Distinct Regulation of T-Cell Death by CD28 Depending on Both Its Aggregation and T-Cell Receptor Triggering: A Role for Fas-FasL

Abstract

CD28 is a major coreceptor that regulates cell proliferation, anergy, and viability of T cells. The negative selection by T-cell receptor (TCR)-induced cell death of immature thymocytes as well as of activated human antigen-specific T-cell clone, requires a costimulatory signal that can be provided by CD28. Conversely, CD28-mediated signals increase expression of Bcl-XL, a survival gene, and promote survival of naive T cells cultured in the absence of antigen or costimulation. Because CD28 appears to both protect from, or induce T-cell death, one important question is to define the activation and cellular parameters that dictate the differential role of CD28 in T-cell apoptosis. Here, we compared different CD28 ligands for their ability to regulate TCR-induced cell death of a murine T-cell hybridoma. In these cells, TCR triggering induced expression of Fas and FasL, and cell death was prevented by anti-Fas blocking monoclonal antibody (MoAb). When provided as a costimulus, both CD28 MoAb and the B7.1 and B7.2 counter receptors downregulated, yet did not completely abolish T-cell receptor–induced apoptosis. This CD28 cosignal resulted in both upregulation of Bcl-XL and prevention of FasL expression. In marked contrast, when given as a single signal, CD28 MoAb or B7.1 and B7.2 induced FasL expression and resulted in T-cell death by apoptosis, which was dependent on the level of CD28 ligation. Furthermore, triggering of CD28 upregulated FasL and induced a marked T-cell death of previously activated normal peripheral T cells. Our results identify Fas and FasL as crucial targets of CD28 in T-cell death regulation and show that within the same cell population, depending on its engagement as a single signal or as a costimulus together with the TCR, CD28 can either induce a dose-dependent death signal or protect from cell death, respectively. These data provide important insights into the role of CD28 in T-cell homeostasis and its possible implication in neoplastic disorders. © 1998 by The American Society of Hematology.

Up-regulation of c-FLIPshort and reduction of activation-induced cell death in CD28-co-stimulated human T cells

“…In this study we demonstrate that TCR/CD3-restimulated mature activated human T cells can be rescued from apoptotic cell death through CD28 co-stimulation [38][39][40]42]. We have found that the CD28 co-stimulatory anti-apoptotic signal acts on multiple levels of TCR/CD3mediated induction of the CD95 pathway.…”

“…Thereby, CD28 regulates cell proliferation, anergy and viability of T cells. CD28 appears to act both as a protector and an activator of apoptosis, depending on the stimulation conditions [38]. Several reports demonstrated that CD28-mediated signaling increases the expression of Bcl-x L and thereby promotes survival [39][40][41].…”

The role of CD95 in the regulation of peripheral T‐cell apoptosis

“…The impact of CD28-mediated costimulation on CD95-triggered AICD was investigated only recently. It has been reported that under certain conditions, stimulation via CD28 prevents CD3-mediated induction of CD95L and, thus, AICD (94,115). The modulation of downstream signaling events in the CD95 pathway upon costimulation has been partially elucidated (94,116).…”

Enhanced allogeneic skin-graft survival using sCD95L, sCD152, interleukin-10 and transforming growth factor-β in combination, and comparison with ciclosporin

“…23 Independent treatment with these four cytokines can induce immunotolerance and prolong the survival of grafts to some extent. Collette et al 24 showed that blockade of the CD28:B7 costimulatory pathway can enhance T-cell sensitivity to CD95:CD95L-mediated apoptosis. Jay et al 25 revealed the synergistic effects of IL-10 and TGF-b in inducing CD4+ T cell-mediated, antigen-specific, low-level immune response.…”