The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory.

Abstract

SummaryThe bcl-2 gene product has been shown to prevent apoptotic cell death. We have now investigated the bcl-2 protein expression by resting and activated mature T cell populations. Freshly isolated CD45RO + T cells within CD4 + and CD8 + subsets expressed significantly less bcl-2 than CD45RO-(CD45RA +) T cells ~ <0.001). When CD45RA + T cells within both CD4 ~ and CD8 + subsets were activated in vitro, the transition to CD45RO phenotype was associated with a decrease in bcl-2 expression. Patients with acute viral infections such as infectious mononucleosis caused by Epstein-Barr virus infections or chickenpox, resulting from variceUa zoster virus infection, had circulating populations of activated CD45RO + T cells which also showed low bcl-2 expression. In these patients, a significant correlation was seen between low bcl-2 expression by activated T cells and their apoptosis in culture (r = 0.94, p <0.001). These results suggest that the primary activation of T cells leads to the expansion of a population that is destined to perish unless rescued by some extrinsic event. Thus the suicide of CD45RO + T cells could be prevented by the addition ofinterleukin 2 to the culture medium which resulted in a concomitant increase in the bcl-2 expression of these cells. Alternatively, apoptosis was also prevented by coculturing the activated T lymphocytes with fibroblasts, which maintained the viability of lymphoid cells in a restinglike state but with low bcl-2 expression. The paradox that the CD45RO + population contains the primed/memory T cell pool yet expresses low bcl-2 and is susceptible to apoptosis can be reconciled by the observations that maintenance of T cell memory may be dependent on the continuous restimulation of T cells, which increases their bcl-2 expression. Furthermore, the propensity of CD45RO + T cells to extravasate may facilitate encounter with fibroblast-like cells in tissue stroma and thus be an important additional factor which promotes the survival of selected primed/memory T cells in vivo.

Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vγ9Vδ2 naive, memory and effector T cell subsets

“…Thus, cytokine responses of human Vc9Vd2 T cells recapitulate many aspects of homeostatic T cell proliferation in vivo and provide a valuable tool to extend our knowledge of T cell maintenance in the human system. Memory T cells have an enhanced susceptibility to cell death [33,34] and die upon bystander activation [35], although surviving cells may proliferate and repopulate the memory pool. We show that the resistance of human Vc9Vd2 T cell subsets to cell death is associated with the expression of the anti-apoptotic Bcl-2 protein, which protects T cells from multiple forms of cell death [36].…”

Type 1 IFN Maintains the Survival of Anergic CD4+ T Cells

“…The resulting T:T presentation of this peptide by T cells to each other in the context of MHC class II induces apoptosis in a proportion of the responding cells, while the nondeleted cells are nonresponsive to subsequent challenge with Agpulsed APCs (6, 8 -10). Previous studies have demonstrated that IFN-␤ secreted by fibroblasts and IFN-␣ secreted by other cell types can prevent cytokine deprivation-induced T cell apoptosis in both humans (11,12) and mice (13), achieved in part by the upregulation of Bcl-x L , but not Bcl-2, expression (12,14,15). Fibroblast-conditioned medium (FCM) 4 and IFN-␣␤ could also prevent the translocation of the signaling molecule protein kinase C-␦ (PKC-␦) from the cytoplasm to the nucleus of IL-2-deprived T cell lines, which prevented its activation by caspase-3 (11).…”

“…T cells and fibroblasts were separated by a semipermeable 0.22-m pore size Transwell culture insert (Costar, High Wycombe, U.K.) in 24-well plates (14,15). The T cell clone was placed into the insert above the fibroblasts.…”

“…Viable cells were distinguished by their forward angle scatter and 90 o side scatter profiles and were counted using a Cytoron Absolute flow cytometer (Ortho Diagnostics, High Wycombe, U.K.) and also by trypan blue exclusion as described previously (14). Apoptosis and cell cycling were measured at a particular time point by flow cytometry using propidium iodide as the DNA-specific label (12).…”

TNF-α-induced apoptosis in neonatal lymphocytes: TNFRp55 expression and downstream pathways of apoptosis

“…18,31,32 It has been demonstrated that naïve T cells are less susceptible to apoptosis than memory (CD45RO + ) T cells. 33 Recently, age-related changes in T cell apoptosis have been reported. [34][35][36][37] T cell subsets from aged humans are more susceptible to both Fas-and TNFR-I-mediated apoptosis as compared to young subjects.…”