TNF-α is the critical mediator of the cyclic AMP-induced apoptosis of CD8+4+ double-positive thymocytes

José A. Guevara Patiño, Vladimir N. Ivanov, Elizabeth Lacy, Keith B. Elkon, Michael W. Marino, Janko Nikolić-Žugić

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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-α-TNFR, in apoptosis of murine CD8+4+ double-positive (DP) thymocytes induced via TCR-CD3- and cAMP-mediated signaling. TCR-CD3ε-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-α, as evidenced by 1) the ability of anti-TNF-α mAbs to abrogate cAMP analogue-induced DP apoptosis in a dose-dependent manner; and 2) increased resistance of DP thymocytes from TNF-α(-/-) 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-α production, and, second, they sensitized DP thymocytes to TNF-α. The latter effect may be due to the down-regulation of TNFR-associated factor 2 protein. These results identify TNF-α 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.

Original languageEnglish (US)
Pages (from-to)1689-1694
Number of pages6
JournalJournal of Immunology
Volume164
Issue number4
DOIs
StatePublished - Feb 15 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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