scholarly journals Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s

2016 ◽  
Vol 214 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Jakob von Moltke ◽  
Claire E. O’Leary ◽  
Nora A. Barrett ◽  
Yoshihide Kanaoka ◽  
K. Frank Austen ◽  
...  
Keyword(s):  
T Cells ◽  
Allergic Inflammation ◽  
Primary Source ◽  
Cell Receptor ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Deficient Mice

Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33– and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease.

PKCθ-regulated signalling in health and disease

2014 ◽  
Vol 42 (6) ◽  
pp. 1484-1489 ◽  
Author(s):  
Pulak R. Nath ◽  
Noah Isakov
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
Immunological Synapse ◽  
Cell Types ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Health And Disease

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.

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

2004 ◽  
Vol 279 (50) ◽  
pp. 52762-52771 ◽  
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.

scholarly journals Normal peripheral T-cell function in c-Fos-deficient mice.

1994 ◽  
Vol 14 (3) ◽  
pp. 1566-1574 ◽  
Author(s):  
J Jain ◽  
E A Nalefski ◽  
P G McCaffrey ◽  
R S Johnson ◽  
B M Spiegelman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Family Members ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Activated T Cells ◽  
Peripheral T Cells ◽  
Deficient Mice

The ubiquitous transcription factors Fos and Jun are rapidly induced in T cells stimulated through the T-cell antigen receptor and regulate transcription of cytokines, including interleukin 2, in activated T cells. Since positive and negative selection of thymocytes during T-cell development also depends on activation through the T-cell receptor, Fos and Jun may play a role in thymocyte development as well. Fos and Jun act at several regulatory elements in the interleukin 2 promoter, including the AP-1 and NFAT sites. Using antisera specific to individual Fos and Jun family members, we show that c-Fos as well as other Fos family members are present in the inducible AP-1 and NFAT complexes of activated murine T cells. Nevertheless, c-Fos is not absolutely required for the development or function of peripheral T cells, as shown by using mice in which both copies of the c-fos gene were disrupted by targeted mutagenesis. c-Fos-deficient mice were comparable to wild-type mice in their patterns of thymocyte development and in the ability of their peripheral T cells to proliferate and produce several cytokines in response to T-cell receptor stimulation. Our results suggest that other Fos family members may be capable of substituting functionally for c-Fos during T-cell development and cytokine gene transcription in activated T cells.

scholarly journals A Transcription Function for the T Cell–Specific Adapter (Tsad) Protein in T Cells

2001 ◽  
Vol 193 (12) ◽  
pp. 1425-1430 ◽  
Author(s):  
Francesc Marti ◽  
Nicholas H. Post ◽  
Elena Chan ◽  
Philip D. King
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nuclear Import ◽  
Regulatory Protein ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Nuclear Factor ◽  
Transcription Activator ◽  
Activated T Cells

T cell–specific adapter (TSAd) protein is an Src homology 2 (SH2) domain–containing adapter molecule implicated in T cell receptor for antigen (TCR)-mediated interleukin 2 (IL-2) secretion in T cells. Here, we demonstrate that a substantial fraction of TSAd is found in the T cell nucleus. Nuclear import of TSAd is an active process that depends on TSAd SH2 domain recognition of a phosphotyrosine-containing ligand. Importantly, we show that TSAd can act as a potent transcriptional activator in T cells. Furthermore, the TSAd SH2 domain appears to be essential for this transcription-activating function independent of its role in nuclear import. Biochemical analyses suggest that a single TSAd SH2 domain ligand of 95–100 kD may be involved in these processes. Consistent with a role as a transcription activator, cotransfection of TSAd with an IL-2 promoter–reporter gene construct results in a considerable upregulation of IL-2 promoter activity. Further, we show that this augmentation requires a functional TSAd SH2 domain. However, TSAd does not appear to modulate the activity of the major recognized IL-2 gene transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T cells (NFAT), or activator protein 1 (AP-1). These findings point to the function of TSAd as a novel transcription-regulatory protein in T cells and illustrate the importance of the TSAd SH2 domain in this role.

scholarly journals Enhanced development of CD4+ γδ T cells in the absence of Itk results in elevated IgE production

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 564-571 ◽  
Author(s):  
Qian Qi ◽  
Mingcan Xia ◽  
Jianfang Hu ◽  
Elizabeth Hicks ◽  
Archana Iyer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Th2 Cytokines ◽  
Γδ T Cell ◽  
Histocompatibility Complex ◽  
And Function ◽  
Deficient Mice

