Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac.
Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac.
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DOI：
10.1042/bj20130064
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发表时间：
2013-12
期刊：
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通讯作者：
A. Vang;William J. Housley;Hongli Dong;Chaitali P Basole;S. Ben-Sasson;B. Kream;P. Epstein;R. Clark;S. Brocke
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文献类型：
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作者：
A. Vang;William J. Housley;Hongli Dong;Chaitali P Basole;S. Ben-Sasson;B. Kream;P. Epstein;R. Clark;S. Brocke
cAMP信号传导是诱导免疫耐受的主要途径以及关键治疗靶标，并且参与Treg细胞（调节性T细胞）功能。为了实现有效的免疫调节，cAMP可以通过几种下游效应物起作用。一种提出的机制是cAMP介导的抑制，包括Treg细胞的免疫抑制，是由PKA（蛋白激酶A）的激活导致转录因子ICER（诱导型cAMP早期阻遏物）的诱导引起的。在本研究中，我们检测了缺乏ICER的Crem（cAMP反应元件调节剂）基因缺陷小鼠（Crem（-/-）/ICER缺陷小鼠）中的CD 4（+）CD 25（-）Teff细胞（效应T细胞）和CD 4（+）CD 25（+）Treg细胞免疫应答。ICER缺乏没有显著改变Treg细胞和Teff细胞的频率或数量。Treg细胞或cAMP的药理学增加抑制来自Crem（+/+）和Crem（-/-）/ICER缺陷小鼠的Teff细胞至同等程度，证明ICER在这些功能中是无效的。此外，激活cAMP效应子Epac（由cAMP直接激活的交换蛋白）抑制Teff细胞。Treg细胞表达低水平的所有测试的环核苷酸Pde（磷酸二酯酶）基因，但高水平的Epac。这些数据确定ICER作为Treg细胞和cAMP对Teff细胞作用的冗余介体，并表明Epac可作为促进cAMP依赖性Teff细胞抑制的替代效应物。
cAMP signalling is both a major pathway as well as a key therapeutic target for inducing immune tolerance and is involved in Treg cell (regulatory T-cell) function. To achieve potent immunoregulation, cAMP can act through several downstream effectors. One proposed mechanism is that cAMP-mediated suppression, including immunosuppression by Treg cells, results from activation of PKA (protein kinase A) leading to the induction of the transcription factor ICER (inducible cAMP early repressor). In the present study, we examined CD4(+)CD25(-) Teff cell (effector T-cell) and CD4(+)CD25(+) Treg cell immune responses in Crem (cAMP-response-element modulator) gene-deficient mice which lack ICER (Crem(-/-)/ICER-deficient mice). ICER deficiency did not significantly alter the frequency or number of Treg cells and Teff cells. Treg cells or a pharmacological increase in cAMP suppressed Teff cells from Crem(+/+) and Crem(-/-)/ICER-deficient mice to an equivalent degree, demonstrating that ICER is dispensable in these functions. Additionally, activating the cAMP effector Epac (exchange protein directly activated by cAMP) suppressed Teff cells. Treg cells expressed low levels of all cyclic nucleotide Pde (phosphodiesterase) genes tested, but high levels of Epac. These data identify ICER as a redundant mediator of Treg cells and cAMP action on Teff cells and suggest that Epac may function as an alternative effector to promote cAMP-dependent Teff cell suppression.