scholarly journals IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner

2013 ◽  
Vol 110 (20) ◽  
pp. 8158-8163 ◽  
Author(s):  
R. B. Liu ◽  
B. Engels ◽  
K. Schreiber ◽  
C. Ciszewski ◽  
A. Schietinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Dependent Manner

scholarly journals Histone 3 Lysine 9 (H3K9) Methyltransferase Recruitment to the Interleukin-2 (IL-2) Promoter Is a Mechanism of Suppression of IL-2 Transcription by the Transforming Growth Factor-β-Smad Pathway

2011 ◽  
Vol 286 (41) ◽  
pp. 35456-35465 ◽  
Author(s):  
Yu Wakabayashi ◽  
Taiga Tamiya ◽  
Ichiro Takada ◽  
Tomohiro Fukaya ◽  
Yuki Sugiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Histone Methylation ◽  
Methylation Status ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Proximal Region ◽  
Dependent Manner ◽  
H3k27 Trimethylation

Suppression of IL-2 βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4+ T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2−/−Smad3+/− T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription.

scholarly journals Human Immunodeficiency Virus Reactivation by Phorbol Esters or T-Cell Receptor Ligation Requires both PKCα and PKCθ

2005 ◽  
Vol 79 (15) ◽  
pp. 9821-9830 ◽  
Author(s):  
Sergey A. Trushin ◽  
Gary D. Bren ◽  
Susana Asin ◽  
Kevin N. Pennington ◽  
Carlos V. Paya ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Phorbol Esters ◽  
Cell Receptor ◽  
Therapeutic Drug ◽  
Dependent Manner ◽  
Pkc Isoforms ◽  
Immunodeficiency Virus

ABSTRACT Latently human immunodeficiency virus (HIV)-infected memory CD4+ T cells represent the major obstacle to eradicating HIV from infected patients. Antigens, T-cell receptor (TCR) ligation, and phorbol esters can reactivate HIV from latency in a protein kinase C (PKC)-dependent manner; however, it is unknown which specific PKC isoforms are required for this effect. We demonstrate that constitutively active (CA) forms of both PKCθ, PKCθA148E, and PKCα, PKCαA25E, induce HIV long terminal repeat (LTR)-dependent transcription in Jurkat and primary human CD4+ T cells and that both PKCθA148E and PKCαA25E cause HIV reactivation in J1.1 T cells. Suppression of both PKCα and PKCθ with short hairpinned (sh) RNA inhibited CD3/CD28-induced HIV LTR-dependent transcription and HIV reactivation in J1.1 T cells. Both prostratin and phorbol myristate 13-acetate induced HIV LTR-dependent transcription and HIV reactivation in J1.1 T cells that was blocked by shRNA against either PKCα or PKCθ. Since suppression of PKCα and PKCθ together has no greater inhibitory effect on HIV reactivation than inhibition of PKCα alone, our data confirm that PKCα and PKCθ act in sequence. The requirement for PKCα and PKCθ for prostratin-induced HIV reactivation and the ability of selective PKCα or PKCθ agonists to induce HIV transcription indicate that these PKC isoforms are important targets for therapeutic drug design.

scholarly journals ERM-Dependent Assembly of T-Cell Receptor Signaling and Co-stimulatory Molecules on Microvilli Prior to Activation

2019 ◽  
Author(s):  
Shirsendu Ghosh ◽  
Vincenzo Di Bartolo ◽  
Liron Tubul ◽  
Eyal Shimoni ◽  
Elena Kartvelishvily ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Signaling Molecules ◽  
Dominant Negative ◽  
Actin Binding ◽  
Dependent Manner ◽  
Proximal Signaling

SummaryT-cell surfaces are covered with microvilli, actin-rich and flexible protrusions. We use super-resolution microscopy to show that ≥90% T-cell receptor (TCR) complex molecules TCRαβ and TCRζ, as well as the co-receptor CD4 and the co-stimulatory molecule CD2 reside on microvilli of human T cells. Furthermore, TCR proximal signaling molecules involved in the initial stages of the immune response, such as the protein tyrosine kinase Lck and the key adaptor molecule LAT, are also enriched on microvilli. Notably, phosphorylated proteins of the ERM (ezrin, radixin, moesin) family colocalize with these heterodimers as well as with actin filaments within the microvilli of resting T cells. This finding implies a role for one or more phosphorylated ERMs in linking the TCR complex to the actin cytoskeleton within microvilli. Indeed, expression of a dominant-negative ezrin fragment effectively redistributes TCR molecules over the whole T cell surface. Our results establish microvilli as key signaling hubs, in which the TCR complex and its proximal signaling molecules and adaptors are pre-assembled prior to activation in an ERM-dependent manner. The preformed positioning of these actin-binding TCR assemblies on individual microvilli can facilitate the local transmission of TCR signals seconds after TCR occupancy and impacts the slower subsequent events that lead to the assembly of immunological synapses.

