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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-06-1665.
Submitted June 10, 2002
Accepted September 2, 2002
cAMP inhibits both Ras and Rap1 activiation in primary human T lymphocytes, but only Ras inhibition correlates with blockade of cell cycle progression
Thomas Grader-Beck, Andre A F L van Puijenbroek, Lee M Nadler, and Vassiliki A Boussiotis*
Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA, USA
* Corresponding author; email: vassiliki_boussiotis{at}dfci.harvard.edu.
Cyclic AMP (cAMP) is a negative regulator of T cell activation. However, the effects of cAMP on signaling pathways that regulate cytokine production and cell cycle progression remain unclear. Here, using primary human T lymphocytes in which endogenous cAMP was increased by the use of Forskolin and IBMX, we show that increase of cAMP resulted in inhibition of TCR/CD3-plus-CD28-mediated T cell activation and cytokine production and blockade of cell cycle progression at the G1 phase. Increase of cAMP inhibited Ras activation and phosphorylation of MEK downstream targets ERK1/2, and phosphatidylinositol-3-kinase (PI3K) downstream target protein kinase B (PKB;c-Akt). These functional and biochemical events were secondary to the impaired activation of ZAP-70 and phosphorylation of LAT and did not occur when cells were stimulated with phorbol ester, which bypasses the TCR proximal signaling events and activates Ras. Increase of cAMP also inhibited activation of Rap1 mediated by TCR/CD3-plus-CD28. Importantly, inhibition of Rap1 activation by cAMP was also observed when cells were stimulated with phorbol ester, although under these conditions Ras was activated and cells progressed into the cell cycle. Thus, TCR-plus-CD28-mediated activation of ERK1/2 and PKB, cytokine production and cell cycle progression, all of which are inhibited by cAMP, require activation of Ras but not Rap1. These results indicate that signals which regulate cAMP levels after encounter of T cells by antigen will likely determine the functional fate towards clonal expansion or repression of primary T cell responses.
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