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Telomeres in T and B cells

Key Points

  • Telomeres are structures at the ends of linear eukaryotic chromosomes. Mammalian telomeres consist of hexanucleotide (TTAGGG)n repeats and several protein components.

  • In the absence of compensatory mechanisms, telomeres shorten with each cell division due to incomplete replication of chromosomal termini.

  • Telomeres are crucial for several functions, including the maintenance of chromosomal integrity and replicative capacity. When telomeres reach a critically short length, or lose functional integrity due to other alterations in the telomeric complex, cells are prone to apoptotic death and/or replicative senescence, a state in which no further cell division occurs.

  • Human T and B cells undergo telomere shortening with age, as has been observed for other somatic cells. The functional consequences of this shortening for human immune function are unknown.

  • The best-characterized compensatory mechanism for the maintenance of telomere length in the face of cell division is mediated by telomerase, an enzyme that can synthesize terminal telomere repeats. Telomerase is a unique enzyme consisting of an RNA-template component that encodes telomeric DNA and a catalytic-protein component that is an RNA-dependent DNA polymerase or reverse transcriptase.

  • Telomerase is expressed at high levels in germ-line cells and most cancer cells. Most normal somatic cells express little or no telomerase enzymatic activity and, therefore, undergo progressive telomere shortening with cell division.

  • The function of T and B cells in the immune response is highly dependent on extensive cell division and clonal expansion. In contrast to many other somatic-cell lineages, T and B cells express high levels of telomerase activity at regulated stages of development and after the activation of mature T and B cells. Telomerase might have a role in at least partially compensating for telomere loss in dividing lymphocytes.

  • A definitive role for telomerase or telomere-length change has not been established during normal human immune responses. However, several lines of evidence indicate that abnormalities in telomerase and telomere-length maintenance can affect somatic-cell function, including immune function. Such evidence has been provided by mouse models of telomerase deficiency and by a recently characterized human genetic syndrome, dyskeratosis congenita, that is marked by abnormal telomerase function.

Abstract

Telomeres are the structures at the ends of linear chromosomes. In mammalian cells, they consist of hexanucleotide (TTAGGG) repeats, together with many associated proteins. In the absence of a compensatory mechanism, dividing cells undergo gradual telomere erosion until a critical degree of shortening results in chromosomal abnormalities and cell death or senescence. For T and B cells, the ability to undergo extensive cell division and clonal expansion is crucial for effective immune function. This article describes our current understanding of telomere-length regulation in lymphocytes and its implications for immune function.

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Figure 1: Telomere length increases with the differentiation of naive to germinal-centre B cells.
Figure 2: The relationship between cell division and telomere length is not constant.

References

  1. 1

    Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    CAS  Article  Google Scholar 

  2. 2

    McEachern, M. J., Krauskopf, A. & Blackburn, E. H. Telomeres and their control. Annu. Rev. Genet. 34, 331–358 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Blackburn, E. H. Switching and signaling at the telomere. Cell 106, 661–673 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Greider, C. W. Telomere length regulation. Annu. Rev. Biochem. 65, 337–365 (1996).

    CAS  Article  Google Scholar 

  5. 5

    Blasco, M. A., Funk, W., Villeponteau, B. & Greider, C. W. Functional characterization and developmental regulation of mouse telomerase. Science 269, 1267–1270 (1995).

    CAS  Article  Google Scholar 

  6. 6

    Feng, J. et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Meyerson, M. et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90, 785–795 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Nakamura, T. M. et al. The telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959 (1997).

    CAS  Article  Google Scholar 

  9. 9

    Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    CAS  Article  Google Scholar 

  10. 10

    Weng, N. P., Levine, B. L., June, C. H. & Hodes, R. J. Regulated expression of telomerase activity in human T-lymphocyte development and activation. J. Exp. Med. 183, 2471–2479 (1996).

    CAS  Article  Google Scholar 

  11. 11

    Weng, N. P., Granger, L. & Hodes, R. J. Regulation of telomere length and telomerase expression in human B-lymphocyte subsets. Proc. Natl Acad. Sci. USA 94, 10827–10832 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Weng, N. P., Hathcock, K. S. & Hodes, R. J. Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential. Immunity 9, 151–157 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Hiyama, K. et al. Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J. Immunol. 155, 3711–3715 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Bodnar, A. G., Kim, N. W., Effros, R. B. & Chiu, C. P. Mechanism of telomerase induction during T-cell activation. Exp. Cell Res. 228, 58–64 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Ogoshi, M., Takashima, A. & Taylor, R. S. Mechanisms regulating telomerase activity in murine T cells. J. Immunol. 158, 622–628 (1997).

    CAS  PubMed  Google Scholar 

  16. 16

    Norrback, K. F., Dahlenborg, K., Carlsson, R. & Roos, G. Telomerase activation in normal B lymphocytes and non-Hodgkins lymphomas. Blood 88, 222–229 (1996).

    CAS  PubMed  Google Scholar 

  17. 17

    Igarashi, H. & Sakaguchi, N. Telomerase activity is induced in human peripheral B lymphocytes by the stimulation to antigen receptor. Blood 89, 1299–1307 (1997).

