Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1)

Abstract

Inducible cAMP early repressor (ICER) is a transcriptional repressor, which, because of alternate promoter use, is generated from the 3′ region of the cAMP response modulator (Crem) gene. Its expression and nuclear occurrence are elevated by high cAMP levels in naturally occurring regulatory T cells (nTregs). Using two mouse models, we demonstrate that nTregs control the cellular localization of ICER/CREM, and thereby inhibit IL-2 synthesis in conventional CD4 + T cells. Ablation of nTregs in depletion of regulatory T-cell (DEREG) mice resulted in cytosolic localization of ICER/CREM and increased IL-2 synthesis upon stimulation. Direct contacts between nTregs and conventional CD4 + T cells led to nuclear accumulation of ICER/CREM and suppression of IL-2 synthesis on administration of CD28 superagonistic (CD28SA) Ab. In a similar way, nTregs communicated with B cells and induced the cAMPdriven nuclear localization of ICER/CREM. High levels of ICER suppressed the induction of nuclear factor of activated T cell c1 (Nfatc1) gene in T cells whose inducible Nfatc1 P1 promoter bears two highly conserved cAMP-responsive elements to which ICER/ CREM can bind. These findings suggest that nTregs suppress T-cell responses by the cAMP-dependent nuclear accumulation of ICER/ CREM and inhibition of NFATc1 and IL-2 induction.adenosin 3′,5′-cyclic monophospate | transcription | lymphocytes

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 + regulatory T cells

“…If Treg were functionally impaired, an increase in IL-2 production should be evident. Indeed, when Treg are completely depleted, 10 times more IL-2 is secreted (25,26). The similar low amount of IL-2 produced from suppressed effector T cells in both genotypes of mice revealed functional equivalence between WT and NFAT2-deficient nTreg (Fig.…”

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“…Our previous results indicate that PGE 2 may exert direct effects on downregulation of CCR5 expression in human peripheral blood monocytes (Figure 2). These preliminary studies suggest that in addition to ICER-mediated down regulation of interleukin 2 (IL-2) in autoreactive CD4 + conventional T cells (Tcons) [5][6][7] ICER could also transcriptionally attenuate expression of CCR5 receptor in the presence of PGE 2 ( Figure 2). Therefore genomewide analysis of the pulse treatment of dmPGE 2 for Tregs, Tcons, and HSCs and their consequent CCR5 downregulation along with downregulation of other chemokines and chemokine receptors (such as CXCR4) will be informative.…”

“…Analogous effect could be achieved by direct activation of adenylyl cyclase (AC) by forskolin or inhibition of phosphodiesterases (PDEs) responsible for degradation of cAMP e.g. by Rolipram [6,7]. In response to cAMP/PKA, ICER is induced (after 2-4 h of delay, necessary for ICER synthesis) in the Foxp3 neg Tcons and later ICER protein is enforced to the nucleus in response to cAMP/PKA where it may attenuate CCR5 expression in cAMP dependent fashion (Figure 2).…”

“…Upon TCR activation (not shown), prostaglandin E 2 (PGE 2 ) leads to activation of adenylyl cyclase, intracellular cAMP formation [5], and subsequent protein kinase A (PKA) activation(not shown) followed by the immediate, early induction of inducible cAMP early repressor (ICER) in TCR-activated Foxp3 neg Tcons [6]. Analogous effect could be achieved by direct activation of adenylyl cyclase (AC) by forskolin or inhibition of phosphodiesterases (PDEs) responsible for degradation of cAMP e.g.…”

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“…Inter alia, during nTreg-mediated suppression we have shown that ICER preferentially inhibits the production of IL-2, an essential growth factor for auto-reactive Tcons [14]. We have recently shown that the transcription factors (TFs) ICER and nuclear factor of activated T cell c1 (NFATc1) are decisively involved in the suppression of CD4 + T cells by nTregs [15]. Deficiency in these TFs led to a resistance of CD4 + T cells against nTreg cell-mediated suppression [16].…”