Suppression of T-cell responsiveness by inducible cAMP early repressor (ICER)

Abstract

Depending on the nature of the costimulation of T lymphocytes, expression of regulatory cytokines and chemokines is either susceptibleor resistant to cyclic AMP (cAMP)-mediated inhibition. Our data showthat cAMP-mediated inhibition of endogenously expressed cytokines, which is characteristic for T helper (Th) 1- and Th 2-like phenotypes, correlates with the induction of a potent transcriptional repressor, inducible cAMP early repressor (ICER), in both subsets of T cellsactivated under conditions of suboptimal interleukin-2 (IL-2)expression. Importantly, Th-specific expression of certain chemokinesis also susceptible to cAMP-mediated transcriptional attenuation. Todetermine whether ICER per se, rather than forskolin-mediated elevationof intracellular cAMP, is responsible for the observed inhibitoryeffect, we generated transgenic mice expressing ICER under the controlof a lymphocyte-specific lck promoter. On stimulation, transgenic thymocytes overexpressing ICER exhibited reduced levels of IL-2 and interferon (IFN)-γ and failed to express the macrophageinflammatory protein (MIP)-1α and MIP-1β genes. Splenic T cellsfrom ICER-transgenic mice showed a defect in proliferation and lacked amixed lymphocyte reaction response, implying that ICER-mediatedinhibition of cytokine and chemokine expression might play an importantrole in T-cell inactivation.