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Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Costimulation (signal 2) has been proposed to inhibit the induction
of T cell clonal anergy by either directly antagonizing negative
signals arising from TCR engagement (signal 1) or by synergizing with
signal 1 to produce IL-2, which in turn leads to proliferation and
dilution of negative regulatory factors. To better define the cellular
events that lead to the induction of anergy, we used the
immunosuppressive agent rapamycin, which blocks T cell proliferation in
late G1 phase but does not affect costimulation-dependent IL-2
production. Our data demonstrate that full T cell activation (signal 1
plus 2) in the presence of rapamycin results in profound T cell anergy,
despite the fact that these cells produce copious amounts of IL-2.
Similar to conventional anergy (induction by signal 1 alone), the
rapamycin-induced anergic cells show a decrease in mitogen-activated
protein kinase activation, and these cells can be rescued by culture in
IL-2. Interestingly, the rapamycin-induced anergic cells display a more
profound block in IL-3 and IFN-
production upon rechallenge.
Finally, in contrast to rapamycin, full T cell activation in the
presence of hydroxyurea (which inhibits the cell cycle in early S
phase) did not result in anergy. These data suggest that it is neither
the direct effect of costimulation nor the subsequent T cell
proliferation that prevents anergy induction, but rather the
biochemical events that occur upon progression through the cell cycle
from G1 into S phase.
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