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The cunning little vixen: Foxo and the cycle of life and death

Nature Immunology volume 10, pages 1057–1063 (2009)Cite this article

Abstract

A screen for increased longevity in Caenorhabditis elegans has identified a transcription factor that programs cells for resistance to oxidative stress, DNA repair and cell cycle control. The mammalian orthologs of this factor are referred to as 'Foxo' for 'Forkhead box', with the second 'o' in the name denoting a subfamily of four members related by sequence. This family of factors is regulated by growth factors, oxidative stress or nutrient deprivation. Thus, it might readily control the inflammatory conflagration associated with infection-driven lymphocyte proliferation. Surprisingly, the first insights into Foxo-mediated immune regulation have instead revealed direct control of highly specialized genes of the adaptive immune system.

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Figure 1: Opposing influences on Foxo cellular localization and transcriptional activity.
Figure 2: A typical negative feedback loop controlled by Foxo-regulated transcription.

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References

  1. Burgering, B.M. A brief introduction to FOXOlogy. Oncogene 27, 2258–2262 (2008).

    CAS  PubMed  Google Scholar 

  2. Jacobs, F.M. et al. FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J. Biol. Chem. 278, 35959–35967 (2003).

    CAS  PubMed  Google Scholar 

  3. Calnan, D.R. & Brunet, A. The FoxO code. Oncogene 27, 2276–2288 (2008).

    CAS  PubMed  Google Scholar 

  4. van der Vos, K.E. & Coffer, P.J. FOXO-binding partners: it takes two to tango. Oncogene 27, 2289–2299 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Sun, X.J. et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 73–77 (1991).

    CAS  PubMed  Google Scholar 

  6. Burgering, B.M. & Coffer, P.J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599–602 (1995).

    CAS  PubMed  Google Scholar 

  7. Franke, T.F. et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81, 727–736 (1995).

    CAS  PubMed  Google Scholar 

  8. Alessi, D.R. et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr. Biol. 7, 261–269 (1997).

    CAS  PubMed  Google Scholar 

  9. Stokoe, D. et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 277, 567–570 (1997).

    CAS  PubMed  Google Scholar 

  10. Jacinto, E. et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125–137 (2006).

    CAS  PubMed  Google Scholar 

  11. Guertin, D.A. et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell 11, 859–871 (2006).

    CAS  PubMed  Google Scholar 

  12. Burgering, B.M. & Kops, G.J. Cell cycle and death control: long live Forkheads. Trends Biochem. Sci. 27, 352–360 (2002).

    CAS  PubMed  Google Scholar 

  13. Rena, G., Prescott, A.R., Guo, S., Cohen, P. & Unterman, T.G. Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. Biochem. J. 354, 605–612 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Brownawell, A.M., Kops, G.J., Macara, I.G. & Burgering, B.M. Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX. Mol. Cell. Biol. 21, 3534–3546 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Brunet, A. et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J. Cell Biol. 156, 817–828 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Rena, G. et al. Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J. 21, 2263–2271 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hu, M.C. et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225–237 (2004).

    CAS  PubMed  Google Scholar 

  18. Huang, H., Regan, K.M., Lou, Z., Chen, J. & Tindall, D.J. CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 314, 294–297 (2006).

    CAS  PubMed  Google Scholar 

  19. Asada, S. et al. Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell. Signal. 19, 519–527 (2007).

    CAS  PubMed  Google Scholar 

  20. Yang, J.Y. et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat. Cell Biol. 10, 138–148 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ding, Q. et al. Erk associates with and primes GSK-3β for its inactivation resulting in upregulation of β-catenin. Mol. Cell 19, 159–170 (2005).

    CAS  PubMed  Google Scholar 

  22. Paik, J.H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309–323 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee, Y.H. & Stallcup, M.R. Minireview: protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol. Endocrinol. 23, 425–433 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamagata, K. et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol. Cell 32, 221–231 (2008).

    CAS  PubMed  Google Scholar 

  25. Essers, M.A. et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 23, 4802–4812 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, M.C., Bohmann, D. & Jasper, H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121, 115–125 (2005).

    CAS  PubMed  Google Scholar 

  27. Lehtinen, M.K. et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987–1001 (2006).

    CAS  PubMed  Google Scholar 

  28. Kops, G.J. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321 (2002).

    CAS  PubMed  Google Scholar 

  29. Medema, R.H., Kops, G.J., Bos, J.L. & Burgering, B.M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000).

    CAS  PubMed  Google Scholar 

  30. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

    CAS  PubMed  Google Scholar 

  31. Greer, E.L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007).

    CAS  PubMed  Google Scholar 

  32. Fukuoka, M. et al. Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. Int. J. Mol. Med. 12, 503–508 (2003).

    CAS  PubMed  Google Scholar 

  33. Yang, Y., Hou, H., Haller, E.M., Nicosia, S.V. & Bai, W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 24, 1021–1032 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).

