Academic Commons

Articles

TNF-α Is the Critical Mediator of the Cyclic AMP-Induced Apoptosis of CD8+4+ Double-Positive Thymocytes

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

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.

Files

  • thumnail for JI_2000_Guevara_Patino.pdf JI_2000_Guevara_Patino.pdf application/pdf 182 KB Download File

Also Published In

Title
The Journal of Immunology
DOI
https://doi.org/10.4049/jimmunol.164.4.1689

More About This Work

Academic Units
Center for Radiological Research
Publisher
American Association of Immunologists
Published Here
September 14, 2015
Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.