    CAS  PubMed  Google Scholar 

  18. 18

    Hu, B. T., Lee, S. C., Marin, E., Ryan, D. H. & Insel, R. A. Telomerase is up-regulated in human germinal-center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J. Immunol. 159, 1068–1071 (1997).

    CAS  PubMed  Google Scholar 

  19. 19

    Wright, W. E. & Shay, J. W. Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nature Med. 6, 849–851 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Akbar, A. N., Soares, M. V., Plunkett, F. J. & Salmon, M. Differential regulation of CD8+ T-cell senescence in mice and men. Mech. Ageing Dev. 121, 69–76 (2000).

    CAS  Article  Google Scholar 

  21. 21

    Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    CAS  Article  Google Scholar 

  22. 22

    Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114–10118 (1992).

    CAS  Article  Google Scholar 

  23. 23

    Weng, N. P., Levine, B. L., June, C. H. & Hodes, R. J. Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc. Natl Acad. Sci. USA 92, 11091–11094 (1995).

    CAS  Article  Google Scholar 

  24. 24

    Son, N. H., Murray, S., Yanovski, J., Hodes, R. J. & Weng, N. P. Lineage-specific telomere shortening and unaltered capacity for telomerase expression in human T and B lymphocytes with age. J. Immunol. 165, 1191–1196 (2000).

    CAS  Article  Google Scholar 

  25. 25

    Frenck, R. W., Blackburn, E. H. & Shannon, K. M. The rate of telomere sequence loss in human leukocytes varies with age. Proc. Natl Acad. Sci. USA 95, 5607–5610 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Slagboom, P. E., Droog, S. & Boomsma, D. I. Genetic determination of telomere size in humans: a twin study of three age groups. Am. J. Hum. Genet. 55, 876–882 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Iwama, H. et al. Telomeric length and telomerase activity vary with age in peripheral blood cells obtained from normal individuals. Hum. Genet. 102, 397–402 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Rufer, N. 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. 190, 157–167 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Monteiro, J., Batliwalla, F., Ostrer, H. & Gregersen, P. K. Shortened telomeres in clonally expanded CD28CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J. Immunol. 156, 3587–3590 (1996).

    CAS  PubMed  Google Scholar 

  30. 30

    Effros, R. B. et al. Shortened telomeres in the expanded CD28-CD8+ subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 10, F17–F22 (1996).

    CAS  Article  Google Scholar 

  31. 31

    Maini, M. K., Soares, M. V. D., Zilch, C. F., Akbar, A. N. & Beverly, P. C. L. Virus-induced CD8+ T-cell clonal expansion is associated with telomerase up-regulation and telomere length preservation: a mechanism for rescue from replicative senescence. J. Immunol. 162, 4521–4526 (1999).

    CAS  PubMed  Google Scholar 

  32. 32

    Plunkett, F. J. et al. The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein–Barr virus infection. Blood 97, 700–707 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Hathcock, K. S., Weng, N. P., Merica, R., Jenkins, M. K. & Hodes, R. J. Antigen-dependent regulation of telomerase activity in murine T cells. J. Immunol. 160, 5702–5706 (1998).

    CAS  PubMed  Google Scholar 

  34. 34

    Weng, N. P. et al. Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation and aging. Immunol. Rev. 160, 43–54 (1997).

    CAS  Article  Google Scholar 

  35. 35

    Adibzadeh, M. et al. Lifespans of T lymphocytes. Mech. Ageing Dev. 91, 145–154 (1996).

    CAS  Article  Google Scholar 

  36. 36

    Hooijberg, E. et al. Immortalization of human CD8+ T-cell clones by ectopic expression of telomerase reverse transcriptase. J. Immunol. 165, 4239–4245 (2000).

    CAS  Article  Google Scholar 

  37. 37

    Rufer, N. et al. Transfer of the human telomerase reverse transcriptase (TERT) gene into T lymphocytes results in extension of replicative potential. Blood 98, 597–603 (2001).

    CAS  Article  Google Scholar 

  38. 38

    Kelsoe, G. In situ studies of the germinal-center reaction. Adv. Immunol. 60, 267–288 (1995).

    CAS  Article  Google Scholar 

  39. 39

    Zhang, J., MacLennan, I. C., Liu, Y. & Lane, P. Is rapid proliferation in B centroblasts linked to somatic mutation in memory B-cell clones? Immunol. Lett. 18, 297–300 (1988).

    CAS  Article  Google Scholar 

  40. 40

    Herrera, E., Martínez-A, C. & Blasco, M. A. Impaired germinal-center reaction in mice with short telomeres. EMBO J. 19, 472–481 (2000).

    CAS  Article  Google Scholar 

  41. 41

    Allsopp, R. C., Cheshier, S. & Weissman, I. L. Telomere shortening accompanies cell-cycle activity during serial transplantation of hematopoietic stem cells. J. Exp. Med. 193, 917–924 (2001).

    CAS  Article  Google Scholar 

  42. 42

    Vaziri, H. et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc. Natl Acad. Sci. USA 91, 9857–9860 (1994).

