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Is the Critical Mediator of the Cyclic AMP-Induced Apoptosis of CD8+4+ Double-Positive Thymocytes1
-
ugi4,*
*
Immunology and
Molecular Biology Programs, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
The Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY 10021; and
§
Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Apoptosis is one of the key regulatory mechanisms in tissue
modeling and development. In the thymus, 95–98% of all thymocytes die
by apoptosis because they failed to express a TCR with an optimal
affinity for the selecting intrathymic peptide-MHC complexes. We
studied the possible role of two prominent nerve growth factor
(NGF-TNF) family member systems, Fas ligand (FasL)-Fas receptor (FasR)
and TNF-
-TNFR, in apoptosis of murine CD8+4+
double-positive (DP) thymocytes induced via TCR-CD3- and cAMP-mediated
signaling. TCR-CD3
-mediated apoptosis of DP thymocytes was found not
to be dependent on either of the two systems. The FasL-FasR system was
also found to be dispensable for the cAMP-mediated apoptosis. By
contrast, cAMP agonists (dibutyryl-cAMP and forskolin) induced
apoptosis via TNF-, as evidenced by 1) the ability of
anti-TNF- mAbs to abrogate cAMP analogue-induced DP apoptosis in
a dose-dependent manner; and 2) increased resistance of DP thymocytes
from TNF--/- and TNFR
I-/-II-/- animals to cAMP agonist-mediated
apoptosis. cAMP agonists induced DP thymocyte death by a combination of
two mechanisms: first, they induced selective up-regulation of TNF-
production, and, second, they sensitized DP thymocytes to TNF-. The
latter effect may be due to the down-regulation of TNFR-associated
factor 2 protein. These results identify TNF- as the critical
mediator of cAMP-induced apoptosis in thymocytes and provide a
molecular explanation for how the cAMP stimulators, including the sex
steroids, may modulate T cell production output, as observed under
physiological and pharmacological conditions.
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