Skip to main content

Advertisement

SpringerLink
Log in

Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces “aging-like” effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Trowell OA (1952) The sensitivity of lymphocytes to ionising radiation. J Pathol Bacteriol 64(4):687–704

    Article  CAS  PubMed  Google Scholar 

  2. Goldrath AW, Bevan MJ (1999) Selecting and maintaining a diverse T-cell repertoire. Nature 402(6759):255–262. doi:10.1038/46218

    Article  CAS  PubMed  Google Scholar 

  3. Nikolich-Zugich J, Slifka MK, Messaoudi I (2004) The many important facets of T-cell repertoire diversity. Nat Rev Immunol 4(2):123–132. doi:10.1038/nri1292

    Article  CAS  PubMed  Google Scholar 

  4. Gardner ID (1980) The effect of aging on susceptibility to infection. Rev Infect Dis 2(5):801–810

    Article  CAS  PubMed  Google Scholar 

  5. Yu HT, Park S, Shin EC, Lee WW (2015) T cell senescence and cardiovascular diseases. Clin Exp Med. doi:10.1007/s10238-015-0376-z

    Google Scholar 

  6. Haynes L, Swain SL (2012) Aged-related shifts in T cell homeostasis lead to intrinsic T cell defects. Semin Immunol 24(5):350–355. doi:10.1016/j.smim.2012.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kamiya K, Ozasa K, Akiba S, Niwa O, Kodama K, Takamura N, Zaharieva EK, Kimura Y, Wakeford R (2015) Long-term effects of radiation exposure on health. Lancet 386(9992):469–478. doi:10.1016/S0140-6736(15)61167-9

    Article  CAS  PubMed  Google Scholar 

  8. Preston DL, Pierce DA, Shimizu Y, Cullings HM, Fujita S, Funamoto S, Kodama K (2004) Effect of recent changes in atomic bomb survivor dosimetry on cancer mortality risk estimates. Radiat Res 162(4):377–389

    Article  CAS  PubMed  Google Scholar 

  9. Hsu WL, Preston DL, Soda M, Sugiyama H, Funamoto S, Kodama K, Kimura A, Kamada N, Dohy H, Tomonaga M, Iwanaga M, Miyazaki Y, Cullings HM, Suyama A, Ozasa K, Shore RE, Mabuchi K (2013) The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950-2001. Radiat Res 179(3):361–382. doi:10.1667/RR2892.1

    Article  CAS  PubMed  Google Scholar 

  10. Major IR (1979) Induction of myeloid leukaemia by whole-body single exposure of CBA male mice to X-rays. Br J Cancer 40(6):903–913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Suraweera N, Meijne E, Moody J, Carvajal-Carmona LG, Yoshida K, Pollard P, Fitzgibbon J, Riches A, van Laar T, Huiskamp R, Rowan A, Tomlinson IP, Silver A (2005) Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia. Oncogene 24(22):3678–3683. doi:10.1038/sj.onc.1208422

    Article  CAS  PubMed  Google Scholar 

  12. Verbiest T, Bouffler S, Nutt SL, Badie C (2015) PU.1 downregulation in murine radiation-induced acute myeloid leukaemia (AML): from molecular mechanism to human AML. Carcinogenesis 36(4):413–419. doi:10.1093/carcin/bgv016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Goodhead DT (2009) Fifth Warren K. Sinclair Keynote Address: issues in quantifying the effects of low-level radiation. Health Phys 97(5):394–406. doi:10.1097/HP.0b013e3181ae8acf

    Article  CAS  PubMed  Google Scholar 

  14. Mettler FA Jr, Bhargavan M, Faulkner K, Gilley DB, Gray JE, Ibbott GS, Lipoti JA, Mahesh M, McCrohan JL, Stabin MG, Thomadsen BR, Yoshizumi TT (2009) Radiologic and nuclear medicine studies in the United States and worldwide: frequency, radiation dose, and comparison with other radiation sources—1950–2007. Radiology 253(2):520–531. doi:10.1148/radiol.2532082010

