The Loss of Telomerase Activity in Highly Differentiated CD8+CD28−CD27− T Cells Is Associated with Decreased Akt (Ser473) Phosphorylation

Abstract

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.

Dynamics of T cell memory in human cytomegalovirus infection

“…A recent study has suggested that CD8+ CD28¡ T cells are able to upregulate telomerase activity but that CD8+ CD28¡ CD27¡ T cells cannot [118]. Both telomerase activity and proliferation by CD8+ CD28¡ CD27¡ T cells following anti-CD3 and APC stimulation were restored almost to the level of other CD8+ T cells on the addition of IL-2 or IL-15 [118].…”

“…An early study showed that CD45RA+ cells had longer telomeres than CD45RO+ cells [115], however, separating CD45RA+ T cells, which lack CD27 expression (memory cells) showed that their telomere length was similar to CD45RO+ memory cells [116,117]. A recent study has suggested that CD8+ CD28¡ T cells are able to upregulate telomerase activity but that CD8+ CD28¡ CD27¡ T cells cannot [118]. Both telomerase activity and proliferation by CD8+ CD28¡ CD27¡ T cells following anti-CD3 and APC stimulation were restored almost to the level of other CD8+ T cells on the addition of IL-2 or IL-15 [118].…”

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

“…8 , 9 The loss of both CD28 and CD27 molecules defines a late differentiation status of T cells. 10 , 11 On the other hand, inhibitory receptors, including Lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-3 (TIM-3) and Programmed death-1 (PD-1) have been strongly associated with “T-cell exhaustion”. 12 , 13 However, PD-1 expression may also reflect a particular differentiation and/or activation status of T cells.…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Two recent studies showed that frequencies of highly cytotoxic CD8 + CD28 − T cells in inflamed muscle and in peripheral blood of IBM patients are significantly increased and their capability to secrete IFN γ was superior compared to healthy controls 82, 83. CD8 + CD28 − T cells are devoid of costimulatory interaction between CD80:CD28, however, it is reported that CD8 + CD28 − T cells after CD3 ligation in turn upregulate alternative costimulatory molecules such as inducible costimulator (ICOS), CD134 and CD13784 which could facilitate T cell: muscle fiber interaction and is in keeping with the observed upregulation of ICOS‐L on muscle fibers during IBM 48…”

“…It is believed that CD8 + CD57 + T cells are highly differentiated antigen‐driven effector cells in a state of replicative senescence with limited capacities to proliferate 88, 89, 90, 91, 92. Recent reports, however, suggest that these CD8 + CD57 + CD28 − T cells might comprise a rather heterogeneous group of highly antigen‐experienced cells that, depending on the immunobiological context and stimuli, differ in their susceptibility to apoptosis and their capability to proliferate and expand 84, 93, 94, 95…”