Sustained CD28 Expression Delays Multiple Features of Replicative Senescence in Human CD8 T Lymphocytes

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Journal of Clinical Immunology (Impact Factor: 3.18). 11/2010; 30(6):798-805. DOI: 10.1007/s10875-010-9449-7
Source: PubMed


CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence.

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    • "Representative time courses for three cultures show that loss of CD28 surface expression was more rapid in the treated cultures than in controls (Fig. 4A). These results may explain the reduced telomerase activity described above, since CD28 has been shown to play a direct regulatory role on gene expression of TERT, the catalytic subunit of telomerase, and telomerase activity [10]. "
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    ABSTRACT: Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect.
    PLoS ONE 06/2014; 9(6):e99432. DOI:10.1371/journal.pone.0099432 · 3.23 Impact Factor
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    • "Interaction of this costimulatory molecule with its ligands increases the expression of antiapoptotic proteins and improves interleukin (IL)-2 production. The increase in circulation of T cells with a CD4+ CD28 null phenotype is consistent with a process known as replicative senescence [11, 13, 17–19]. T cells that lack CD28 surface expression are nonanergic, oligoclonally expanded, and terminally differentiated, with limited replicative capacity and increased sensitivity to apoptosis [20, 21]. "
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    ABSTRACT: Objective . During the course of HIV infection, progressive immune deficiency occurs. The aim of this prospective substudy was to evaluate the recovery of functional immunity in a subset of patients from the GRACE (Gender, Race, And Clinical Experience) study treated with a DRV/r-based regimen. Methods . The recovery of functional immunity with a darunavir/ritonavir-based regimen was assessed in a subset of treatment-experienced, HIV-1 infected patients from the GRACE study. Results . 19/32 patients (59%) enrolled in the substudy were virologically suppressed (
    12/2013; 2013(3):358294. DOI:10.1155/2013/358294
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    • "Loss of CD28 expression is a phenotypic change associated with senescence in T lymphocytes, and it has been associated with functional alterations such as enhanced cytotoxicity, suppressive functions, and resistance of CD4+ T cells to apoptosis. Loss of CD28 expression is characterized by telomere shortening and reduced proliferative ability, both ex vivo and in vitro [41, 42]. At birth, virtually all T cells express CD28, but with age, the marker decreases about 40 to 50% for CD8+ T cells and 85 to 90% for CD4+. "
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    ABSTRACT: Senescence is a normal biological process that occurs in all organisms and involves a decline in cell functions. This process is caused by molecular regulatory machinery alterations, and it is closely related to telomere erosion in chromosomes. In the context of the immune system, this phenomenon is known as immunosenescence and refers to the immune function deregulation. Therefore, functions of several cells involved in the innate and adaptive immune responses are severely compromised with age progression (e.g., changes in lymphocyte subsets, decreased proliferative responses, chronic inflammatory states, etc.). These alterations make elderly individuals prone to not only infectious diseases but also to malignancy and autoimmunity. This review will explore the molecular aspects of processes related to cell aging, their importance in the context of the immune system, and their participation in elderly SLE patients.
    10/2013; 2013(18):267078. DOI:10.1155/2013/267078
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