    Article  PubMed  Google Scholar 

  15. Kusunoki Y, Hayashi T, Morishita Y, Yamaoka M, Maki M, Bean MA, Kyoizumi S, Hakoda M, Kodama K (2001) T-cell responses to mitogens in atomic bomb survivors: a decreased capacity to produce interleukin 2 characterizes the T cells of heavily irradiated individuals. Radiat Res 155(1 Pt 1):81–88

    Article  CAS  PubMed  Google Scholar 

  16. Kusunoki Y, Yamaoka M, Kasagi F, Hayashi T, MacPhee DG, Kyoizumi S (2003) Long-lasting changes in the T-cell receptor V beta repertoires of CD4 memory T-cell populations in the peripheral blood of radiation-exposed people. Br J Haematol 122(6):975–984

    Article  CAS  PubMed  Google Scholar 

  17. Kusunoki Y, Yamaoka M, Kubo Y, Hayashi T, Kasagi F, Douple EB, Nakachi K (2010) T-cell immunosenescence and inflammatory response in atomic bomb survivors. Radiat Res 174(6):870–876. doi:10.1667/RR1847.1

    Article  CAS  PubMed  Google Scholar 

  18. Yamaoka M, Kusunoki Y, Kasagi F, Hayashi T, Nakachi K, Kyoizumi S (2004) Decreases in percentages of naive CD4 and CD8 T cells and increases in percentages of memory CD8 T-cell subsets in the peripheral blood lymphocyte populations of A-bomb survivors. Radiat Res 161(3):290–298

    Article  CAS  PubMed  Google Scholar 

  19. Gyuleva IM, Penkova KI, Rupova IT, Panova DY, Djounova JN (2015) Assessment of some immune parameters in occupationally exposed nuclear power plant workers: flow cytometry measurements of T lymphocyte subpopulations and immunoglobulin determination. Dose Response 13(4):1–11. doi:10.1177/1559325815611901

    Article  Google Scholar 

  20. Rybkina VL, Azizova TV, Scherthan H, Meineke V, Doerr H, Adamova GV, Teplyakova OV, Osovets SV, Bannikova MV, Zurochka AV (2014) Expression of blood serum proteins and lymphocyte differentiation clusters after chronic occupational exposure to ionizing radiation. Radiat Environ Biophys 53(4):659–670. doi:10.1007/s00411-014-0556-3

    Article  CAS  PubMed  Google Scholar 

  21. Scherthan H, Abend M, Muller K, Beinke C, Braselmann H, Zitzelsberger H, Kohn FM, Pillekamp H, Schiener R, Das O, Peter RU, Herzog G, Tzschach A, Dorr HD, Fliedner TM, Meineke V (2007) Radiation-induced late effects in two affected individuals of the Lilo radiation accident. Radiat Res 167(5):615–623. doi:10.1667/RR0774.1

    Article  CAS  PubMed  Google Scholar 

  22. Chambers KA, Harrington NP, Ross WM, Filion LG (1998) Relative alterations in blood mononuclear cell populations reflect radiation injury in mice. Cytometry 31(1):45–52

    Article  CAS  PubMed  Google Scholar 

  23. Mullenders L, Atkinson M, Paretzke H, Sabatier L, Bouffler S (2009) Assessing cancer risks of low-dose radiation. Nat Rev Cancer 9(8):596–604. doi:10.1038/nrc2677

    Article  CAS  PubMed  Google Scholar 

  24. Rees GS, Daniel CP, Morris SD, Whitehouse CA, Binks K, MacGregor DH, Tawn EJ (2004) Occupational exposure to ionizing radiation has no effect on T- and B-cell total counts or percentages of helper, cytotoxic and activated T-cell subsets in the peripheral circulation of male radiation workers. Int J Radiat Biol 80(7):493–498