scholarly journals T cell receptor specificity drives accumulation of a reparative population of regulatory T cells within acutely injured skeletal muscle

2019 ◽  
Vol 116 (52) ◽  
pp. 26727-26733 ◽  
Author(s):  
Jun Cho ◽  
Wilson Kuswanto ◽  
Christophe Benoist ◽  
Diane Mathis
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Receptor ◽  
Muscle Regeneration ◽  
Cell Receptor ◽  
Dependent Manner ◽  
Chronic Injury ◽  
Hindlimb Muscle

Foxp3+CD4+regulatory T cells (Tregs) play important roles in controlling both homeostatic processes and immune responses at the tissue and organismal levels. For example, Tregs promote muscle regeneration in acute or chronic injury models by direct effects on local muscle progenitor cells, as well as on infiltrating inflammatory cells. Muscle Tregs have a transcriptome, a T cell receptor (TCR) repertoire, and effector capabilities distinct from those of classical, lymphoid-organ Tregs, but it has proven difficult to study the provenance and functions of these unique features due to the rarity of muscle Tregs and their fragility on isolation. Here, we attempted to sidestep these hindrances by generating, characterizing, and employing a line of mice carrying rearranged transgenes encoding the TCRα and TCRβ chains from a Treg clone rapidly and specifically expanded within acutely injured hindlimb muscle of young mice. Tregs displaying the transgene-encoded TCR preferentially accumulated in injured hindlimb muscle in a TCR-dependent manner both in the straight transgenic model and in adoptive-transfer systems; non-Treg CD4+T cells expressing the same TCR did not specifically localize in injured muscle. The definitive muscle-Treg transcriptome was not established until the transgenic Tregs inhabited muscle. When crossed onto themdxmodel of Duchenne muscular dystrophy, the muscle-Treg TCR transgenes drove enhanced accumulation of Tregs in hindlimb muscles and improved muscle regeneration. These findings invoke the possibility of harnessing muscle Tregs or their TCRs for treatment of skeletal muscle pathologies.

scholarly journals Positive and Negative Selection in Transgenic Mice Expressing a T-Cell Receptor Specific for Influenza Nucleoprotein and Endogenous Superantigen

1993 ◽  
Vol 3 (3) ◽  
pp. 159-174 ◽  
Author(s):  
Clio Mamalaki ◽  
James Elliott ◽  
Trisha Norton ◽  
Nicholas Yannoutsos ◽  
Alain R. Townsend ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Class Ii ◽  
Cytotoxic T Cell ◽  
Dependent Manner ◽  
Class Ii Mhc ◽  
Peripheral T Cells

A transgenic mouse was generated expressing on most (>80%) of thymocytes and peripheral T cells a T-cell receptor isolated from a cytotoxic T-cell clone (F5). This clone is CD8+and recognizes αα366-374 of the nucleoprotein (NP 366-374) of influenza virus (A/NT/60/68), in the context of Class ,MHC Db(Townsend et al., 1986). The receptor utilizes the Vβ11 and Vα4 gene segments for the β chain and α chain, respectively (Palmer et al., 1989). The usage of Vβ11 makes this TcR reactive to Class II IE molecules and an endogenous ligand recently identified as a product of the endogenous mammary tumour viruses (Mtv) 8, 9, and 11 (Dyson et al., 1991). Here we report the development of F5 transgenic T cells and their function in mice of the appropriate MHC (C57BL/10 H-2b, IE-) or in mice expressing Class II MHC IE (e.g., CBA/Ca H-2kand BALB/c H-2d) and the endogenous Mtv ligands. Positive selection of CD8+T cells expressing the Vβ11 is seen in C57BL/10 transgenic mice (H-2b). Peripheral T cells from these mice are capable of killing target cells in an antigen-dependent manner after a period ofin vitroculture with IL-2. In the presence of Class II MHC IE molecules and the endogenous Mtv ligand, most of the single-positive cells carrying the transgenic T-cell receptor are absent in the thymus. Unexpectedly, CD8+peripheral T-cells in these (H-2kor H-2d) F5 mice are predominantly Vβ11 positive and also have the capacity to kill targets in an antigen-dependent manner. This is true even following backcrossing of the F5 TcR transgene to H-2dscid/scid mice, in which functional rearrangement of endogenous TcR alpha- and beta-chain genes is impaired.

Bet v 1–specific T-cell receptor/forkhead box protein 3 transgenic T cells suppress Bet v 1–specific T-cell effector function in an activation-dependent manner

2011 ◽  
Vol 127 (1) ◽  
pp. 238-245.e3 ◽  
Author(s):  
Klaus G. Schmetterer ◽  
Daniela Haiderer ◽  
Victoria M. Leb-Reichl ◽  
Alina Neunkirchner ◽  
Beatrice Jahn-Schmid ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Effector Function ◽  
Dependent Manner ◽  
Bet V 1 ◽  
Forkhead Box ◽  
Cell Effector Function ◽  
Cell Effector
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