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* Center for Immunology, Departments of
Biochemistry, Molecular Biology, and Biophysics, and
Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455
Both CD8 and CD4 T cells undergo autocrine IL-2-induced
proliferation and clonal expansion following stimulation with Ag and
costimulation. The CD8 T cell response is transient because the cells
rapidly become activation-induced nonresponsive (AINR) and exhibit
split anergy. In these cells, the capacity for IL-2 production is lost,
but TCR-mediated IFN-
production and cytotoxicity are maintained. At
this point, the CTL become dependent on IL-2 provided by CD4 Th cells
for continued expansion. If IL-2 is available to support expansion for
a brief period, AINR is reversed and the cells regain the ability to
produce IL-2. In this study, we show that CD4 T cells do not become
AINR, but instead are rendered susceptible to Fas-mediated
activation-induced cell death following stimulation through TCR and
CD28. Using z-VAD-fmk or anti-Fas ligand mAb to inhibit cell
death, we demonstrate that previously activated CD4 T cells retain the
ability to up-regulate c-Jun N-terminal kinase activity and IL-2 mRNA
levels upon TCR engagement and no longer require costimulation. This
rewiring of signaling pathways is similar to that seen following
reversal of AINR in CD8 T cells. Thus, CD8 and CD4 T cells appear to
use distinct mechanisms, AINR and activation-induced cell death,
respectively, to limit excessive clonal expansion following a
productive response, while permitting important effector functions to
be expressed.
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