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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4841-4848.
Prepublished online as a Blood First Edition Paper on March 2, 2006; DOI 10.1182/blood-2005-10-4044.
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IMMUNOBIOLOGY
PKC and PKA are antagonistic partners in the NF-AT transactivation pathway of primary mouse CD3+ T lymphocytes
Natascha Hermann-Kleiter,
Nikolaus Thuille,
Christa Pfeifhofer,
Thomas Gruber,
Michaela Schäfer,
Christof Zitt,
Armin Hatzelmann,
Christian Schudt,
Michael Leitges, and
Gottfried Baier
From the Department for Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria; ALTANA Pharma, Konstanz, Germany; and Medical University, Hanover, Germany.
We here investigate the crosstalk of PKC and PKA signaling during primary CD3+ T-lymphocyte activation using pharmacologic inhibitors and activators in combination with our established panel of PKC isotype–deficient mouse T cells in vitro. PKC and PKA inversely affect the CD3/CD28-induced IL-2 expression, whereas other PKC isotypes are dispensable in this signaling pathway. Gene ablation of PKC selectively results in a profound reduction of IL-2 production; however, complete abrogation of IL-2 production in these PKC–/– T cells was achieved only by simultaneous coactivation of the cAMP/PKA pathway in CD3+ T cells. Conversely, the reduced IL-2 production in PKC inhibitor–treated T cells can be rescued by inhibition of the cAMP/PKA pathway in wild-type but not in PKC–/– T cells. Mechanistically, the cAMP/PKA and PKC pathways converge at the level of NF-AT, as shown by DNA binding analysis. The combined increase in PKA and decrease in PKC activity leads to an enhanced inhibition of nuclear NF-AT translocation. This PKC/PKA crosstalk significantly affects neither the NF- B, the AP-1, nor the CREB pathways. Taken together, this opposite effect between the positive PKC and the negative cAMP/PKA signaling pathways appears rate limiting for NF-AT transactivation and IL-2 secretion responses of CD3+ T lymphocytes.
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