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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.
Costimulation-dependent production and autocrine use of IL-2 by
activated CD8 T cells results in initial clonal expansion, but this is
transient. The cells quickly become anergic, unable to produce IL-2 in
response to Ag and costimulation, irrespective of the form of
costimulation. This activation-induced non-responsiveness (AINR)
differs from "classical" anergy in that it results despite the
cells receiving both signal 1 and signal 2. AINR cells can still
proliferate in response to exogenous IL-2, but can no longer produce
it. Other TCR-mediated events including cytolytic function and IFN-
production are not affected in the AINR state. To characterize the
mechanism(s) responsible for lack of IL-2 production in CD8 T cells in
the AINR state, microspheres bearing immobilized anti-TCR Abs or
peptide-MHC complexes, B7-1, and ICAM-1 were used to provide
well-defined stimuli to the cells. Comparison of normal and AINR cells
revealed that in AINR cells extracellular signal-regulated kinase
(ERK) is upregulated more transiently, Janus kinase activation
is substantially reduced, and activation of p38 is eliminated. PMA and
ionomycin restored proliferation and IL-2 production in AINR cells,
indicating a signaling defect upstream of Ras and protein kinase C.
Inhibitors of ERK (PD98059) and of p38 kinase (SB202190) blocked IL-2
mRNA expression and proliferation of both
peptide-MHC/B7-1/ICAM-1-stimulated normal cells and
PMA/ionomycin-stimulated AINR cells. Together these results demonstrate
that activation of at least ERK and p38 is essential for IL-2
production by CD8 T cells and that up-regulation of these
mitogen-activated protein kinases, along with Janus kinase, is
defective in AINR cells.
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