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(Journal of Leukocyte Biology. 2001;69:1053-1059.)
© 2001 by Society for Leukocyte Biology

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

Josef Bodor^*, Lionel Feigenbaum, Jana Bodorova, Cathy Bare^*, Marvin S. Reitz, Jr and Ronald E. Gress^*

^* Experimental Immunology Branch, Division of Basic Sciences, and
Transplantation Therapy Section, Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892;
Transgenic Mouse Model, Science Application International Corporation, National Cancer Institute Frederick Cancer Research and Development Center, Frederick, Maryland 21702; and
Institute of Human Virology, University of Maryland, Baltimore, Maryland 21201

Correspondence: Dr. Ronald E. Gress, National Cancer Institute, Experimental Immunology Branch, Bldg. 10, Rm. 4B14, 10 Center Dr., Bethesda, MD 20892-1360. E-mail: gressr{at}dc10a.nci.nih.gov

Depending on the nature of the costimulation of T lymphocytes, expression of regulatory cytokines and chemokines is either susceptible or resistant to cyclic AMP (cAMP)-mediated inhibition. Our data show that 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 cells activated under conditions of suboptimal interleukin-2 (IL-2) expression. Importantly, Th-specific expression of certain chemokines is also susceptible to cAMP-mediated transcriptional attenuation. To determine whether ICER per se, rather than forskolin-mediated elevation of intracellular cAMP, is responsible for the observed inhibitory effect, we generated transgenic mice expressing ICER under the control of a lymphocyte-specific lck promoter. On stimulation, transgenic thymocytes overexpressing ICER exhibited reduced levels of IL-2 and interferon (IFN)- and failed to express the macrophage inflammatory protein (MIP)-1 and MIP-1ß genes. Splenic T cells from ICER-transgenic mice showed a defect in proliferation and lacked a mixed lymphocyte reaction response, implying that ICER-mediated inhibition of cytokine and chemokine expression might play an important role in T-cell inactivation.

Key Words: transcription factors • cytokines • chemokines

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