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

Xiangli Li, Fiona Murray, Naoki Koide, Jonathan Goldstone, Sara M. Dann, Jianzhong Chen, Samuel Bertin, Guo Fu, Lee S. Weinstein, Min Chen, Maripat Corr, Lars Eckmann, Paul A. Insel, Eyal Raz*

*Corresponding author for this work

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 Gα subunit of Gs (Gαs) could be deleted in T cells using CD4-Cre (GnasΔCD4). GnasΔCD4 CD4+ T cells had reduced cAMP accumulation and Ca2+ influx. In vitro and in vivo, GnasΔCD4 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, GnasΔCD4 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 GnasΔCD4 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.
Original languageEnglish
Pages (from-to)963-973
Number of pages11
JournalThe Journal of Clinical Investigation
Volume122
Issue number3
Early online date13 Feb 2012
DOIs
Publication statusPublished - 1 Mar 2012

Keywords

  • activation
  • generation
  • channels
  • stimulation
  • phosphorylation
  • G-protein
  • adenylate-cyclase
  • cell-differentiation
  • pathogenesis
  • growth-factor receptor

Cite this

Li, X., Murray, F., Koide, N., Goldstone, J., Dann, S. M., Chen, J., Bertin, S., Fu, G., Weinstein, L. S., Chen, M., Corr, M., Eckmann, L., Insel, P. A., & Raz, E. (2012). Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets. The Journal of Clinical Investigation, 122(3), 963-973. https://doi.org/10.1172/JCI59097