Regulation of Telomere Length and Telomerase in T and B Cells
1998; Cell Press; Volume: 9; Issue: 2 Linguagem: Inglês
10.1016/s1074-7613(00)80597-x
ISSN1097-4180
AutoresNan‐ping Weng, Karen S. Hathcock, Richard J. Hodes,
Tópico(s)T-cell and B-cell Immunology
ResumoPrior to antigenic stimulation, the precursor frequency of T cells or B cells with receptor specificity for any given antigen is extremely low, and it is the proliferative response to antigen that generates clonally expanded populations of effector cells as well as populations of long-lived memory cells that are capable of additional clonal expansion on reencounter with the same antigen. Thus, the ability of lymphocytes to undergo repeated cell division is essential for effective immune function. This review will focus on evidence suggesting that T and B lymphocytes, antigen-specific cells of the immune system, have adapted a mechanism otherwise used by malignant cells and germline cells to extend the replicative capacity necessary for lymphocyte function. In marked contrast to malignant cells and cells of the germline lineage, normal somatic cells have a finite capacity for cellular replication, as first demonstrated in the seminal observation of Hayflick that human fibroblasts cultured in vitro undergo a limited number of cell divisions before reaching a state termed replicative senescence, in which further cell division cannot occur (23Hayflick L The limited in vitro lifetime of human diploid cell strains.Exp. Cell Res. 1965; 37: 614-636Crossref PubMed Scopus (4044) Google Scholar). Recently, considerable attention has focused on the possible role of telomeres and telomere length regulation in determining the replicative capacity of normal somatic cells, transformed cells, and cells of germline lineage. The telomeric ends of chromosomes have been identified as a candidate for the "replicative clock" that monitors cell division and accounts for cessation of replication. Telomeres are complex DNA–protein structures at the ends of linear chromosomes; they are composed of hexameric DNA repeats, (TTAGGG)n in vertebrates, and a number of tolemere-associated proteins (reviewed in 1Blackburn E.H Structure and function of telomeres.Nature. 1991; 350: 569-573Crossref PubMed Scopus (2911) Google Scholar, 16Greider C.W Telomere length regulation.Annu. Rev. Biochem. 1996; 65: 337-365Crossref PubMed Scopus (879) Google Scholar). Telomeres appear to be important in maintaining the integrity of chromosomes, protecting against illegitimate fusion events such as the formation of dicentric chromosomes, mediating chromosomal localization in the nucleus, and possibly in mediating selective silencing of subtelomeric genes (reviewed in 16Greider C.W Telomere length regulation.Annu. Rev. Biochem. 1996; 65: 337-365Crossref PubMed Scopus (879) Google Scholar). As proposed by Watson (51Watson J Origin of concatemeric T7 DNA.Nat. New Biol. 1972; 239: 197-201Crossref PubMed Scopus (48) Google Scholar), the template priming requirement of DNA polymerases results in loss of terminal bases during lagging strand chromosomal replication, leading (in the absence of compensatory mechanisms) to the shortening of telomeres with each cell division. As a consequence, telomere length has the potential of acting as a mitotic clock, reflecting the summated outcome of prior chromosomal replication and providing a measure of the residual replicative capacity of cells prior to reaching a critically short telomere length, at which time processes are activated that result in clonal replicative senescence. Consistent with this model, telomere shortening has been identified in vivo in normal somatic tissues as a consequence of human aging as well as in in vitro cultured human fibroblasts (18Harley C.B Futcher A.B Greider C.W Telomeres shorten during ageing of human fibroblasts.Nature. 1990; 345: 458-460Crossref PubMed Scopus (4391) Google Scholar, 21Hastie N.D Dempster M Dunlop M.G Thompson A.M Green D.K Allshire R.C Telomere reduction in human colorectal carcinoma and with ageing.Nature. 