The enzyme telomerase is essential for maintaining the replicative capacity of memory T cells. Although CD28 costimulatory signals can up-regulate telomerase activity, human CD8+ T cells lose CD28 expression after repeated activation. Nevertheless, telomerase is still inducible in CD8+CD28− T cells. To identify alternative costimulatory pathways that may be involved, we introduced chimeric receptors containing the signaling domains of CD28, CD27, CD137, CD134, and ICOS in series with the CD3 zeta (ζ) chain into primary human CD8+ T cells. Although CD3 ζ-chain signals alone were ineffective, triggering of all the other constructs induced proliferation and telomerase activity. However, not all CD8+CD28− T cells could up-regulate this enzyme. The further fractionation of CD8+CD28− T cells into CD8+CD28− CD27+ and CD8+CD28−CD27− subsets showed that the latter had significantly shorter telomeres and extremely poor telomerase activity. The restoration of CD28 signaling in CD8+CD28−CD27− T cells could not reverse the low telomerase activity that was not due to decreased expression of human telomerase reverse transcriptase, the enzyme catalytic subunit. Instead, the defect was associated with decreased phosphorylation of the kinase Akt, that phosphorylates human telomerase reverse transcriptase to induce telomerase activity. Furthermore, the defective Akt phosphorylation in these cells was specific for the Ser473 but not the Thr308 phosphorylation site of this molecule. Telomerase down-regulation in highly differentiated CD8+CD28−CD27− T cells marks their inexorable progress toward a replicative end stage after activation. This limits the ability of memory CD8+ T cells to be maintained by continuous proliferation in vivo.
Due to their ability to inhibit antigeninduced T-cell activation in vitro and in vivo, anergic T cells can be considered part of the spectrum of immunoregulatory T lymphocytes. Here we report that both murine and human anergic T cells can impair the ability of parenchymal cells (including endothelial and epithelial cells) to establish cell-cell interactions necessary to sustain leukocyte migration in vitro and tissue infiltration in vivo. The inhibition is reversible and cell-contact dependent but does not require cognate recognition of the parenchymal cells to occur. Instrumental to this effect is the increased cell surface expression and enzymatic activity of molecules such as CD26 (dipeptidyl-peptidase IV), which may act by metabolizing chemoattractants bound to the endothelial/epithelial cell surface. These results describe a previously unknown antigen-independent antiinflammatory activity by locally generated anergic T cells and define a novel mechanism for the long-known immunoregulatory properties of these cells. IntroductionT-cell anergy has been defined as a "cellular state in which a lymphocyte is alive but fails to display certain functional responses (including cell division and interleukin 2 [IL-2] production) when optimally stimulated through both its antigen-specific receptor and any other receptor that is normally required for full activation." 1 Anergic T cells can be generated in vitro and in vivo by various mechanisms, 1,2 all involving partial or inappropriate stimulation. While losing their proliferative and effector potential, anergic T cells have long been known to be able to exert immunoregulation. The potential for anergic T cells to act as suppressor cells came first from a superantigen in vivo model in which anergic T cells acted as efficient suppressor cells in an antigen-nonspecific manner. 3 More recently, murine anergic T cells either generated in vivo or rendered anergic in vitro with immobilized anti-CD3 and adoptively transferred have been shown to prolong skin allograft survival in an antigen-specific manner. 4,5 In the human system, anergic CD4 ϩ T cells were shown to exert contact-dependent and antigen-specific suppression in vitro. 6,7 The mechanism by which anergic T cells exert their immunoregulatory properties appears to be indirect by altering the antigen presenting cells (APCs) immunogenicity 8,9 in a cell-cell contactdependent manner. The molecular basis for this effect is still unknown and it has been hypothesized to involve the induction of "regulatory" molecules on the anergic T cells, capable of delivering negative signals to the APC. 2 It has recently become clear that the initial stages of T-cell activation are mediated by antigen-independent interactions, which establish areas of focal contact between T cells and APCs. 10,11 Such interactions are initiated by chemoattractant-induced cell polarization and subsequent redistribution of adhesion molecules on the T-cell surface. These, in turn, allow T-cell receptor (TCR) interactions with the major histocompatibili...
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