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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1350-1363
Distinct Regulation of T-Cell Death by CD28 Depending on Both Its
Aggregation and T-Cell Receptor Triggering: A Role for Fas-FasL
Y. Collette,
A. Benziane,
D. Razanajaona, and
D. Olive
From U119 INSERM, Université de Méditerranée, Bd
Leï Roure, 27, 13009 Marseille, France.
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.
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