    Article  CAS  PubMed  Google Scholar 

  25. Bogdandi EN, Balogh A, Felgyinszki N, Szatmari T, Persa E, Hildebrandt G, Safrany G, Lumniczky K (2010) Effects of low-dose radiation on the immune system of mice after total-body irradiation. Radiat Res 174(4):480–489. doi:10.1667/RR2160.1

    Article  CAS  PubMed  Google Scholar 

  26. Lacoste-Collin L, Jozan S, Cances-Lauwers V, Pipy B, Gasset G, Caratero C, Courtade-Saidi M (2007) Effect of continuous irradiation with a very low dose of gamma rays on life span and the immune system in SJL mice prone to B-cell lymphoma. Radiat Res 168(6):725–732. doi:10.1667/RR1007.1

    Article  CAS  PubMed  Google Scholar 

  27. Davis MM, Bjorkman PJ (1988) T-cell antigen receptor genes and T-cell recognition. Nature 334(6181):395–402. doi:10.1038/334395a0

    Article  CAS  PubMed  Google Scholar 

  28. Hoffman ES, Passoni L, Crompton T, Leu TM, Schatz DG, Koff A, Owen MJ, Hayday AC (1996) Productive T-cell receptor beta-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo. Genes Dev 10(8):948–962

    Article  CAS  PubMed  Google Scholar 

  29. Outters P, Jaeger S, Zaarour N, Ferrier P (2015) Long-range control of V(D)J recombination and allelic exclusion: modeling views. Adv Immunol 128:363–413. doi:10.1016/bs.ai.2015.08.002

    Article  PubMed  Google Scholar 

  30. Witherden D, van Oers N, Waltzinger C, Weiss A, Benoist C, Mathis D (2000) Tetracycline-controllable selection of CD4(+) T cells: half-life and survival signals in the absence of major histocompatibility complex class II molecules. J Exp Med 191(2):355–364

    Article  CAS  PubMed  Google Scholar 

  31. Attaf M, Legut M, Cole DK, Sewell AK (2015) The T cell antigen receptor: the Swiss army knife of the immune system. Clin Exp Immunol 181(1):1–18. doi:10.1111/cei.12622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Verbiest T, Finnon R, Brown N, Finnon P, Bouffler S, Badie C (2016) NOD scid gamma mice are permissive to allogeneic HSC transplantation without prior conditioning. Int J Mol Sci 17(11):E1850. doi:10.3390/ijms17111850

    Article  PubMed  Google Scholar 

  33. Vandervieren E, Hubert M (2004) An adjusted boxplot for skewed distribution. In: Antoch J (ed) Proceedings in computational statistics. Springer, Heidelberg, pp 1933–1940

    Google Scholar 

  34. Lefranc MP, Giudicelli V, Ginestoux C, Jabado-Michaloud J, Folch G, Bellahcene F, Wu Y, Gemrot E, Brochet X, Lane J, Regnier L, Ehrenmann F, Lefranc G, Duroux P (2009) IMGT, the international ImMunoGeneTics information system. Nucleic Acids Res 37(Database issue):D1006–D1012. doi:10.1093/nar/gkn838

    Article  CAS  PubMed  Google Scholar 

  35. Pielou EC (1966) Measurement of diversity in different types of biological collections. J Theor Biol 13:131. doi:10.1016/0022-5193(66)90013-0

    Article  Google Scholar 

  36. Hutcheson K (1970) A test for comparing diversities based on Shannon formula. J Theor Biol 29(1):151. doi:10.1016/0022-5193(70)90124-4

    Article  CAS  PubMed  Google Scholar 

  37. Bonferroni CE (1936) Teoria statistica delle classi e calcolo delle probabilità. Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commerciali di Firenze

  38. Cohen J (1977) The t test for means. In: Press A (ed) Statistical power analysis for the behavioral sciences, revised edition. Academic Press, New York, pp 19–74