1990; 346: 866-868Crossref PubMed Scopus (1445) Google Scholar, 32Lindsey J McGill N.I Lindsey L.A Green D.K Cooke H.J In vivo loss of telomeric repeats with age in humans.Mutat. Res. 1991; 256: 45-48Crossref PubMed Scopus (393) Google Scholar, 50Vaziri H Dragowska W Allsopp R.C Thomas T.E Harley C.B Lansdorp P.M Evidence for a mitotic clock in human hematopoietic stem cells loss of telomeric DNA with age.Proc. Natl. Acad. Sci. USA. 1994; 91: 9857-9860Crossref PubMed Scopus (989) Google Scholar, 10Chang E Harley C.B Telomere length and replicative aging in human vascular tissues.Proc. Natl. Acad. Sci. USA. 1995; 92: 11190-11194Crossref PubMed Scopus (526) Google Scholar). Transformed cells and germline cells appear to have an unlimited capacity to divide and proliferate, suggesting that a compensatory mechanism must exist capable of avoiding the consequences of telomere shortening. Indeed, one such mechanism is mediated by the ribonucleoprotein enzyme telomerase, a subject of intensive recent experimentation (reviewed in 2Blackburn E.H Telomerases.Annu. Rev. Biochem. 1992; 61: 113-129Crossref PubMed Scopus (572) Google Scholar, 16Greider C.W Telomere length regulation.Annu. Rev. Biochem. 1996; 65: 337-365Crossref PubMed Scopus (879) Google Scholar). The enzymatic activity termed telomerase is capable of synthesizing terminal TTAGGG telomeric repeats, thus extending telomere length and compensating for loss that occurs during chromosmal replication. Recent discoveries have identified the genes encoding two mammalian telomerase components, one a catalytic subunit that belongs to the reverse transcriptase family (19Harrington L Zhou W McPhail T Oulton R Yeung D.S Mar V Bass M.B Robinson M.O Human telomerase contains evolutionarily conserved catalytic and structural subunits.Genes Dev. 1997; 11 (a): 3109-3115Crossref PubMed Scopus (401) Google Scholar, 35Meyerson M Counter C.M Eaton E.N Ellisen L.W Steiner P Caddle S.D Ziaugra L Beijersbergen R.L Davidoff M.J Liu Q et al.hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization.Cell. 1997; 90: 785-795Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar, 38Nakamura T.M Morin G.B Chapman K.B Weinrich S.L Andrews W.H Lingner J Harley C.B Cech T.R Telomerase catalytic subunit homologs from fission yeast and human.Science. 1997; 277: 955-959Crossref PubMed Scopus (2002) Google Scholar, 39Nakayama J Tahara H Tahara E Saito M Ito K Nakamura H Nakanishi T Tahara E Ide T Ishikawa F Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas.Nat. Genet. 1998; 18: 65-68Crossref PubMed Scopus (575) Google Scholar) and the other an RNA template component (3Blasco M.A Funk W Villeponteau B Greider C.W Functional characterization and developmental regulation of mouse telomerase.Science. 1995; 269: 1267-1270Crossref PubMed Scopus (343) Google Scholar, 15Feng J Funk W.D Wang S.S Weinrich S.L Avilion A.A Chiu C.P Adama R.R Chang E Allsopp R.C Yu J et al.The RNA component of human telomerase.Science. 1995; 269: 1236-1241Crossref PubMed Scopus (2019) Google Scholar), which together are sufficient to reconstitute telomerase activity in vitro (52Weinrich S.L Pruzan R Ma L Ouellette M Tesmer V.M Holt S.E Bodnar A.G Lichtsteiner S Kim N.W Trager J.B et al.Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT.Nat. Genet. 1997; 17: 498-502Crossref PubMed Scopus (829) Google Scholar) (Figure 1). In addition, a number of telomere-binding or telomerase-binding proteins have been identified, some of which are functionally active in the regulation of telomere length (11Chong L van Steensel B Broccoli D Erdjument-Bromage H Hanish J Tempst P de Lange T A human telomeric protein.Science. 1995; 270: 1663-1667Crossref PubMed Scopus (601) Google Scholar: 19Harrington L Zhou W McPhail T Oulton R Yeung D.S Mar V Bass M.B Robinson M.O Human telomerase contains evolutionarily conserved catalytic and structural subunits.Genes Dev. 1997; 11 (a): 3109-3115Crossref PubMed Scopus (401) Google Scholar and 20Harrington L McPhail T Mar V Zhou W Oulton R Bass M.B Arruda I Robinson M.O A mammalian telomerase-associated protein.Science. 1997; 275 (b): 973-977Crossref PubMed Scopus (620) Google Scholar, 46Smith S de Lange T TRF1, a mammalian telomeric protein.Trends Genet. 