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Divergent requirement for G?s and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets.

ABSTRACT: cAMP, the intracellular signaling molecule produced in response to GPCR signaling, has long been recognized as an immunosuppressive agent that inhibits T cell receptor activation and T cell function. However, recent studies show that cAMP also promotes T cell-mediated immunity. Central to cAMP production downstream of GPCR activation is the trimeric G protein Gs. In order to reconcile the reports of divergent effects of cAMP in T cells and to define the direct effect of cAMP in T cells, we engineered mice in which the stimulatory G? subunit of Gs (G?s) could be deleted in T cells using CD4-Cre (Gnas(?CD4)). Gnas(?CD4) CD4(+) T cells had reduced cAMP accumulation and Ca2(+) influx. In vitro and in vivo, Gnas(?CD4) CD4(+) T cells displayed impaired differentiation to specific Th subsets: Th17 and Th1 cells were reduced or absent, but Th2 and regulatory T cells were unaffected. Furthermore, Gnas(?CD4) CD4(+) T cells failed to provoke colitis in an adoptive transfer model, indicating reduced inflammatory function. Restoration of cAMP levels rescued the impaired phenotype of Gnas(?CD4) CD4(+) T cells, reinstated the PKA-dependent influx of Ca2(+), and enhanced the ability of these cells to induce colitis. Our findings thus define an important role for cAMP in the differentiation of Th subsets and their subsequent inflammatory responses, and provide evidence that altering cAMP levels in CD4(+) T cells could provide an immunomodulatory approach targeting specific Th subsets.

SUBMITTER: Li X

PROVIDER: S-EPMC3287220 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets.

Li Xiangli X Murray Fiona F Koide Naoki N Goldstone Jonathan J Dann Sara M SM Chen Jianzhong J Bertin Samuel S Fu Guo G Weinstein Lee S LS Chen Min M Corr Maripat M Eckmann Lars L Insel Paul A PA Raz Eyal E

The Journal of clinical investigation 20120213 3

cAMP, the intracellular signaling molecule produced in response to GPCR signaling, has long been recognized as an immunosuppressive agent that inhibits T cell receptor activation and T cell function. However, recent studies show that cAMP also promotes T cell-mediated immunity. Central to cAMP production downstream of GPCR activation is the trimeric G protein Gs. In order to reconcile the reports of divergent effects of cAMP in T cells and to define the direct effect of cAMP in T cells, we engin ...[more]

PMID: 22326954

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Project description:Isolated Schwann cells (SCs) respond to cAMP elevation by adopting a differentiated post-mitotic state that exhibits high levels of Krox-20, a transcriptional enhancer of myelination, and mature SC markers such as the myelin lipid galactocerebroside (O1). To address how cAMP controls myelination, we performed a series of cell culture experiments which compared the differentiating responses of isolated and axon-related SCs to cAMP analogs and ascorbate, a known inducer of axon ensheathment, basal lamina formation and myelination. In axon-related SCs, cAMP induced the expression of Krox-20 and O1 without a concomitant increase in the expression of myelin basic protein (MBP) and without promoting axon ensheathment, collagen synthesis or basal lamina assembly. When cAMP was provided together with ascorbate, a dramatic enhancement of MBP expression occurred, indicating that cAMP primes SCs to form myelin only under conditions supportive of basal lamina formation. Experiments using a combination of cell permeable cAMP analogs and type-selective adenylyl cyclase (AC) agonists and antagonists revealed that selective transmembrane AC (tmAC) activation with forskolin was not sufficient for full SC differentiation and that the attainment of an O1 positive state also relied on the activity of the soluble AC (sAC), a bicarbonate sensor that is insensitive to forskolin and GPCR activation. Pharmacological and immunological evidence indicated that SCs expressed sAC and that sAC activity was required for morphological differentiation and the expression of myelin markers such as O1 and protein zero. To conclude, our data indicates that cAMP did not directly drive myelination but rather the transition into an O1 positive state, which is perhaps the most critical cAMP-dependent rate limiting step for the onset of myelination. The temporally restricted role of cAMP in inducing differentiation independently of basal lamina formation provides a clear example of the uncoupling of signals controlling differentiation and myelination in SCs.

Dataset Information

Divergent requirement for G?s and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets.

Publications

Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets.

Similar Datasets

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