    Chapter  Google Scholar 

  39. Nikolich-Zugich J (2014) Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol 193(6):2622–2629. doi:10.4049/jimmunol.1401174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bauer ME, Fuente Mde L (2016) The role of oxidative and inflammatory stress and persistent viral infections in immunosenescence. Mech Ageing Dev 158:27–37. doi:10.1016/j.mad.2016.01.001

    Article  CAS  PubMed  Google Scholar 

  41. McLean-Tooke A, Barge D, Spickett GP, Gennery AR (2008) T cell receptor Vbeta repertoire of T lymphocytes and T regulatory cells by flow cytometric analysis in healthy children. Clin Exp Immunol 151(1):190–198. doi:10.1111/j.1365-2249.2007.03536.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dudley EC, Petrie HT, Shah LM, Owen MJ, Hayday AC (1994) T cell receptor beta chain gene rearrangement and selection during thymocyte development in adult mice. Immunity 1(2):83–93

    Article  CAS  PubMed  Google Scholar 

  43. Chen H, Yang T, Zhu L, Zhao Y (2015) Cellular metabolism on T-cell development and function. Int Rev Immunol 34(1):19–33. doi:10.3109/08830185.2014.902452

    Article  CAS  PubMed  Google Scholar 

  44. Ciofani M, Zuniga-Pflucker JC (2005) Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 6(9):881–888. doi:10.1038/ni1234

    Article  CAS  PubMed  Google Scholar 

  45. Bleul CC, Boehm T (2000) Chemokines define distinct microenvironments in the developing thymus. Eur J Immunol 30(12):3371–3379. doi:10.1002/1521-4141(2000012)30:12<3371:AID-IMMU3371>3.0.CO;2-L

    Article  CAS  PubMed  Google Scholar 

  46. Rothenberg EV (2014) The chromatin landscape and transcription factors in T cell programming. Trends Immunol 35(5):195–204. doi:10.1016/j.it.2014.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Serhan CN, Savill J (2005) Resolution of inflammation: the beginning programs the end. Nat Immunol 6(12):1191–1197. doi:10.1038/ni1276

    Article  CAS  PubMed  Google Scholar 

  48. El-Saghire H, Thierens H, Monsieurs P, Michaux A, Vandevoorde C, Baatout S (2013) Gene set enrichment analysis highlights different gene expression profiles in whole blood samples X-irradiated with low and high doses. Int J Radiat Biol 89(8):628–638. doi:10.3109/09553002.2013.782448

    Article  CAS  PubMed  Google Scholar 

  49. El-Saghire H, Michaux A, Thierens H, Baatout S (2013) Low doses of ionizing radiation induce immune-stimulatory responses in isolated human primary monocytes. Int J Mol Med 32(6):1407–1414. doi:10.3892/ijmm.2013.1514

    Article  CAS  PubMed  Google Scholar 

  50. Candeias SM, Testard I (2015) The many interactions between the innate immune system and the response to radiation. Cancer Lett 368(2):173–178. doi:10.1016/j.canlet.2015.02.007

    Article  CAS  PubMed  Google Scholar 

  51. Lowe JM, Menendez D, Bushel PR, Shatz M, Kirk EL, Troester MA, Garantziotis S, Fessler MB, Resnick MA (2014) p53 and NF-kappaB coregulate proinflammatory gene responses in human macrophages. Cancer Res 74(8):2182–2192. doi:10.1158/0008-5472.CAN-13-1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sabatel H, Di Valentin E, Gloire G, Dequiedt F, Piette J, Habraken Y (2012) Phosphorylation of p65(RelA) on Ser(547) by ATM represses NF-kappaB-dependent transcription of specific genes after genotoxic stress. PLoS One 7(6):e38246. doi:10.1371/journal.pone.0038246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Seki H, Iwai K, Kanegane H, Konno A, Ohta K, Ohta K, Yachie A, Taniguchi N, Miyawaki T (1995) Differential protective action of cytokines on radiation-induced apoptosis of peripheral lymphocyte subpopulations. Cell Immunol 163(1):30–36. doi:10.1006/cimm.1995.1095

