title: Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-κB, and NFAT signaling in conventional T cells.
abstract: CD4(+)CD25(hi)Foxp3(+) regulatory T cells (T(regs)) are critical mediators of self-tolerance, which is crucial for the prevention of autoimmune disease, but T(regs) can also inhibit antitumor immunity. T(regs) inhibit the proliferation of CD4(+)CD25(-) conventional T cells (T(cons)), as well as the ability of these cells to produce effector cytokines; however, the molecular mechanism of suppression remains unclear. Here, we showed that human T(regs) rapidly suppressed the release of calcium ions (Ca(2+)) from intracellular stores in response to T cell receptor (TCR) activation in T(cons). The inhibition of Ca(2+) signaling resulted in decreased dephosphorylation, and thus decreased activation, of the transcription factor nuclear factor of activated T cells 1 (NFAT1) and reduced the activation of nuclear factor κB (NF-κB). In contrast, Ca(2+)-independent events in T(cons), such as TCR-proximal signaling and activation of the transcription factor activator protein 1 (AP-1), were not affected during coculture with T(regs). Despite suppressing intracellular Ca(2+) mobilization, coculture with T(regs) did not block the generation of inositol 1,4,5-trisphosphate in TCR-stimulated T(cons). The T(reg)-induced suppression of the activity of NFAT and NF-κB and of the expression of the gene encoding the cytokine interleukin-2 was reversed in T(cons) by increasing the concentration of intracellular Ca(2+). Our results elucidate a previously unrecognized and rapid mechanism of T(reg)-mediated suppression. This increased understanding of T(reg) function may be exploited to generate possible therapies for the treatment of autoimmune diseases and cancer.
authors.affiliation: Division of Immunogenetics (D030), Tumor Immunology Program, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Schmidt
authors.forename: Nina
authors.initials: N
authors.lastname: Oberle
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Weiss
authors.forename: Diana
authors.initials: D
authors.lastname: Vobis
authors.forename: Stefan
authors.initials: S
authors.lastname: Frischbutter
authors.forename: Ria
authors.initials: R
authors.lastname: Baumgrass
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.forename: Mathias
authors.initials: M
authors.lastname: Haag
authors.forename: Britta
authors.initials: B
authors.lastname: Brügger
authors.forename: Hongying
authors.initials: H
authors.lastname: Lin
authors.forename: Georg W
authors.initials: GW
authors.lastname: Mayr
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Matthias
authors.initials: M
authors.lastname: Gunzer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Suri-Payer
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000276:immunology* / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D018129:Phosphatidylinositol Phosphates / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D018129:Phosphatidylinositol Phosphates; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D002118:Calcium