Immunologic Research

, Volume 49, Issue 1–3, pp 44–48

The long and the short of telomeres in bone marrow recipient SCID patients

  • Marcella Sarzotti-Kelsoe
  • Xiaoju G. Daniell
  • John F. Whitesides
  • Rebecca H. Buckley
Article

Abstract

Telomeres are noncoding DNA regions at the end of the chromosomes that are crucial for genome stability. Since telomere length decreases with cell division, they can be used as a signature of cell proliferation history. T-cell reconstitution in severe combined immunodeficiency (SCID) subjects, recipients of T-cell-depleted, allogeneic-related bone marrow cells, is due to the development and maturation of donor T-cell precursors in the infant’s vestigial thymus and to homeostatic proliferation of mature T cells in the peripheral organs. Since T-cell function, thymic output, and T-cell clonal diversity are maintained long term in these patients, we investigated whether donor T-cell engraftment resulted in increased telomere shortening. Our study of seven SCID patients, following successful bone marrow transplantation, demonstrates that the patients’ peripheral T cells did not exhibit greater than normal telomere shortening.

Keywords

SCID Telomere Transplantation T cell TREC 

References

  1. 1.
    Szostak JW, Blackburn EH. Cloning yeast telomeres on linear plasmid vectors. Cell. 1982;1:245–55.CrossRefGoogle Scholar
  2. 2.
    Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43:405–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Lansdorp PM. Major cutbacks at chromosome ends. Trends Biochem. 2005;30:388–95.CrossRefGoogle Scholar
  4. 4.
    Harley CB, Futcher AB, Greiner CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60.PubMedCrossRefGoogle Scholar
  5. 5.
    Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13:1549–56.PubMedCrossRefGoogle Scholar
  6. 6.
    Hathcock KS, Chiang YJ, Hodes RJ. In vivo regulation of telomerase activity and telomere length. Immunol Rev. 2005;205:104–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Li Y, Zhi W, Wareski P, Weng N. IL-15 activates telomerase and minimizes telomere loss and may preserve the replicative life span of memory CD8 + T cells in vitro. J Immunol. 2005;174:4019–24.PubMedGoogle Scholar
  8. 8.
    Lansdorp PM. Telomeres, stem cells, and hematology. Blood. 2008;111:1759–66.PubMedCrossRefGoogle Scholar
  9. 9.
    Marleau AM, Sarvetnick N. T cell homeostasis in tolerance and immunity. J Leukoc Biol. 2005;78:575–84.PubMedCrossRefGoogle Scholar
  10. 10.
    Awaya N, Baerlocher GM, Manley TJ, et al. Telomere shortening in hematopoietic stem cell transplantation: a potential mechanism for late graft failure? Biol Blood Marrow Transplant. 2002;8:597–600.PubMedCrossRefGoogle Scholar
  11. 11.
    Notaro R, Cimmino A, Tabarini D, et al. In vivo telomere dynamics of human hematopoietic stem cells. PNAS. 1997;94:13782–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999;340:508–16.PubMedCrossRefGoogle Scholar
  13. 13.
    Patel DD, Gooding ME, Parrott RE, et al. Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 2000;342:1325–32.PubMedCrossRefGoogle Scholar
  14. 14.
    Sarzotti M, Patel DD, Li X, et al. T cell repertoire development in humans with SCID after nonablative allogeneic marrow transplantation. J Immunol. 2003;170:2711–8.PubMedGoogle Scholar
  15. 15.
    Sarzotti-Kelsoe M, Win CM, Parrott RE, et al. Thymic output, T cell diversity and T cell function in long-term human SCID Chimeras. Blood. 2009;114:1445–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Baerlocher GM, Vulto I, de Jong G. Lansdorp. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc. 2006;1:2365–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Kapoor V, Hakim FT, Rehman N, et al. Quantum dots thermal stability improves simultaneous phenotype-specific telomere length measurement by FISH-flow cytometry. J Immunol Meth. 2009;344:6–14.CrossRefGoogle Scholar
  18. 18.
    Rufer N, Brummendorf TH, Kolvraa S, et al. Telomere fluorescence Measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med. 1999;190:157–67.PubMedCrossRefGoogle Scholar
  19. 19.
    Borghans JA, Bredius RG, Hazenberg MD, et al. Early determinants of long-term T-cell reconstitution after hematopoietic stem cell transplantation for severe combined immunodeficiency. Blood. 2006;108:763–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Palmer LD, Weng N, Levine B, et al. Telomere length, telomerase activity, and replicative potential in HIV infection: analysis of CD4 + and CD8 + T cells from HIV-discordant monozygotic twins. J Exp Med. 1997;185:1381–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Schwarz K, Gauss GH, Ludwig L, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274:97–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Marcella Sarzotti-Kelsoe
    • 1
    • 2
  • Xiaoju G. Daniell
    • 2
  • John F. Whitesides
    • 3
  • Rebecca H. Buckley
    • 1
    • 4
  1. 1.Department of ImmunologyDuke University Medical CenterDurhamUSA
  2. 2.Department of SurgeryDuke University Medical CenterDurhamUSA
  3. 3.Department of MedicineDuke University Medical CenterDurhamUSA
  4. 4.Department of PediatricsDuke University Medical CenterDurhamUSA

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