Biogerontology

, Volume 14, Issue 6, pp 617–628 | Cite as

Immunosurveillance of senescent cells: the bright side of the senescence program

Review Article

Abstract

Cellular senescence, a state of irreversible cell cycle arrest, is a robust mechanism used to mediate tumor suppression and control the tissue damage response following short-term insults. In addition, the senescence associated-secretory phenotype (SASP), one of the most profound characteristics of the senescence program, facilitates the immunosurveillance of senescent cells. The SASP includes many chemokines, cytokines and adhesion molecules that can recruit and activate distinct immune cells from both the innate and adaptive immune system such as NK cells, monocytes/macrophages and T cells. Furthermore, senescent cells can upregulate specific immune ligands on their cell surface that can mediate the recognition of these cells by specific immune cell subsets and lead to activation of the immune cells. Consequently, the activated immune cells engage explicit regulatory mechanisms to eliminate senescent cells. For example, recent work from our laboratory showed that perforin-granzyme exocytosis mediates NK-cell killing of senescent cells. Here, we summarize the current advances in our knowledge of the mechanisms underlying specific immune-mediated elimination of senescent cells.

Keywords

Cellular senescence SASP Immunosurveillance Immune response 

Notes

Acknowledgments

We are grateful to D. Burton for insightful comments and to other members of the Krizhanovsky lab for helpful discussions. This work was supported by grants to V. K. from European Research Council under the European Union’s FP7 (ERC grant n 309688), from Israel Science Foundation and from DKFZ-MOST program. V. K. is an incumbent of the Karl and Frances Korn Career Development Chair in Life Sciences.

