Th17 Cells Exhibit a Distinct Calcium Profile from Th1 and Th2 Cells and Have Th1-Like Motility and NF-AT Nuclear Localization

Weber, K. Scott; Miller, Mark J.; Allen, Paul M.

doi:10.4049/jimmunol.180.3.1442

Cited by 47 publications

(52 citation statements)

References 69 publications

(63 reference statements)

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“…Importantly, these effects were not observed for Th2 cells, thus implying that their differentiation is independent of cAMP and cAMP/PKA-induced Ca 2+ influx. This observation is consistent with evidence that the activation of Th1 and Th2 under the same conditions results in different patterns of Ca 2+ signaling and cytokine production (33).…”

Section: Discussionsupporting

confidence: 80%

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

Li¹,

Murray²,

Koide³

et al. 2012

J. Clin. Invest.

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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 (Gnas ΔCD4 ). Gnas ΔCD4 CD4 + T cells had reduced cAMP accumulation and Ca 2+ influx. In vitro and in vivo, Gnas ΔCD4 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 ΔCD4 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 ΔCD4

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Section: Discussionsupporting

confidence: 80%

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

Li¹,

Murray²,

Koide³

et al. 2012

J. Clin. Invest.

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“…Ca 2ϩ concentration was estimated as described previously. 12 To measure intracellular cAMP, HUVECs were pretreated for 10 minutes with 0.75mM 3-isobutyl-1-methylxanthine (IBMX) and challenged with agonists for 1-5 minutes. Levels of cAMP were determined in cell lysates with a CatchPoint cAMP fluorescent assay kit (Molecular Devices) and VICTOR 2 microplate reader.…”

Section: Measurement Of Intracellular Ca 2؉ and Campmentioning

confidence: 99%

Shiga toxin (Stx)1B and Stx2B induce von Willebrand factor secretion from human umbilical vein endothelial cells through different signaling pathways

Liu

Huang

Sadler

2011

Blood

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IntroductionIngestion of food contaminated with Shiga toxin (Stx)-producing Escherichia coli, such as strain O157:H7, can cause bloody diarrhea that develops into diarrhea-associated hemolytic uremic syndrome (D ϩ HUS) that is characterized by acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. D ϩ HUS is the most common cause of acute renal failure in children and is fatal in ϳ 3%-5% of cases. 1 Several mechanisms seem to influence the course of tissue injury by Stx. Stx-producing E coli make 2 major types of Stx, each of which is composed of 1 catalytically active A subunit (ϳ 33 kDa) and 5 B subunits (ϳ 7.7 kDa) that form a homopentameric ring. Stx1 is identical to the major toxin produced by Shigella dysenteriae serotype 1. Stx2 is ϳ 50%-60% identical in sequence to Stx1 and occurs in several variants. Stx1 binds to globotriaosylceramide (Gb3) more tightly than Stx2, but Stx2 is more toxic in animal models and is more often associated with D ϩ HUS in humans than Stx1. [2][3][4] The Stx B subunits bind to Gb3 on cell surfaces and facilitate internalization of the Stx holotoxin that undergoes retrograde transport to the endoplasmic reticulum. The Stx A subunit is then translocated into the cytoplasm where it cleaves the adenine base at position 4324 of 28S ribosomal RNA, thereby blocking protein synthesis and initiating a series of responses that culminate in cell death. 5 In addition, treatment of human umbilical vein endothelial cells (HUVECs) or glomerular microvascular endothelial cells (HGMECs) with nanomolar concentrations of Stx1 or Stx2 induces rapid VWF secretion and the formation of long cellassociated VWF strings. 6 Administration of Stx2 to Adamts13 Ϫ/Ϫ mice also causes fatal microvascular thrombosis that resembles thrombotic thrombocytopenic purpura, and Adamts13 Ϫ/Ϫ mice are protected from the lethal effects of Stx if they also lack VWF. 7 We recently found that the B subunits from Stx1 or Stx2, in the absence of the A subunits, are sufficient to stimulate VWF secretion by HUVECs or HGMECs and that Stx2B subunits can induce thrombotic microangiopathy in Adamts13 Ϫ/Ϫ mice. 8 These responses indicate the existence of Stx B-induced signaling pathways that may be responsible for some of the biologic effects attributed previously to the cytotoxic Stx A subunit.At least 3 signaling pathways can contribute to agonist-induced secretion of VWF. Histamine and thrombin activate phospholipase C (PLC)-␤ that generates inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol. IP 3 increases the level of intracellular Ca 2ϩ that is required for VWF secretion induced by these agonists. In contrast, epinephrine and vasopressin induce VWF secretion by increasing intracellular cAMP and activating protein kinase A (PKA). 9 Alternatively, vascular endothelial growth factor (VEGF) stimulates VWF secretion through a pathway that depends on protein kinase C (PKC)-␦ but not on Ca 2ϩ or cAMP. 10 Whether any of these pathways contribute to Stx B-induced VWF secretion has not been determined previous...

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“…Flow cytometry also precludes investigation of temporal dynamics within a single-cell pair. Alternative approaches include immobilization of one of the interacting partners on poly-L-lysine-coated cover slips and then adding the second partner from the top [18][19][20][21][22][23] . Although these studies have provided key insights into immune cell activation, this approach has limited throughput and does not provide adequate control over pairing (for example, timing of interactions, movement of partner cells, duration of contacts and so on), thus complicating analysis and interpretation of results.…”

mentioning

confidence: 99%

Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing

et al. 2015

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Establishing a successful immune response requires cell-cell interactions, where the nature of antigen presentation dictates functional outcomes. Methods to study these interactions, however, suffer from limited throughput and a lack of control over cell pairing. Here we describe a microfluidic platform that achieves high-throughput deterministic pairing of lymphocytes with a defined contact time, thereby allowing accurate assessment of early activation events for each pair in controlled microenvironments. More importantly, the platform allows the capture of dynamic processes and static parameters from both partners simultaneously, thus enabling pairwise-correlated multiparametric profiling of lymphocyte interactions over hundreds of pairs in a single experiment. Using our platform, we characterized early activation dynamics of CD8 T cells (OT-1 and TRP1 transnuclear (TN)) and investigated the extent of heterogeneity in T-cell activation and the correlation of multiple readouts. The results establish our platform as a promising tool for quantitative investigation of lymphocyte interactions.

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Th17 Cells Exhibit a Distinct Calcium Profile from Th1 and Th2 Cells and Have Th1-Like Motility and NF-AT Nuclear Localization

Cited by 47 publications

References 69 publications

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

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

Shiga toxin (Stx)1B and Stx2B induce von Willebrand factor secretion from human umbilical vein endothelial cells through different signaling pathways

Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing

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