1997; 13: 21-26Abstract Full Text PDF PubMed Scopus (105) Google Scholar, 48van Steensel B de Lange T Control of telomere length by the human telomeric protein TRF1.Nature. 1997; 385: 740-743Crossref PubMed Scopus (1025) Google Scholar, 47van Steensel B Smogorzewska A de Lange T TRF2 protects human telomeres from end-to-end fusions.Cell. 1998; 92: 401-413Abstract Full Text Full Text PDF PubMed Scopus (1391) Google Scholar). This review will summarize recent experimental findings that establish a clear relationship between telomere length and differentiation stage in both T and B cell lineages and demonstrate that there is stringent regulation of telomerase activity during T and B lymphocyte activation. These observations are consistent with a model in which maintenance of telomere length, mediated at least in part through the activity of telomerase, may function to support the capacity of lymphocytes for extensive clonal expansion. In addition to considering the limitations of currently available data in addressing this hypothesis, this review will discuss the opportunities created by recent genetic discoveries for more direct analysis of this seminal issue. Analysis of telomere length in human peripheral blood mononuclear cells reveals that telomere length decreases progressively with increasing age of the donor (45Slagboom 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. 1994; 55: 876-882PubMed Google Scholar), including telomere reduction in both CD4+ and CD8+ T cells with age. Telomere length decreases in both naive (CD45RA+) and memory (CD45RO+) human CD4+ T cells as a function of age at the rate of approximately 33 base pairs (bp) per year (54Weng N Levine B.L June C.H Hodes R.J Regulated expression of telomerase activity in human T lymphocyte development and activation.J. Exp. Med. 1996; 183: 2471-2479Crossref PubMed Scopus (352) Google Scholar). Strikingly, naive CD4+ T cells have longer telomeres than those of memory T cells from the same individual, suggesting that differentiation from naive to memory cells reflects cell division in vivo; the difference in telomere length in naive and memory cells is remarkably consistent (1.4 ± 0.1 kb) at all ages, suggesting that the differentiation of naive to memory T cells involves a relatively constant number of cell divisions independent of the donor's age. A similar difference in telomere length is also observed in comparisons of human CD8+ T cell subsets with CD28−CD8+ T cells, which may be derived from CD28+CD8+ T cells, exhibiting shorter telomeres than CD28+CD8+ T cells (36Monteiro J Batliwalla F Ostrer H Gregersen P.K Shortened telomeres in clonally expanded CD28−CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts.J. Immunol. 1996; 156: 3587-3590PubMed Google Scholar). Collectively, these results suggest that telomere length may correlate with the replicative history of T cells during in vivo activation and/or differentiation. Previous studies of human fibroblasts indicated that telomere shortening during in vitro culture correlates with the induction of replicative senescence and have been interpreted to suggest that telomere shortening is in fact causally related to senescence (18Harley C.B Futcher A.B Greider C.W Telomeres shorten during ageing of human fibroblasts.Nature. 1990; 345: 458-460Crossref PubMed Scopus (4391) Google Scholar, 21Hastie N.D Dempster M Dunlop M.G Thompson A.M Green D.K Allshire R.C Telomere reduction in human colorectal carcinoma and with ageing.Nature. 1990; 346: 866-868Crossref PubMed Scopus (1445) Google Scholar). A similar phenomenon occurs during culturing of human lymphocytes (49Vaziri H Schachter F Uchida I Wei L Zhu X Effros R Cohen D Harley C.B Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes.Am. J. Hum. Genet. 