References

  1. Adams PD (2009) Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol Cell 36:2–14PubMedCrossRefGoogle Scholar
  2. Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O’Mahony L, Palomares O et al (2011) Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases. J Allergy Clin Immunol 127(701–721):e701–770CrossRefGoogle Scholar
  3. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236PubMedCrossRefGoogle Scholar
  4. Barry M, Bleackley RC (2002) Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2:401–409PubMedGoogle Scholar
  5. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L et al (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596PubMedCrossRefGoogle Scholar
  6. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dorken B, Jenuwein T, Schmitt CA (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436:660–665PubMedCrossRefGoogle Scholar
  7. Braumuller H, Wieder T, Brenner E, Assmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C et al (2013) T-helper-1-cell cytokines drive cancer into senescence. Nature 494:361–365PubMedCrossRefGoogle Scholar
  8. Bromley SK, Mempel TR, Luster AD (2008) Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat Immunol 9:970–980PubMedCrossRefGoogle Scholar
  9. Burton DG (2009) Cellular senescence, ageing and disease. Age (Dordr) 31:1–9CrossRefGoogle Scholar
  10. Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705PubMedCrossRefGoogle Scholar
  11. Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740PubMedCrossRefGoogle Scholar
  12. Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610–621PubMedCrossRefGoogle Scholar
  13. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W et al (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730PubMedCrossRefGoogle Scholar
  14. Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut P, Luo W, Chicas A, Lee CS et al (2011) Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev 25:2125–2136PubMedCrossRefGoogle Scholar
  15. Choy JC, McDonald PC, Suarez AC, Hung VH, Wilson JE, McManus BM, Granville DJ (2003) Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity. Mod Pathol 16:460–470PubMedCrossRefGoogle Scholar
  16. Collado M, Serrano M (2010) Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 10:51–57PubMedCrossRefGoogle Scholar
  17. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M et al (2005) Tumour biology: senescence in premalignant tumours. Nature 436:642PubMedCrossRefGoogle Scholar
  18. Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233PubMedCrossRefGoogle Scholar
  19. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868PubMedCrossRefGoogle Scholar
  20. Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118PubMedCrossRefGoogle Scholar
  21. Cullen SP, Martin SJ (2008) Mechanisms of granule-dependent killing. Cell Death Differ 15:251–262PubMedCrossRefGoogle Scholar
  22. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367PubMedCrossRefGoogle Scholar
  23. Farag SS, Caligiuri MA (2006) Human natural killer cell development and biology. Blood Rev 20:123–137PubMedCrossRefGoogle Scholar
  24. Fitzner B, Muller S, Walther M, Fischer M, Engelmann R, Muller-Hilke B, Putzer BM, Kreutzer M, Nizze H, Jaster R (2012) Senescence determines the fate of activated rat pancreatic stellate cells. J Cell Mol Med. doi: 10.1111/j.1582-4934.2012.01573.x PubMedGoogle Scholar
  25. Freund A, Orjalo AV, Desprez PY, Campisi J (2010) Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med 16:238–246PubMedCrossRefGoogle Scholar
  26. Geijtenbeek TBH, Engering A, van Kooyk Y (2002) DC-SIGN, a C-type lectin on dendritic cells that unveils many aspects of dendritic cell biology. J Leukoc Biol 71:921–931PubMedGoogle Scholar
  27. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964PubMedCrossRefGoogle Scholar
  28. Gregoire C, Chasson L, Luci C, Tomasello E, Geissmann F, Vivier E, Walzer T (2007) The trafficking of natural killer cells. Immunol Rev 220:169–182PubMedCrossRefGoogle Scholar
  29. Hamann A, Syrbe U (2000) T-cell trafficking into sites of inflammation. Rheumatology (Oxford) 39:696–699CrossRefGoogle Scholar
  30. Hayakawa Y, Smyth MJ (2006) NKG2D and cytotoxic effector function in tumor immune surveillance. Semin Immunol 18:176–185PubMedCrossRefGoogle Scholar
  31. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621PubMedCrossRefGoogle Scholar
  32. Hazeldine J, Lord JM (2013) The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev. doi: 10.1016/j.arr.2013.04.003 PubMedGoogle Scholar
  33. Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311:1257PubMedCrossRefGoogle Scholar
  34. Ingersoll MA, Platt AM, Potteaux S, Randolph GJ (2011) Monocyte trafficking in acute and chronic inflammation. Trends Immunol 32:470–477PubMedCrossRefGoogle Scholar
  35. Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT (2006) Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443:421–426PubMedGoogle Scholar
  36. Johnstone RW, Frew AJ, Smyth MJ (2008) The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer 8:782–798PubMedCrossRefGoogle Scholar
  37. Jun JI, Lau LF (2010) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 12:676–685PubMedCrossRefGoogle Scholar
  38. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A et al (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547–551PubMedCrossRefGoogle Scholar
  39. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457PubMedCrossRefGoogle Scholar
  40. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657–667PubMedCrossRefGoogle Scholar
  41. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479PubMedCrossRefGoogle Scholar
  42. La Cava A, Matarese G (2004) The weight of leptin in immunity. Nat Rev Immunol 4:371–379PubMedCrossRefGoogle Scholar
  43. Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274PubMedCrossRefGoogle Scholar
  44. Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, Zhao Z, Thapar V, Joyce JA, Krizhanovsky V et al (2013) Non-cell-autonomous tumor suppression by p53. Cell 153:449–460PubMedCrossRefGoogle Scholar
  45. Luster AD (2002) The role of chemokines in linking innate and adaptive immunity. Curr Opin Immunol 14:129–135PubMedCrossRefGoogle Scholar
  46. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720–724PubMedCrossRefGoogle Scholar
  47. Miyazaki H, Kuwano K, Yoshida K, Maeyama T, Yoshimi M, Fujita M, Hagimoto N, Yoshida R, Nakanishi Y (2004) The perforin mediated apoptotic pathway in lung injury and fibrosis. J Clin Pathol 57:1292–1298PubMedCrossRefGoogle Scholar
  48. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452PubMedCrossRefGoogle Scholar
  49. Murdoch C, Finn A (2000) Chemokine receptors and their role in inflammation and infectious diseases. Blood 95:3032–3043PubMedGoogle Scholar
  50. Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737PubMedCrossRefGoogle Scholar
  51. Naylor RM, Baker DJ, van Deursen JM (2013) Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther 93:105–116PubMedCrossRefGoogle Scholar
  52. O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275–283PubMedCrossRefGoogle Scholar
  53. Pitiyage GN, Slijepcevic P, Gabrani A, Chianea YG, Lim KP, Prime SS, Tilakaratne WM, Fortune F, Parkinson EK (2011) Senescent mesenchymal cells accumulate in human fibrosis by a telomere-independent mechanism and ameliorate fibrosis through matrix metalloproteinases. J Pathol 223:604–617PubMedCrossRefGoogle Scholar
  54. Pixley FJ, Stanley ER (2004) CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol 14:628–638PubMedCrossRefGoogle Scholar
  55. Rabin RL, Park MK, Liao F, Swofford R, Stephany D, Farber JM (1999) Chemokine receptor responses on T cells are achieved through regulation of both receptor expression and signaling. J Immunol 162:3840–3850PubMedGoogle Scholar
  56. Roberts AI, Lee L, Schwarz E, Groh V, Spies T, Ebert EC, Jabri B (2001) NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J Immunol 167:5527–5530PubMedGoogle Scholar
  57. Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V (2013) Granule exocytosis mediates immune surveillance of senescent cells. Oncogene 32:1971–1977PubMedCrossRefGoogle Scholar
  58. Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, Lowe SW (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109:335–346PubMedCrossRefGoogle Scholar
  59. Schnabl B, Purbeck CA, Choi YH, Hagedorn CH, Brenner D (2003) Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology 37:653–664PubMedCrossRefGoogle Scholar
  60. Semerad CL, Poursine-Laurent J, Liu F, Link DC (1999) A role for G-CSF receptor signaling in the regulation of hematopoietic cell function but not lineage commitment or differentiation. Immunity 11:153–161PubMedCrossRefGoogle Scholar
  61. Semerad CL, Liu F, Gregory AD, Stumpf K, Link DC (2002) G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 17:413–423PubMedCrossRefGoogle Scholar
  62. Shi C, Pamer EG (2011) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11:762–774PubMedCrossRefGoogle Scholar
  63. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795PubMedCrossRefGoogle Scholar
  64. Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, Cippitelli M, Fionda C, Petrucci MT, Guarini A et al (2009) ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113:3503–3511PubMedCrossRefGoogle Scholar
  65. te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP (2002) DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 62:1876–1883Google Scholar
  66. Tseng SY, Dustin ML (2002) T-cell activation: a multidimensional signaling network. Curr Opin Cell Biol 14:575–580PubMedCrossRefGoogle Scholar
  67. von Andrian UH, Mackay CR (2000) T-cell function and migration. Two sides of the same coin. N Engl J Med 343:1020–1034CrossRefGoogle Scholar
  68. Woollard KJ, Geissmann F (2010) Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 7:77–86PubMedCrossRefGoogle Scholar
  69. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660PubMedCrossRefGoogle Scholar
  70. Yawalkar N, Schmid S, Braathen LR, Pichler WJ (2001) Perforin and granzyme B may contribute to skin inflammation in atopic dermatitis and psoriasis. Br J Dermatol 144:1133–1139PubMedCrossRefGoogle Scholar
  71. Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, Tavare S, Arakawa S, Shimizu S, Watt FM (2009) Autophagy mediates the mitotic senescence transition. Genes Dev 23:798–803PubMedCrossRefGoogle Scholar
  72. Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael

Personalised recommendations