    CAS  PubMed  Google Scholar 

  35. Haigis, M.C. & Guarente, L.P. Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006).

    CAS  PubMed  Google Scholar 

  36. Housley, M.P. et al. O-GlcNAc regulates FoxO activation in response to glucose. J. Biol. Chem. 283, 16283–16292 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hatta, M. & Cirillo, L.A. Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J. Biol. Chem. 282, 35583–35593 (2007).

    CAS  PubMed  Google Scholar 

  38. Ramaswamy, S., Nakamura, N., Sansal, I., Bergeron, L. & Sellers, W.R. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2, 81–91 (2002).

    CAS  PubMed  Google Scholar 

  39. Galili, N. et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat. Genet. 5, 230–235 (1993).

    CAS  PubMed  Google Scholar 

  40. Ouyang, W., Beckett, O., Flavell, R.A. & Li, M.O. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 30, 358–371 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang, W. et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J. Biol. Chem. 281, 10105–10117 (2006).

    CAS  PubMed  Google Scholar 

  42. Li, M.O. & Flavell, R.A. TGF-β: a master of all T cell trades. Cell 134, 392–404 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Massague, J. & Gomis, R.R. The logic of TGFβ signaling. FEBS Lett. 580, 2811–2820 (2006).

    CAS  PubMed  Google Scholar 

  44. Shi, Y. & Massague, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).

    CAS  PubMed  Google Scholar 

  45. Seoane, J., Le, H.V., Shen, L., Anderson, S.A. & Massague, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211–223 (2004).

    CAS  PubMed  Google Scholar 

  46. Gomis, R.R., Alarcon, C., Nadal, C., Van Poznak, C. & Massague, J. C/EBPbeta at the core of the TGFβ cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10, 203–214 (2006).

    CAS  PubMed  Google Scholar 

  47. Shull, M.M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kulkarni, A.B. et al. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Li, M.O., Sanjabi, S. & Flavell, R.A. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455–471 (2006).

    CAS  PubMed  Google Scholar 

  50. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).

    CAS  PubMed  Google Scholar 

  51. Stahl, M. et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J. Immunol. 168, 5024–5031 (2002).

    CAS  PubMed  Google Scholar 

  52. Dijkers, P.F. et al. FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. J. Cell Biol. 156, 531–542 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. You, H. et al. FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J. Exp. Med. 203, 1657–1663 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Riou, C. et al. Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells. J. Exp. Med. 204, 79–91 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. van Grevenynghe, J. et al. Transcription factor FOXO3a controls the persistence of memory CD4+ T cells during HIV infection. Nat. Med. 14, 266–274 (2008).

    CAS  PubMed  Google Scholar 

  56. Pandiyan, P. et al. CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. J. Exp. Med. 199, 831–842 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Asselin-Labat, M.L. et al. FoxO3 mediates antagonistic effects of glucocorticoids and interleukin-2 on glucocorticoid-induced leucine zipper expression. Mol. Endocrinol. 19, 1752–1764 (2005).

    CAS  PubMed  Google Scholar 

  58. Hur, E.M. et al. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat. Immunol. 8, 74–83 (2007).

    CAS  PubMed  Google Scholar 

  59. Marrack, P. & Kappler, J. Control of T cell viability. Annu. Rev. Immunol. 22, 765–787 (2004).

    CAS  PubMed  Google Scholar 

  60. Lin, L., Hron, J.D. & Peng, S.L. Regulation of NF-κB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity 21, 203–213 (2004).

    CAS  PubMed  Google Scholar 

  61. Hosaka, T. et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc. Natl. Acad. Sci. USA 101, 2975–2980 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Castrillon, D.H., Miao, L., Kollipara, R., Horner, J.W. & DePinho, R.A. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science 301, 215–218 (2003).

    CAS  PubMed  Google Scholar 

  63. Dengler, H.S. et al. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat. Immunol. 9, 1388–1398 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Hinman, R.M. et al. Foxo3−/− mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution. Int. Immunol. 21, 831–842 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Dejean, A.S. et al. Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells. Nat. Immunol. 10, 504–513 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59 (1998).

    CAS  PubMed  Google Scholar 

  67. Bickerstaff, M.C. et al. Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat. Med. 5, 694–697 (1999).

    CAS  PubMed  Google Scholar 

  68. Santiago-Raber, M.L. et al. Role of cyclin kinase inhibitor p21 in systemic autoimmunity. J. Immunol. 167, 4067–4074 (2001).

    CAS  PubMed  Google Scholar 

  69. Fallarino, F. et al. CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice. J. Exp. Med. 200, 1051–1062 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lawrence, T., Bebien, M., Liu, G.Y., Nizet, V. & Karin, M. IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation. Nature 434, 1138–1143 (2005).

