Cyclic AMP-mediated shuffling of ICER alters NFAT-dependent suppression by regulatory T cells

摘要

There is growing evidence that cyclic adenosine monophosphate (cAMP) is directly involved in suppression by naturally occurring regulatory T cells (Treg cells). The inducible cAMP early repressor (ICER) is expressed in Treg cells as well as in effector CD4~+ T cells. In CD3/CD28-activated effector CD4~+ T cells transcriptional repressor ICER is sequestered to the cytoplasm thus unable to oppose NFAT-driven transcription. However, in Treg cells, ICER remains nuclear while NFAT fails to translocate into the nucleus even after CD3/CD28 re-stimulation. Importantly, upon administration of super agonistic CD28-specific monoclonal antibodies (CD28SA) in vivo, ICER is nuclear in effector CD4~+T cells in the presence of Treg cells (no diphteria toxin treatment) but cytosolic in their absence (after diphteria toxin treatment) in "depletion of regulatory T cell" (DEREG) mice. Thus, naturally occurring Treg cells similarly to forskolin could enforce nuclear localization of ICER in vivo.