AbstractThe Tec kinase Itk is critical for the development of αβ T cells as well as differentiation of CD4+ T cells into Th2 cells. Itk null mice have defects in the production of Th2 cytokines; however, they paradoxically have significant elevations in serum IgE. Here we show that Itk null mice have increased numbers of γδ T cells in the thymus and spleen. This includes elevated numbers of CD4+ γδ T cell, the majority of which carry the Vγ1.1 and Vδ6.2/3 γδ T-cell receptor with a distinct phenotype. The development of these CD4+ γδ T cells is T cell intrinsic, independent of either major histocompatibility complex class I or class II, and is favored during development in the absence of Itk. Itk null CD4+ γδ T cells secrete significant amounts of Th2 cytokines and can induce the secretion of IgE by wild-type B cells. Our data indicate that Itk plays important role in regulating γδ T-cell development and function. In addition, our data indicate that the elevated IgE observed in Itk-deficient mice is due in part to the enhanced development of CD4+ γδ T cells in the absence of Itk.

scholarly journals SAT0025 NEUROMEDIN U SUPPRESSES COLLAGEN-INDUCED ARTHRITIS THROUGH ACTIVATION OF ILC2

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 942.2-942
Author(s):  
Y. Zhang ◽  
Y. Qin ◽  
Z. Chen
Keyword(s):  
Flow Cytometry ◽  
Molecular Mechanisms ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Repeated Injection ◽  
Collagen Induced Arthritis ◽  
Clinical Onset ◽  
Deficient Mice

Background:Reduction and dysregulation of ILC2 was linked to delayed resolution of arthritis. The neuropeptide Neuromedin U (NMU) has been reported to rapidly activate ILC2 and initiate a Th2 type immune response through NMUR1 expressed on the surface of ILC2. However, one previous study reported that NMU promoted autoantibody-mediated arthritis.Objectives:The aim of this work was to investigate the effect of NMU on collagen-induced arthritis (CIA) mice and the potential mechanisms.Methods:CIA was induced in C57BL/6 WT and C57BL/6Nmudeficient mice on day 1. WT mice were treated i.p. daily by NMU-23 (20ug/mice) or by PBS for 10 days from day 1 to 5 and day 21 to 25. The clinical scores of CIA mice were assessed every two days from day 22 and determined on a scale of 0–4 for each paw. The proportion of ILC2 as well as Th1, Th2, Th17 and Treg in spleen, mesenteric lymph node (mLN) and joints of arthritic mice were analyzed by flow cytometry on day 42.Results:NMU-23 dramatically inhibited clinical onset and severity of arthritis in treated WT mice compared with control mice. Interestingly, NMU-deficient mice also developed significantly less severe arthritis compared with WT control (Fig 1). Flow cytometry analyses showed that the proportion of ILC2, which defined as Lin-CD45+CD127+KLRG1+ICOS+ST2+, was elevated in the joint but not in the spleen and mLN of arthritic mice treated with NMU-23. In contrast, the proportion of ILC2 was significantly lower in the spleen of NMU-deficient mice than WT control. The percentage of Th2 cells in the spleen and mLN tend to be higher in NMU-23 treated mice, but there is no statistical significance. Surprisingly, Th1 cells were increased in the mLN of NMU-23 treated and NMU-deficient mice compared with control whereas Th17 was comparable among groups. In addition, the proportion of Treg was decreased in the joint of NMU-23 treated and NMU-deficient mice compared with control mice.Conclusion:Our preliminary results show that repeated injection of NMU-23 during induction (early) and development (late) stage of CIA strongly suppressed clinical onset and severity of arthritis, which might be ascribed to activation of ILC2 in the joint. Further study is needed to explore other cellular and molecular mechanisms in the effect.References:[1] Cardoso V, Chesne J, Ribeiro H et al (2017) Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549 (7671):277-281.[2] Klose CSN, Mahlakoiv T, Moeller JB et al (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549 (7671):282-286.[3] Wallrapp A, Riesenfeld SJ, Burkett PR et al (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549 (7672):351-356.[4] Sindhuja M Rao, Jennifer L Auger, Philippe Gaillard et al (2012) The Neuropeptide Neuromedin U Promotes Autoantibody-Mediated Arthritis. Arthritis Res Ther, 14 (1), R29.Disclosure of Interests:None declared

Effects of OX40–OX40L Interaction on the Nuclear Factor of Activated T Cells c1 in ApoE-Deficient Mice