    Article  CAS  PubMed  Google Scholar 

  54. Sempowski GD, Hale LP, Sundy JS, Massey JM, Koup RA, Douek DC, Patel DD, Haynes BF (2000) Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol 164(4):2180–2187

    Article  CAS  PubMed  Google Scholar 

  55. Rothkamm K, Lobrich M (2003) Evidence for a lack of DNA double-strand break repair in human cells exposed to very low X-ray doses. Proc Natl Acad Sci USA 100(9):5057–5062. doi:10.1073/pnas.0830918100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gentil Dit Maurin A, Lemercier C, Collin-Faure V, Marche PN, Jouvin-Marche E, Candeias SM (2015) Developmental regulation of p53-dependent radiation-induced thymocyte apoptosis in mice. Clin Exp Immunol 179(1):30–38. doi:10.1111/cei.12329

    Article  CAS  PubMed  Google Scholar 

  57. Sprent J, Surh CD (2011) Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat Immunol 12(6):478–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Min B, McHugh R, Sempowski GD, Mackall C, Foucras G, Paul WE (2003) Neonates support lymphopenia-induced proliferation. Immunity 18(1):131–140

    Article  CAS  PubMed  Google Scholar 

  59. Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10(12):826–837. doi:10.1038/nri2873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Schaue D, Kachikwu EL, McBride WH (2012) Cytokines in radiobiological responses: a review. Radiat Res 178(6):505–523. doi:10.1667/RR3031.1

    Article  PubMed  PubMed Central  Google Scholar 

  61. Pugh JL, Foster SA, Sukhina AS, Petravic J, Uhrlaub JL, Padilla-Torres J, Hayashi T, Nakachi K, Smithey MJ, Nikolich-Zugich J (2016) Acute systemic DNA damage in youth does not impair immune defense with aging. Aging Cell 15(4):686–693. doi:10.1111/acel.12478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work has been supported by the European Commissions [DoReMi, European Atomic Energy Community’s Seventh Framework Program (FP7/2007–2011) under Grant Agreement No. 249689] and National Science Centre Grants HARMONIA 4 No. 2013/08/M/ST6/00924 and OPUS No. 2015/19/B/ST6/01736 (JP). JM was supported by GeCONil project (POIG.02.03.01-24-099).

Author information

Authors and Affiliations

  1. CEA, Fundamental Research Division, Biosciences and Biotechnologies Institute, Laboratory of Chemistry and Biology of Metals, 38054, Grenoble, France

    Serge M. Candéias

  2. Laboratory of Chemistry and Biology of Metals, CNRS, UMR5249, 38054, Grenoble, France

    Serge M. Candéias

  3. Laboratory of Chemistry and Biology of Metals, UMR5249, University of Grenoble-Alpes, 38054, Grenoble, France

    Serge M. Candéias

  4. Data Mining Group, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Gliwice, Poland

    Justyna Mika & Joanna Polanska

  5. Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, CRCE, Public Health England, Didcot, UK

    Paul Finnon, Tom Verbiest, Rosemary Finnon, Natalie Brown, Simon Bouffler & Christophe Badie

Authors
  1. Serge M. Candéias
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Justyna Mika
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Finnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tom Verbiest
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rosemary Finnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Natalie Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Simon Bouffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joanna Polanska
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christophe Badie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Serge M. Candéias or Christophe Badie.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 1223 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Candéias, S.M., Mika, J., Finnon, P. et al. Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice. Cell. Mol. Life Sci. 74, 4339–4351 (2017). https://doi.org/10.1007/s00018-017-2581-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2581-2

Keywords

Search

Navigation