Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis

Effros, Rita B.; Allsopp, Richard; Chiu, Choy‐Pik; Hausner, Mary Ann; Hirji, Karim F.; Wang, Lili; Harley, Calvin B.; Villeponteau, Bryant; West, Michael; Giorgi, Janis V.

doi:10.1097/00002030-199607000-00001

Cited by 394 publications

(248 citation statements)

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“…CD4 þ and CD8 þ T cells expressing CD28 were reduced in Ethiopians compared with the Dutch. Loss of CD28 on T cells has been associated with increased cytolytic T cell activity, impaired response to costimulation via B7, anergy to anti-CD3-induced proliferation and also shorter telomere length, which is indicated to be a result of chronic immune system activation [26,[34][35][36][37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts

Messele¹,

Abdulkadir²,

Fontanet³

et al. 1999

Clinical and Experimental Immunology

101

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SUMMARYTo assess possible differences in immune status, proportions and absolute numbers of subsets of CD4 þ and CD8 þ T cells were compared between HIV ¹ healthy Ethiopians (n ¼ 52) and HIV ¹ Dutch (n ¼ 60). Both proportions and absolute numbers of naive CD4 þ and CD8 þ T cells were found to be significantly reduced in HIV ¹ Ethiopians compared with HIV ¹ Dutch subjects. Also, both proportions and absolute numbers of the effector CD8 þ T cell population as well as the CD4 þ CD45RA ¹ CD27 ¹ and CD8 þ CD45RA ¹ CD27 ¹ T cell populations were increased in Ethiopians. Finally, both proportions and absolute numbers of CD4 þ and CD8 þ T cells expressing CD28 were significantly reduced in Ethiopians versus Dutch. In addition, the possible association between the described subsets and HIV status was studied by comparing the above 52 HIV ¹ individuals with 32 HIV þ Ethiopians with CD4 counts > 200/ml and/or no AIDS-defining conditions and 39 HIV þ Ethiopians with CD4 counts < 200/ml or with AIDS-defining conditions. There was a gradual increase of activated CD4 þ and CD8 þ T cells, a decrease of CD8 þ T cells expressing CD28 and a decrease of effector CD8 þ T cells when moving from HIV ¹ to AIDS. Furthermore, a decrease of naive CD8 þ T cells and an increase of memory CD8 þ T cells in AIDS patients were observed. These results suggest a generally and persistently activated immune system in HIV ¹ Ethiopians. The potential consequences of this are discussed, in relation to HIV infection.

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Section: Discussionmentioning

confidence: 99%

Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts

Messele¹,

Abdulkadir²,

Fontanet³

et al. 1999

Clinical and Experimental Immunology

101

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“…In this context it is of interest that expansion of blood CD8 + T lymphocytes is associated with all-cause mortality (Wikby et al, 2002;Pawelec et al, 2005). CD8 + CD28 − T lymphocytes have telomeres that are shorter than those of other white blood cells from the same individual (Monteiro et al, 1996;Effros et al, 1996); this may be connected to the observation that loss of CD28 expression is also associated with loss of ability of T lymphocytes to upregulate telomerase activity (Valenzuela and Effros, 2002).…”

Section: Do Telomere Biology and Telomerase Activity Determine Aging?mentioning

confidence: 99%

Telomerase and the aging process

Hornsby¹

2007

Experimental Gerontology

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The level of telomerase activity is important in determining telomere length in aging cells and tissues. Here evidence on the importance of telomerase activity is reviewed with respect to aging rates of mammalian species and the health and life span of individuals within a species. The significance of telomerase reactivation for both cancer development and for immortalizing cells for therapeutic processes is assessed. KeywordsTelomerase; telomeres; senescence; cancer; immortalization Telomeres are the specialized repetitive DNA sequences at the ends of the linear chromosomes, and associated proteins, that serve to maintain the integrity of the chromosomes. Telomerase is a ribonucleoprotein DNA polymerase complex that maintains telomere length. The complex comprises the protein telomerase reverse transcriptase (TERT, or hTERT in humans) and a catalytic RNA (TERC) (Shay and Wright, 2007). In the absence of telomerase activity telomeres progressively shorten. Telomerase activity is absent in most normal human somatic cells because of the lack of expression of TERT; TERC is usually present. On the other hand most mouse cells have telomerase activity (Blasco, 2005). Without telomerase, telomere shortening eventually limits the growth of cells, either by senescence, in cells with intact cell cycle checkpoints (a G1 cell cycle block), or by crisis in cells with inactivated checkpoints (telomeric end-to-end fusions cause chromosome breakage and mitotic catastrophe) (Shay and Wright, 2007). Expression of TERT in cells that otherwise lack telomerase activity causes cells to bypass senescence and crisis, and such cells are usually termed "immortalized." The significance of senescence, crisis and immortalization is explored further in this revew (see Figure 1). Do telomere biology and telomerase activity determine aging?The first aspect to this question is whether differences in aging rates among mammalian species are caused in whole or in part by species-specific differences in telomerase/telomere biology. A very brief consideration of this question will show that this is unlikely. Mice are short-lived compared to humans, yet mice have long telomeres and adult mouse somatic cells often have telomerase activity (Blasco, 2005). On the other hand, humans have relatively short telomeres, even when compared to closely related primates (Kakuo et al., 1999), and telomerase activity

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“…In both situations, the majority of CD28 − T cells are within the CD8 subset. Indeed, during both HIV infection and aging, the proportion of CD28 − T cells within the peripheral blood CD8 T cell pool can be as high as 65% [23].…”

Section: Senescent Cd8 T Cells Accumulate In Vivomentioning

confidence: 99%

Telomerase induction in T cells: A cure for aging and disease?

Effros

2007

Experimental Gerontology

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Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3-5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 co-stimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8 + CD28 − T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically-suitable formulation.

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Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis

Cited by 394 publications

References 0 publications

Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts

Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts

Telomerase and the aging process

Telomerase induction in T cells: A cure for aging and disease?

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