    CAS  Article  Google Scholar 

  43. 43

    Morrison, S. J., Prowse, K. R., Ho, P. & Weissman, I. L. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5, 207–216 (1996).

    CAS  Article  Google Scholar 

  44. 44

    Blasco, M. A. et al. Telomerase shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    CAS  Article  Google Scholar 

  45. 45

    Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998).

    CAS  Article  Google Scholar 

  46. 46

    Rudolph, K. L., et al. Longevity, stress response and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).

    CAS  Article  Google Scholar 

  47. 47

    Mitchell, J. R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999).

    CAS  Article  Google Scholar 

  48. 48

    Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001).

    CAS  Article  Google Scholar 

  49. 49

    Zhu, L. et al. Telomere length regulation in mice is linked to a novel chromosome locus. Proc. Natl Acad. Sci. USA 95, 8648–8653 (1998).

    CAS  Article  Google Scholar 

  50. 50

    Hathcock, K. S. et al. Haploinsufficiency of mTR results in defects in telomere elongation. Proc. Natl Acad. Sci. USA 99, 3591–3596 (2002).

    CAS  Article  Google Scholar 

  51. 51

    Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998).

    CAS  Article  Google Scholar 

  52. 52

    Liu, K., Hodes, R. J. & Weng, N. P. Telomerase activation in human lymphocytes does not require increase in telomere reverse transcriptase (hTERT) protein, but is associated with hTERT phosphorylation and nuclear translocation. J. Immunol. 166, 4826–4830 (2001).

    CAS  Article  Google Scholar 

  53. 53

    Wolthers, K. C. et al. T-cell telomere length in HIV-1 infection: no evidence for increased CD4+ T-cell turnover. Science 274, 1543–1547 (1996).

    CAS  Article  Google Scholar 

  54. 54

    Palmer, L. D. et al. Telomere length, telomerase activity and replicative potential in HIV infection: differences in telomere length in CD4+ and CD8+ T cells from HIV-discordant monozygotic twins. J. Exp. Med. 185, 1381–1386 (1997).

    CAS  Article  Google Scholar 

  55. 55

    Hemann, M. T., Strong, M. A., Hao, L. Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).

    CAS  Article  Google Scholar 

  56. 56

    Steinert, S., Shay, J. W. & Wright, W. E. Transient expression of human telomerase extends the life span of normal human fibroblasts. Biochem. Biophys. Res. Commun. 273, 1095–1098 (2000).

    CAS  Article  Google Scholar 

  57. 57

    Bryan, T. M., Englezou, A., Dalla-Pozza, L., Dunham, M. A. & Reddel, R. R. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nature Med. 3, 1271–1274 (1997).

    CAS  Article  Google Scholar 

  58. 58

    Griffith, J. D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999).

    CAS  Article  Google Scholar 

  59. 59

    De Lange, T. Protection of mammalian telomeres. Oncogene 21, 532–540 (2002).

    CAS  Article  Google Scholar 

  60. 60

    Van Steensel, B. & de Lange, T. Control of telomere length by the human telomeric protein TRF1. Nature 385, 740–743 (1997).

    CAS  Article  Google Scholar 

  61. 61

    Karlseder, J., Broccoli, D., Dai, Y., Hardy, S. & de Lange, T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321–1325 (1999).

    CAS  Article  Google Scholar 

  62. 62

    Baumnn, P. & Cech, T. R. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292, 1171–1175 (2001).

    Article  Google Scholar 

  63. 63

    Hsu, H. L., Gilley, D., Blackburn, E. H. & Chen, D. J. Ku is associated with the telomere in mammals. Proc. Natl Acad. Sci. USA 96, 12454–12458 (1999).

    CAS  Article  Google Scholar 

  64. 64

    Zhu, X. D., Kuster, B., Mann, M., Petrini, J. H. & de Lange, T. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nature Genet. 25, 347–352 (2000).

    CAS  Article  Google Scholar 

  65. 65

    Zijlmans, J. M. et al. Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats. Proc. Natl Acad. Sci. USA 94, 7423–7428 (1997).

    CAS  Article  Google Scholar 

  66. 66

    Rufer, N., Dragowska, W., Thornbury, G., Roosnek, E. & Lansdorp, P. M. Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nature Biotechnol. 16, 743–747 (1998).

    CAS  Article  Google Scholar 

  67. 67

    von Zglinicki, T. Role of oxidative stress in telomere length regulation and replicative senescence. Ann. NY Acad. Sci. 908, 99–110 (2000).

    CAS  Article  Google Scholar 

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Correspondence to Richard J. Hodes.

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DATABASES

Entrez

EBV

HIV-1

LocusLink

CD3

CD28

dyskerin

Ku

MRE11

mTR

NBS

RAD50

TERT

TR

TRF1

TRF2

OMIM

autosomal-dominant DKC

X-linked DKC

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Hodes, R., Hathcock, K. & Weng, Np. Telomeres in T and B cells. Nat Rev Immunol 2, 699–706 (2002). https://doi.org/10.1038/nri890

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