T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry

Protein kinase Cθ (PKCθ) is a key enzyme in T-lymphocytes where it plays an important role in signal transduction downstream of the activated T-cell receptor (TCR) and the CD28 co-stimulatory receptor. Antigenic stimulation of T-cells triggers PKCθ translocation to the centre of the immunological synapse (IS) at the contact site between antigen-specific T-cells and antigen-presenting cells (APCs). The IS-residing PKCθ phosphorylates and activates effector molecules that transduce signals into distinct subcellular compartments and activate the transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T-cells (NFAT) and activating protein 1 (AP-1), which are essential for the induction of T-cell-mediated responses. Besides its major biological role in T-cells, PKCθ is expressed in several additional cell types and is involved in a variety of distinct physiological and pathological phenomena. For example, PKCθ is expressed at high levels in platelets where it regulates signal transduction from distinct surface receptors, and is required for optimal platelet activation and aggregation, as well as haemostasis. In addition, PKCθ is involved in physiological processes regulating insulin resistance and susceptibility to obesity, and is expressed at high levels in gastrointestinal stromal tumours (GISTs), although the functional importance of PKCθ in these processes and cell types is not fully clear. The present article briefly reviews selected topics relevant to the biological roles of PKCθ in health and disease.

Download Full-text

Regulation of the T-cell receptor delta enhancer by functional cooperation between c-Myb and core-binding factors.

Molecular and Cellular Biology ◽

10.1128/mcb.14.1.473 ◽

1994 ◽

Vol 14 (1) ◽

pp. 473-483 ◽

Cited By ~ 98

Author(s):

C Hernandez-Munain ◽

M S Krangel

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Transcriptional Activation ◽

Cell Receptor ◽

Enhancer Activity ◽

Control Of Gene Expression ◽

Enhancer Element ◽

The Core ◽

Core Site ◽

Factor C

A T-cell-specific transcriptional enhancer lies within the J delta 3-C delta intron of the human T-cell receptor (TCR) delta gene. The 30-bp minimal enhancer element denoted delta E3 carries a core sequence (TGTGGTTT) that binds a T-cell-specific factor, and that is necessary but not sufficient for transcriptional activation. Here we demonstrate that the transcription factor c-Myb regulates TCR delta enhancer activity through a binding site in delta E3 that is adjacent to the core site. Both v-Myb and c-Myb bind specifically to delta E3. The Myb site is necessary for enhancer activity, because a mutation that eliminates Myb binding abolishes transcriptional activation by the delta E3 element and by the 370-bp TCR delta enhancer. Transfection of cells with a c-Myb expression construct upregulates delta E3 enhancer activity, whereas treatment of cells with an antisense c-myb oligonucleotide inhibits delta E3 enhancer activity. Since intact Myb and core sites are both required for delta E3 function, our data argue that c-Myb and core binding factors must cooperate to mediate transcriptional activation through delta E3. Efficient cooperation depends on the relative positioning of the Myb and core sites, since only one of two overlapping Myb sites within delta E3 is functional and alterations of the distance between this site and the core site disrupt enhancer activity. Cooperative regulation by c-Myb and core-binding factors is likely to play an important role in the control of gene expression during T-cell development.

Download Full-text

CRE-Mediated transcriptional activation is involved in cAMP protection of T-cell receptor-induced apoptosis but not in cAMP potentiation of glucocorticoid-mediated programmed cell death

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/s0167-4889(01)00174-4 ◽

2002 ◽

Vol 1542 (1-3) ◽

pp. 139-148 ◽

Cited By ~ 12

Author(s):

Lionel Müller Igaz ◽

Damián Refojo ◽

Mónica A. Costas ◽

Florian Holsboer ◽

Eduardo Arzt

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

T Cell Receptor ◽

Transcriptional Activation ◽

Cell Receptor ◽

Induced Apoptosis

Download Full-text

Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17

Journal of Biological Chemistry ◽

10.1074/jbc.m405764200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 52762-52771 ◽

Cited By ~ 116

Author(s):

