p. 808–13.

153.Fischer, S.F., et al. Pro-apoptotic BH3-only protein Bim is essential for developmentally programmed death of germinal center-derived memory B cells and antibody forming cells. Blood, 2007. 110(12): p. 3978–84.

154.Hildeman, D., et al. Apoptosis and the homeostatic control of immune responses. Curr Opin Immunol, 2007. 19(5):

p.516–21.

155.Hanahan, D. and R.A. Weinberg. The hallmarks of cancer.

Cell, 2000. 100(1): p. 57–70.

156.Reed, J.C.. Apoptosis-targeted therapies for cancer. Cancer Cell, 2003. 3(1): p. 17–22.

157.Tsujimoto, Y. and C.M. Croce. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci U S A, 1986. 83(14): p. 5214–18.

158.Strasser, A., et al. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature, 1990. 348: p. 331–3.

159.Cory, S. and J.M. Adams. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer, 2002. 2(9):

p.647–56.

160.Kelly, P.N., et al. Endogenous bcl-2 is not required for the development of {micro}-myc-induced B-cell lymphoma.

Blood, 2007. 109(11): p. 4907–13.

161.Zhou, P., et al. MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood, 2001. 97(12): p. 3902–9.

162.Campbell, K.J., et al. Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance.

Blood 2010. 116(17): p. 3197–207.

163.Nieborowska-Skorska, M., et al. Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis.

Blood, 2002. 99(12): p. 4531–9.

164.Packham, G., et al. Selective regulation of Bcl-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies. Genes Dev, 1998. 12(16):

p.2475–87.

165.Egle, A., et al. Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci U S A, 2004. 101: p. 6164– 9.

166.Hemann, M.T., et al. Suppression of tumorigenesis by the p53 target PUMA. Proc Natl Acad Sci U S A, 2004. 101(25): p. 9333–8.

167.Tagawa, H., et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene, 2005. 24(8): p. 1348–58.

168.Mestre-Escorihuela, C., et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas.

Blood, 2007. 109(1): p. 271–80.

169.Ventura, A., et al. Targeted deletion reveals essential and overlapping functions of the mIR-17 92 family of miRNA clusters. Cell, 2008. 132(5): p. 875–86.

170.Xiao, C., et al. Lymphoproliferative disease and autoim-

munity in mice with increased miR-17–92 expression in lymphocytes. Nat Immunol, 2008. 9: p. 404– 14.

171.Adams, J.M. and S. Cory. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene, 2007. 26(9):

p.1324–37.

172.Kuribara, R., et al. Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitor. Mol Cell Biol, 2004. 24: p. 6172–83.

173.Kuroda, J., et al. Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci U S A, 2006. 103(40): p. 14907–12.

174.Zhang, L., Ming, L., Yu, J. BH3 mimetics to improve cancer therapy; mechanisms and examples. Drug Resist Updat. 2007.10(6): 207–217.

175.Oltersdorf, T., et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 2005. 435(7042): p. 677–81.

176.van Delft, M.F., et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell., 2006. 10:

p.389–99.