1993; 52: 661-667PubMed Google Scholar). When CD4+ naive and memory T cells are grown in vitro by stimulating with immobilized anti-CD3 + anti-CD28 MAbs, naive T cells are capable of substantially more extensive division than memory T cells before reaching replicative senescence (54Weng N Levine B.L June C.H Hodes R.J Regulated expression of telomerase activity in human T lymphocyte development and activation.J. Exp. Med. 1996; 183: 2471-2479Crossref PubMed Scopus (352) Google Scholar), a difference that corresponds to a 128-fold greater replicative capacity in naive CD4+ T cells. Telomeres shorten at a rate of 50–100 bp per mean population doublings (MPD) for both naive and memory T cell subsets. Recently, it was proposed that depletion of CD4+ T cells occuring during HIV infection reflects the destruction and ultimate replicative exhaustion of the CD4+ T cell lineage (25Ho D.D Neumann A.U Perelson A.S Chen W Leonard J.M Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3694) Google Scholar). If such clonal exhaustion and senescence occurs, it might be reflected in a critical level of telomere shortening in CD4+ cells from HIV-infected donors. In contrast to this prediction, it was found that CD4+ T cells from HIV+ donors have telomeres that are equal to or slightly longer than those from HIV− donors (58Wolthers K.C Bea G Wisman A Otto S.A de Roda Husman A.M Schaft N de Wolf F Goudsmit J Coutinho R.A van der Zee A.G et al.T cell telomere length in HIV-1 infection no evidence for increased CD4+ T cell turnover.Science. 1996; 274: 1543-1547Crossref PubMed Scopus (226) Google Scholar, 42Palmer L.D Weng N.P Levine B.L June C.H Lane H.C Hodes R.J 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: 1381-1386Crossref PubMed Scopus (113) Google Scholar). Consistent with these findings, the replicative capacity of CD4+ cells from HIV+ patients is undiminished (42Palmer L.D Weng N.P Levine B.L June C.H Lane H.C Hodes R.J 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: 1381-1386Crossref PubMed Scopus (113) Google Scholar), which fails to support the contention that CD4+ T cells undergo clonal exhaustion in HIV patients. (However, these studies do not exclude the possibility that CD4+ T cells in HIV patients are predominantly a new cohort of cells recently derived from stem cells with long telomeres.) In contrast to the behavior of CD4+ T cells, telomeres in CD8+ T cells from HIV+ donors are shortened relative to HIV− donors (14Effros R.B Allsopp R Chiu C.P Hausner M.A Hirji K Wang L Harley C.B Villeponteau B West M.D Giorgi J.V Shortened telomeres in the expanded CD28−CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis.AIDS. 1996; 10: F17-F22Crossref PubMed Scopus (381) Google Scholar, 42Palmer L.D Weng N.P Levine B.L June C.H Lane H.C Hodes R.J 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: 1381-1386Crossref PubMed Scopus (113) Google Scholar), suggesting that HIV infection is associated with some alterations in the dynamics of T cell subpopulations. In other disorders, accelerated telomere loss has been reported in lymphocytes from individuals with Down's syndrome (49Vaziri H Schachter F Uchida I Wei L Zhu X Effros R Cohen D Harley C.B Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes.Am. J. Hum. Genet. 1993; 52: 661-667PubMed Google Scholar) and ataxia telangiectasia (34Metcalfe J.A Parkhill C Campbell L Stacey M Biggs P Byrd P.J Taylor A.M Accelerated telomere shortening in ataxia telangiectasia.Nat. Genet. 1996; 13: 350-353Crossref PubMed Scopus (286) Google Scholar), suggesting that telomere loss may somehow relate to the immune dysfunction in these disorders. Although telomeres from human and from the mouse species Mus musculus and Mus spretus all consist of (TTAGGG)n repeats, these species differ in the average length of their telomeres. Telomeric restriction fragments (TRF) from M. musculus have mean lengths of 25–150 kb, whereas M. spretus have mean TRF lengths similar to those in human (5–15 kb) (30Kipling D Cooke H.J Hypervariable ultra-long telomeres in mice.Nature. 