Inflammation ◽  
2013 ◽  
Vol 37 (1) ◽  
pp. 205-213 ◽  
Author(s):  
Jin-chuan Yan ◽  
Liang-jie Xu ◽  
Cui-ping Wang ◽  
Zhong-qun Wang
Keyword(s):  
T Cells ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Deficient Mice

scholarly journals Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK

2021 ◽  
Vol 118 (35) ◽  
pp. e2025825118
Author(s):  
Michael P. Gallagher ◽  
James M. Conley ◽  
Pranitha Vangala ◽  
Manuel Garber ◽  
Andrea Reboldi ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Signal Strength ◽  
Cell Receptor ◽  
Early Gene ◽  
Sequencing Analysis ◽  
Nuclear Factor ◽  
Activated T Cells

The strength of peptide:MHC interactions with the T cell receptor (TCR) is correlated with the time to first cell division, the relative scale of the effector cell response, and the graded expression of activation-associated proteins like IRF4. To regulate T cell activation programming, the TCR and the TCR proximal interleukin-2–inducible T cell kinase (ITK) simultaneously trigger many biochemically separate signaling cascades. T cells lacking ITK exhibit selective impairments in effector T cell responses after activation, but under the strongest signaling conditions, ITK activity is dispensable. To gain insight into whether TCR signal strength and ITK activity tune observed graded gene expression through the unequal activation of distinct signaling pathways, we examined Erk1/2 phosphorylation or nuclear factor of activated T cells (NFAT) and nuclear factor (NF)-κB translocation in naïve OT-I CD8+ cell nuclei. We observed the consistent digital activation of NFAT1 and Erk1/2, but NF-κB displayed dynamic, graded activation in response to variation in TCR signal strength, tunable by treatment with an ITK inhibitor. Inhibitor-treated cells showed the dampened induction of AP-1 factors Fos and Fosb, NF-κB response gene transcripts, and survival factor Il2 transcripts. ATAC sequencing analysis also revealed that genomic regions most sensitive to ITK inhibition were enriched for NF-κB and AP-1 motifs. Specific inhibition of NF-κB during peptide stimulation tuned the expression of early gene products like c-Fos. Together, these data indicate a key role for ITK in orchestrating the optimal activation of separate TCR downstream pathways, specifically aiding NF-κB activation. More broadly, we revealed a mechanism by which variations in TCR signal strength can produce patterns of graded gene expression in activated T cells.

scholarly journals Gene transcription in differentiating immature T cell receptor(neg) thymocytes resembles antigen-activated mature T cells.

1993 ◽  
Vol 178 (4) ◽  
pp. 1139-1149 ◽  
Author(s):  
J C Zúñiga-Pflücker ◽  
H L Schwartz ◽  
M J Lenardo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Intercellular Adhesion Molecule ◽  
Brdu Incorporation ◽  
Nuclear Factor ◽  
Nf Kappa B ◽  
Activated T Cells ◽  
Heat Stable Antigen

Early in ontogeny thymocytes have a surface marker phenotype that resembles activated mature T cells but they lack expression of the T cell receptor (TCR) complex. We have made preparations of day 14/15 triple negative fetal thymocytes that exhibit the activated T lymphocyte markers CD25, intercellular adhesion molecule 1, Ly-6A/E, CD44, and heat stable antigen and are rapidly proliferating as evidenced by flow cytometric examination of BrdU incorporation. We found that binding activities of the gene regulators nuclear factor (NF)-kappa B, the NF-kappa B p50 homodimer complex, nuclear factor of activated T cells (NF-AT), oct-1, oct-2, activator protein 1 (AP-1), and serum response factor (SRF), are all present in these early thymocytes. Whereas the octamer factors and SRF persist during ontogeny, NF-kappa B, NF-AT, and AP-1 decrease and are undetectable in the adult thymus. Transfection of disaggregated thymocytes by electroporation or intact thymic lobes by gold-particle bombardment revealed that reporter constructs for NF-kappa B, NF-AT, AP-1, octamer factors and, to a small extent, the TCR-alpha enhancer were active in early thymocyte development. We rigorously eliminated the possibility that these transcriptional events were due to minor populations of TCR+ cells by showing that these reporter constructs were also active in recombinase activating gene (RAG)-/- thymocytes that are incapable of completing TCR gene rearrangement, and predominantly contain cells that have an activated phenotype. Thus, transcriptional events that are usually triggered by antigen stimulation in mature T cells take place early in thymic ontogeny in the absence of the TCR. Our analysis suggests that there are striking regulatory similarities but also important differences between the activation processes that take place in antigen-stimulated mature T cells and thymic progenitor cells.

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