The CD28~ T cells present in vivo are similar by a variety of criteria to CD28~ cells in senescent cultures, suggesting that they arose by the same mechanism. Extensive research on replicative senescence in nonimmune cell types indicates that once senescent cells are generated, they not only suffer from an inability to enter the cell cycle, but can also affect a variety of physiological processes or organ system functions. For example, senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and also to form tumors in SCID mice, suggestive of a potential role in age-related cancers (Krtolica et al., 2001). In addition, whereas normal fibroblasts function to create intracellular matrix, senescent fibroblasts secrete collagenase and other matrix-destroying enzymes, leading to altered tissue integrity (Campisi, 1998).
The significant correlation between high proportions of CD8+CD28~ T cells and poor antibody response to influenza vaccination documented in two independent clinical studies (Goronzy et al., 2001; Saurwein-Teissl et al., 2002) provides an example of putative suppressive effects of senescent CD8+ T cells on the function of other immune cells. Senescent CD8+ T cells have also been associated with suppressive effects in organ transplant patients. Donor-specific CD8+CD28~ T cells are detectable in the peripheral blood of those patients with stable function of heart, liver and kidney transplants, whereas no such cells were found in patients undergoing acute rejection (Cortesini et al., 2001). Although in the context of organ transplantation, suppression may lead to a favorable outcome, in many other contexts, the CD8+CD28~ T cell populations are associated with deleterious effects. For example, expanded populations of CD8+CD28~ T cells are present in ankylosing spondylitis patients, and, in fact, correlate with a more severe course of this autoimmune disease (Schirmer et al., 2002).
In addition to the role that putatively senescent CD8+ T cells may play in regulating functions of other immune cell types, these cells also show alterations in the normal functional attributes of CD8+ T cells. First, CD8+CD28" T cells isolated ex vivo are unable to proliferate (like their cell culture counterparts), even in response to signals that bypass cell surface receptors, such as PMA and ionomycin (Effros et al., 1996). This observation is consistent with extensive research on replicative senescence in a variety of cell types documenting the irreversible nature of the proliferative block, and its association with upregulation of cell cycle inhibitors and p53-linked checkpoints (Campisi, 2001). If the CD8+CD28" T cells present in elderly persons are virus-specific, their inability to undergo the requisite clonal expansion in response to antigen re-encounter will compromise the immune control over that particular virus. Indeed, as noted above, senescent HIV-specific CD8+ T cells are markedly reduced in lytic activity, IFNg production, and antiviral suppressive function (Dagarag et al., 2004). Thus, CD8+CD28~ T cells in elderly persons may contribute to emergence of latent infections, such as varicella zoster virus (shingles) and EBV (some lymphomas), as well to the reduced control over acute infection with a repeatedly encountered virus (influenza), well-documented in elderly persons (Effros, 2001). Second, since CD28 ligation enhances the binding affinity of T cells to endothelial cells, T cells lacking CD28 may be altered in their trafficking patterns between tissue and blood. Third, if the putatively senescent T cells present in vivo produce high levels of IL-6 and TNFa like their in vitro counterparts, their presence in vivo may be contributing to the well-documented pro-inflammatory milieu present in many elderly persons. Indeed, enhanced inflammation is now believed to play a role in many of the diseases of aging that had not been previously considered immune-mediated pathologies. Overiectomy-induced bone loss in mice, for example, has been specifically linked to TNFa-secreting T cells present within the bone marrow (Raggia et al., 2001).
The apoptosis resistance of CD8+CD28~ T cells tested immediately ex vivo (Posnett et al., 1999) leads to their persistence, which, in turn, affects the quality and composition of the total memory pool, as discussed above. Moreover, since the CD28~ T cells are usually part of oligoclonal expansions (Posnett et al., 1994), their accumulation would presumably also lead to a reduction in the overall spectrum of antigenic specificities within the T cell pool. Elderly persons with high proportions of CD8+ T cell that are CD28~ do, in fact, have reduced repertoires of antigenic specificities (Ouyang et al., 2003b).
A final aspect of senescent T cells that could have broad physiological consequences relates to the role of stress in the aging process. T cells that undergo replicative senescence in culture show transcriptional down-regulation of the hsp70 gene in response to heat shock (Effros et al., 1994b), and T cells from elderly persons show attenuation in the molecular chaperone system hsp70, in the steroid binding hsp90, and the chaperonin hsp60. These immune cell changes may contribute to the well-documented reduction in ability to respond to stress that characterizes organismic aging.
Global Effects of Senescent T Cells on the Aging Organism
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