1990; 347: 400-402Crossref PubMed Scopus (501) Google Scholar). Changes in telomere length with age or in vitro culture have generally not been detected in M. musculus somatic cells, perhaps reflecting the difficulty in detecting small changes in the large telomeres of this species. For this reason several studies have examined telomere length with in vivo aging and in vitro culture for shorter M. spretus telomeres (43Prowse K.R Greider C.W Developmental and tissue-specific regulation of mouse telomerase and telomere length.Proc. Natl. Acad. Sci. USA. 1995; 92: 4818-4822Crossref PubMed Scopus (600) Google Scholar, 13Coviello-McLaughlin G.M Prowse K.R Telomere length regulation during postnatal development and ageing in Mus spretus.Nucleic Acid Res. 1997; 25: 3051-3058Crossref PubMed Scopus (125) Google Scholar). These studies have demonstrated that telomeres of early passage M. spretus fibroblasts shorten with in vitro culture in the absence of detectable telomerase activity. At approximately 60 population doublings (PD) the fibroblast lines appear to undergo crisis as characterized by phenotypic changes, after which the cell lines express telomerase and their telomere lengths stabilize. Significant telomere shortening is detected in vivo as a function of age in M. spretus spleen and brain but not in several other tissues. No more specific analysis of lymphoid tissues has been reported in mice or other nonhuman species. The potential for analyzing telomere length regulation during defined developmental events or immune responses has therefore not yet been fully realized in animal model systems. Until recently, it was proposed that telomerase is expressed in germline and malignant cells but not in normal somatic cells (44Shay J.W Wright W.E Telomerase activity in human cancer.Curr. Opin. Oncol. 1996; 8: 66-71Crossref PubMed Scopus (380) Google Scholar). However, a number of studies have tested the possibility that lymphocytes might use the expression of telomerase as an adaptive strategy for extension of their replicative capacity and have found that telomerase can be expressed at high levels in both T and B cells. Indeed, telomerase expression in T and B cells is highly regulated, as it is, for example, during T cell development in the thymus. High levels of telomerase activity are detected in the CD4−8−, CD4+8+, and CD4+8− subsets of human thymocytes, with intermediate levels in CD4−8+ thymocytes (54Weng N Levine B.L June C.H Hodes R.J Regulated expression of telomerase activity in human T lymphocyte development and activation.J. Exp. Med. 1996; 183: 2471-2479Crossref PubMed Scopus (352) Google Scholar) (Figure 2). Low or undetectable levels of telomerase are expressed in mature peripheral blood T cells, and higher levels in tonsil T cells, suggesting that telomerase may be induced in mature T cells in response to antigenic stimulation (7Broccoli D Young J.W de Lange T Telomerase activity in normal and malignant hematopoietic cells.Proc. Natl. Acad. Sci. USA. 1995; 92: 9082-9086Crossref PubMed Scopus (709) Google Scholar, 24Hiyama K Hirai Y Kyoizumi S Akiyama M Hiyama E Piatyszek M.A Shay J.W Ishioka S Yamakido M Activation of telomerase in human lymphocytes and hematopoietic progenitor cells.J. Immunol. 1995; 155: 3711-3715PubMed Google Scholar, 8Buchkovich K.J Greider C.W Telomerase regulation during entry into the cell cycle in normal human T cells.Mol. Biol. Cell. 1996; 7: 1443-1454Crossref PubMed Scopus (201) Google Scholar, 27Igarashi H Sakaguchi N Telomerase activity is induced by the stimulation to antigen receptor in human peripheral lymphocytes.Biochem. Biophys. Res. Commun. 1996; 219: 649-655Crossref PubMed Scopus (78) Google Scholar, 54Weng N Levine B.L June C.H Hodes R.J Regulated expression of telomerase activity in human T lymphocyte development and activation.J. Exp. Med. 1996; 183: 2471-2479Crossref PubMed Scopus (352) Google Scholar). Telomerase is induced in peripheral blood CD4+ T cells stimulated in vitro with anti-CD3, anti-CD3 + anti-CD28, or PMA/ionomycin. Interestingly, the ability of stimuli to induce telomerase in T cells in vitro is closely correlated with the ability of stimuli to induce entry into cell cycle (8Buchkovich K.J Greider C.W Telomerase regulation during entry into the cell cycle in normal human T cells.Mol. Biol. Cell. 1996; 7: 1443-1454Crossref PubMed Scopus (201) Google Scholar, 54Weng N Levine B.L June C.H Hodes R.J Regulated expression of telomerase activity in human T lymphocyte development and activation.J. Exp. Med. 1996; 183: 2471-2479Crossref PubMed