Xikui K. Liu ◽

Xin Lin ◽

Sarah L. Gaffen

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Promoter Activity ◽

Cell Receptor ◽

Cross Linking ◽

Supporting Evidence ◽

Nuclear Factor ◽

Tcr Signaling ◽

Activated T Cells

The biological activities of the inflammatory cytokine interleukin (IL)-17 have been widely studied. However, comparatively little is known about how IL-17 expression is controlled. Here, we examined the basis for transcriptional regulation of the human IL-17 gene. IL-17 secretion was induced in peripheral blood mononuclear cells following anti-CD3 cross-linking to activate the T cell receptor (TCR), and costimulatory signaling through CD28 strongly enhanced CD3-induced IL-17 production. To definecis-acting elements important for IL-17 gene regulation, we cloned 1.25 kb of genomic sequence upstream of the transcriptional start site. This putative promoter was active in Jurkat T cells following CD3 and CD28 cross-linking, and its activity was inhibited by cyclosporin A and MAPK inhibitors. The promoter was also active in Hut102 T cells, which we have shown to secrete IL-17 constitutively. Overexpression of nuclear factor of activated T cells (NFAT) or Ras enhanced IL-17 promoter activity, and studies in Jurkat lines deficient in specific TCR signaling pathways provided supporting evidence for a role for NFAT. To delineate the IL-17 minimal promoter, we created a series of 5′ truncations and identified a region between -232 and -159 that was sufficient for inducible promoter activity. Interestingly, two NFAT sites were located within this region, which bound to NFATc1 and NFATc2 in nuclear extracts from Hut102 and Jurkat cells. Moreover, mutations of these sites dramatically reduced both specific DNA binding and reporter gene activity, and chromatin immunoprecipitation assays showed occupancy of NFAT at this regionin vivo. Together, these data show that NFAT is the crucial sensor of TCR signaling in the IL-17 promoter.

Download Full-text

Agonist-Selected T Cell Development Requires Strong T Cell Receptor Signaling and Store-Operated Calcium Entry

Immunity ◽

10.1016/j.immuni.2013.02.008 ◽

2013 ◽

Vol 38 (5) ◽

pp. 881-895 ◽

Cited By ~ 72

Author(s):

Masatsugu Oh-hora ◽

Noriko Komatsu ◽

Mojgan Pishyareh ◽

Stefan Feske ◽

Shohei Hori ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

T Cell Development ◽

Cell Receptor ◽

Cell Development ◽

Calcium Entry ◽

Receptor Signaling ◽

T Cell Receptor Signaling ◽

Store Operated Calcium Entry ◽

Cell Receptor Signaling

Download Full-text

T Cell Receptor–initiated Calcium Release Is Uncoupled from Capacitative Calcium Entry in Itk-deficient T Cells

Journal of Experimental Medicine ◽

10.1084/jem.187.10.1721 ◽

1998 ◽

Vol 187 (10) ◽

pp. 1721-1727 ◽

Cited By ~ 240

Author(s):

Karen-Qianye Liu ◽

Stephen C. Bunnell ◽

Christine B. Gurniak ◽

Leslie J. Berg

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Calcium Release ◽

Interleukin 2 ◽

Cell Receptor ◽

Calcium Entry ◽

Tcr Signaling ◽

Store Depletion ◽

High Concentrations

Itk, a Tec family tyrosine kinase, plays an important but as yet undefined role in T cell receptor (TCR) signaling. Here we show that T cells from Itk-deficient mice have a TCR-proximal signaling defect, resulting in defective interleukin 2 secretion. Upon TCR stimulation, Itk−/− T cells release normal amounts of calcium from intracellular stores, but fail to open plasma membrane calcium channels. Since thapsigargin-induced store depletion triggers normal calcium entry in Itk−/− T cells, an impaired biochemical link between store depletion and channel opening is unlikely to be responsible for this defect. Biochemical studies indicate that TCR-induced inositol 1,4,5 tris-phosphate (IP3) generation and phospholipase C γ1 tyrosine phosphorylation are substantially reduced in Itk−/− T cells. In contrast, TCR-ζ and ZAP-70 are phosphorylated normally, suggesting that Itk functions downstream of, or in parallel to, ZAP-70 to facilitate TCR-induced IP3 production. These findings support a model in which quantitative differences in cytosolic IP3 trigger distinct responses, and in which only high concentrations of IP3 trigger the influx of extracellular calcium.

Download Full-text