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.

CTLA-4 blockade of antigen-induced cell death

“…In this regard, T-cell hybridomas have served as a model for the study of AICD 33,34 ; in particular, the hybridoma DC27.10 has been previously studied for the role of costimulation in the induction of apoptosis. 37 In this report, we demonstrate that CTLA-4 can block AICD in transfectants of the murine hybridoma DC27.10 via inhibition of Fas ligand (FasL) surface expression. These findings support a model in which CTLA-4 interferes with an early TCR-signaling event linked to both IL-2 production and FasL expression.…”

Macrophage‐Inducing FasL on Chondrocytes Forms Immune Privilege in Cartilage Tissue Engineering, Enhancing In Vivo Regeneration

“…Meanwhile, FasL is constitutively expressed in physiologically immune‐privileged sites, such as in cells of the anterior chamber of the eye, neurons, and astrocytes of the central nervous system . Regarding the signals for inducing FasL, previous studies have reported that T‐cell‐receptor (TCR)/CD3 , CD28 , CD40, stress signaling , and IFN‐γ could initiate the expression of FasL in T cells. In pathological hepatocytes, the expression of FasL was upregulated by virus or CD40.…”

Long‐Term Proliferation and Survival of In Vitro‐Activated T Cells is Dependent on Interleukin‐2 Receptor Signalling but not on the High‐Affinity IL‐2R

“…Following activation, T cells cluster into two major groups depending on their response to activation: those who proliferate and those who die by AICD. Major determinants of postactivation T‐cell fate seem to be costimulation through CD28, binding of IL‐2 to its receptor on T cells and the state of activation and subset affiliation of the T cell [18–23]. However, the exact roles played by these factors have not yet been determined.…”

“…However, the exact roles played by these factors have not yet been determined. Thus, CD28 costimulation normally reduces AICD, but if given alone, CD28 signalling may induce apoptosis [18, 19]. While IL‐2 has been associated with rescue from apoptosis [20], IL‐2 has also been shown to induce apoptosis in activated T cells [24, 25].…”