Scopus (352) Google Scholar). Although induction of telomerase in peripheral blood T cells requires that these predominantly quiescent G0 cells enter cell cycle, telomerase activity once induced does not appear to be restricted to a particular cell cycle phase (54Weng N Levine B.L June C.H Hodes R.J Regulated expression of telomerase activity in human T lymphocyte development and activation.J. Exp. Med. 1996; 183: 2471-2479Crossref PubMed Scopus (352) Google Scholar). Anti-CD3/CD28-induced telomerase expression in CD4+ T cells requires new RNA and protein synthesis and requires signals mediated via protein tyrosine kinases (54Weng N Levine B.L June C.H Hodes R.J Regulated expression of telomerase activity in human T lymphocyte development and activation.J. Exp. Med. 1996; 183: 2471-2479Crossref PubMed Scopus (352) Google Scholar). Cyclosporin A (CsA) completely blocks telomerase induction in CD4+ T cells stimulated with anti-CD3 alone or with PMA/ionomycin, but it only partially blocks induction in T cells that had been stimulated with anti-CD3 + anti-CD28. Thus, CD28-mediated signals are critical for a CsA-resistant pathway of telomerase induction in combination with CD3-mediated signals. These results identify proximal signaling events that are required for telomerase induction in response to stimulation through CD3/CD28. However, it is not clear whether these requirements are specific for telomerase regulation or are linked to cell cycling events in general. Although a number of human telomerase components have been identified, only one component, telomerase RNA template (hTR), has been analyzed in T cells (55Weng N Levine B.L June C.H Hodes R.J Regulation of telomerase RNA template expression in human T lymphocyte development and activation.J. Immunol. 1997; 158 (a): 3215-3220PubMed Google Scholar). hTR is ubiquitously expressed in all tissues tested regardless of the status of telomerase activity (15Feng J Funk W.D Wang S.S Weinrich S.L Avilion A.A Chiu C.P Adama R.R Chang E Allsopp R.C Yu J et al.The RNA component of human telomerase.Science. 1995; 269: 1236-1241Crossref PubMed Scopus (2019) Google Scholar). However, levels of hTR are higher in thymocytes than in peripheral blood T cells, and in vitro activation of peripheral blood CD4+ T cells leads to a significant, albeit modest, 2- to 5-fold up-regulation of hTR expression (8Buchkovich K.J Greider C.W Telomerase regulation during entry into the cell cycle in normal human T cells.Mol. Biol. Cell. 1996; 7: 1443-1454Crossref PubMed Scopus (201) Google Scholar, 55Weng N Levine B.L June C.H Hodes R.J Regulation of telomerase RNA template expression in human T lymphocyte development and activation.J. Immunol. 1997; 158 (a): 3215-3220PubMed Google Scholar). Thus, hTR expression is regulated to some degree in normal T cell development and activation, correlating with telomerase activity in these T cells. It will be important to analyze during T cell development and activation expression of other telomerase genes, such as hTERT, the expression of which is highly regulated in germline and malignant cells. A more complete understanding of telomerase gene expression should shed light on how telomerase activity is regulated in normal cells and should provide a basis for future experimental interventions designed to modify telomerase activity. Telomerase expression has also been examined in HIV-infected individuals. As discussed above, there is no significant decrease in telomere length in CD4+ T cells from HIV+ donors (58Wolthers K.C Bea G Wisman A Otto S.A de Roda Husman A.M Schaft N de Wolf F Goudsmit J Coutinho R.A van der Zee A.G et al.T cell telomere length in HIV-1 infection no evidence for increased CD4+ T cell turnover.Science. 