    CAS  PubMed  Google Scholar 

  71. Puccetti, P. & Grohmann, U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation. Nat. Rev. Immunol. 7, 817–823 (2007).

    CAS  PubMed  Google Scholar 

  72. Leenders, H., Whiffield, S., Benoist, C. & Mathis, D. Role of the forkhead transcription family member, FKHR, in thymocyte differentiation. Eur. J. Immunol. 30, 2980–2990 (2000).

    CAS  PubMed  Google Scholar 

  73. Patra, A.K., Na, S.Y. & Bommhardt, U. Active protein kinase B regulates TCR responsiveness by modulating cytoplasmic-nuclear localization of NFAT and NF-κB proteins. J. Immunol. 172, 4812–4820 (2004).

    CAS  PubMed  Google Scholar 

  74. Barata, J.T. et al. Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J. Exp. Med. 200, 659–669 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Costello, P.S., Gallagher, M. & Cantrell, D.A. Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nat. Immunol. 3, 1082–1089 (2002).

    CAS  PubMed  Google Scholar 

  76. Fabre, S. et al. Stable activation of phosphatidylinositol 3-kinase in the T cell immunological synapse stimulates Akt signaling to FoxO1 nuclear exclusion and cell growth control. J. Immunol. 174, 4161–4171 (2005).

    CAS  PubMed  Google Scholar 

  77. Yusuf, I., Zhu, X., Kharas, M.G., Chen, J. & Fruman, D.A. Optimal B-cell proliferation requires phosphoinositide 3-kinase-dependent inactivation of FOXO transcription factors. Blood 104, 784–787 (2004).

    CAS  PubMed  Google Scholar 

  78. Fabre, S. et al. FOXO1 regulates L-selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase. J. Immunol. 181, 2980–2989 (2008).

    CAS  PubMed  Google Scholar 

  79. Kerdiles, Y.M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176–184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Park, J.H. et al. Suppression of IL7Rα transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 21, 289–302 (2004).

    CAS  PubMed  Google Scholar 

  81. Puig, O. & Tjian, R. Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev. 19, 2435–2446 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Sinclair, L.V. et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9, 513–521 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Bhaskar, P.T. & Hay, N. The two TORCs and Akt. Dev. Cell 12, 487–502 (2007).

    CAS  PubMed  Google Scholar 

  84. Amin, R.H. & Schlissel, M.S. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nat. Immunol. 9, 613–622 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Buhl, A.M., Pleiman, C.M., Rickert, R.C. & Cambier, J.C. Qualitative regulation of B cell antigen receptor signaling by CD19: selective requirement for PI3-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization. J. Exp. Med. 186, 1897–1910 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ciemerych, M.A. & Sicinski, P. Cell cycle in mouse development. Oncogene 24, 2877–2898 (2005).

    CAS  PubMed  Google Scholar 

  87. Li, G. et al. PTEN deletion leads to up-regulation of a secreted growth factor pleiotrophin. J. Biol. Chem. 281, 10663–10668 (2006).

    CAS  PubMed  Google Scholar 

  88. Yusuf, I. et al. KLF4 is a FOXO target gene that suppresses B cell proliferation. Int. Immunol. 20, 671–681 (2008).

    CAS  PubMed  Google Scholar 

  89. Tang, T.T. et al. The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. J. Biol. Chem. 277, 14255–14265 (2002).

    CAS  PubMed  Google Scholar 

  90. Jonsson, H., Allen, P. & Peng, S.L. Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nat. Med. 11, 666–671 (2005).

    CAS  PubMed  Google Scholar 

  91. Modur, V., Nagarajan, R., Evers, B.M. & Milbrandt, J. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J. Biol. Chem. 277, 47928–47937 (2002).

    CAS  PubMed  Google Scholar 

  92. Nemoto, S. & Finkel, T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295, 2450–2452 (2002).

    CAS  PubMed  Google Scholar 

  93. Tran, H. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530–534 (2002).

    CAS  PubMed  Google Scholar 

  94. Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692–25705 (2008).

    CAS  PubMed  Google Scholar 

  95. Alvarez, B., Martinez-A, C., Burgering, B.M. & Carrera, A.C. Forkhead transcription factors contribute to execution of the mitotic programme in mammals. Nature 413, 744–747 (2001).

    CAS  PubMed  Google Scholar 

  96. Katayama, K., Nakamura, A., Sugimoto, Y., Tsuruo, T. & Fujita, N. FOXO transcription factor-dependent p15INK4b and p19INK4d expression. Oncogene 27, 1677–1686 (2008).

    CAS  PubMed  Google Scholar 

  97. Kops, G.J. et al. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol. Cell. Biol. 22, 2025–2036 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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Hedrick, S. The cunning little vixen: Foxo and the cycle of life and death. Nat Immunol 10, 1057–1063 (2009). https://doi.org/10.1038/ni.1784

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