期刊
JOURNAL OF IMMUNOLOGY
卷 164, 期 4, 页码 1689-1694出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.164.4.1689
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- NCI NIH HHS [CA-08252] Funding Source: Medline
- NIAID NIH HHS [AI-32064] Funding Source: Medline
- NIAMS NIH HHS [P50 AR-42558] Funding Source: Medline
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-alpha-TNFR, in apoptosis of murine CD8(+)4(+) double-positive (DP) thymocytes induced via TCR-CD3- and cAMP-mediated signaling. TCR-CD3 epsilon-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-alpha, as evidenced by 1) the ability of anti-TNF-alpha mAbs to abrogate cAMP analogue-induced DP apoptosis in a dose-dependent manner; and 2) increased resistance of DP thymocytes from TNF-alpha(-/-) 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-alpha production, and, second, they sensitized DP thymocytes to TNF-alpha. The latter effect may be due to the down-regulation of TNFR-associated factor 2 protein. These results identify TNF-alpha 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 acid Pharmacological conditions.
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