1996; 274: 1543-1547Crossref PubMed Scopus (226) Google Scholar, 42Palmer L.D Weng N.P Levine B.L June C.H Lane H.C Hodes R.J 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: 1381-1386Crossref PubMed Scopus (113) Google Scholar). Thus, if there is an excessive proliferation of lymphocytes in HIV-infected individuals (25Ho D.D Neumann A.U Perelson A.S Chen W Leonard J.M Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3694) Google Scholar), the absence of telomere shortening could result from activation of telomerase in vivo in HIV-infected individuals. However, when telomerase activity was analyzed in CD4+ and CD8+ T cells from HIV-discordant monozygous twins ex vivo and after in vitro stimulation, no significant difference was found either in the basal levels or in induced telomerase activity in CD4+ and CD8+ T cells from HIV+ or HIV− monozygotic twins (42Palmer L.D Weng N.P Levine B.L June C.H Lane H.C Hodes R.J 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: 1381-1386Crossref PubMed Scopus (113) Google Scholar). The relationship between telomere length regulation and telomerase expression in human lymphocytes has been further studied in experiments that measured telomere length and telomerase activity in parallel during long-term stimulation of T cells. Stimulation of T cells induces both a rapid initial increase and a high peak level of telomerase activity. However, the magnitude and duration of telomerase activity decreases in long-term cultures with time and decreases with every subsequent stimulation. Strikingly, telomere shortening is not detected early after initial stimulation, when population doubling is extensive, but when telomerase activity is highest. At the later phases of long-term culture, when telomerase activity is significantly diminished, accelerated telomere reduction appears to occur. Similar patterns are observed in long-term cultures of human CD4+ and CD8+ T cells (5Bodnar A.G Kim N.W Effros R.B Chiu C-P Mechanism of telomerase induction during T cell activation.Exp. Cell Res. 1996; 228: 58-64Crossref PubMed Scopus (264) Google Scholar, 56Weng N Palmer L Levine B.L Lane H.C June C.H Hodes R.J Tales of tails regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging.Immunol. Rev. 1997; 160 (b): 43-54Crossref PubMed Scopus (179) Google Scholar). Thus, the relationship of telomere shortening to population doubling appears to be more complex in telomerase-expressing T lymphocytes than in human fibroblasts, which have no detectable telomerase activity and in which telomere shortening appears to be a more constant function of population doubling. These findings suggest, but do not directly demonstrate, that telomere length in activated CD4+ and CD8+ T cells may be stabilized by high levels of telomerase that are induced in these cells and may serve to prolong the capacity for extensive clonal expansion that is critical to physiologic T cell function. In the mouse, high levels of telomerase activity are expressed in hematopoietic stem cells isolated from bone marrow and fetal liver (3Blasco M.A Funk W Villeponteau B Greider C.W Functional characterization and developmental regulation of mouse telomerase.Science. 1995; 269: 1267-1270Crossref PubMed Scopus (343) Google Scholar, 9Chadeneau C Siegel P Harley C.B Muller W.J Bacchetti S Telomerase activity in normal and malignant murine tissues.Oncogene. 1995; 11: 893-898PubMed Google Scholar, 43Prowse K.R Greider C.W Developmental and tissue-specific regulation of mouse telomerase and telomere length.Proc. Natl. Acad. Sci. USA. 1995; 92: 4818-4822Crossref PubMed Scopus (600) Google Scholar, 37Morrison S.J Prowse K.R Ho P Weissman I.L Telomerase activity in hematopoietic cells is associated with self-renewal potential.Immunity. 1996; 5: 207-216Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar). Telomerase expression is also detected in lymphoid organs including spleen and thymus (43Prowse K.R Greider C.W Developmental and tissue-specific regulation of mouse telomerase and telomere length.Proc. Natl. Acad. Sci. USA. 1995; 92: 4818-4822Crossref PubMed Scopus (600) Google Scholar, 9Chadeneau C Siegel P Harley C.B Muller W.J Bacchetti S Telomerase activity in normal and malignant murine tissues.Oncogene. 1995; 11: 893-898PubMed Google Scholar, 4Blasco M.A Lee H.W Hande M.P Samper E Lansdorp P.M DePinho R.A Greider C.W Telomerase shortening and tumor formation by mouse cells lacking telomerase RNA.Cell. 1997; 91: 25-34Abstract Full Text Full Text PDF PubMed Scopus (1730) Google Schol
Referência(s)