scholarly journals Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

2012 ◽  
Vol 209 (6) ◽  
pp. 1201-1217 ◽  
Author(s):  
Tadashi Yokosuka ◽  
Masako Takamatsu ◽  
Wakana Kobayashi-Imanishi ◽  
Akiko Hashimoto-Tane ◽  
Miyuki Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

scholarly journals The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3247
Author(s):  
Lingxiao Ye ◽  
Zhengxin Zhu ◽  
Xiaochuan Chen ◽  
Haoran Zhang ◽  
Jiaqi Huang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Progression ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Escape ◽  
Tumor Treatment

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance. Here, the effects of various tumor-derived exosomes and tumor-derived exosomal PD-L1 on tumor progression are summarized and discussed. Researchers have found that high expression of exosomal PD-L1 can inhibit T cell activation in in vitro experiments, but the function of exosomal PD-L1 in vivo remains controversial. In addition, the circulating exosomal PD-L1 has high potential to act as an indicator to evaluate the clinical effect. Moreover, therapeutic strategy targeting exosomal PD-L1 is discussed, such as inhibiting the biogenesis or secretion of exosomes. Besides, some specific methods based on the strategy of inhibiting exosomes are concluded. Further study of exosomal PD-L1 may provide an effective and safe approach for tumor treatment, and targeting exosomal PD-L1 by inhibiting exosomes may be a potential method for tumor treatment.

scholarly journals Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.

1993 ◽  
Vol 178 (5) ◽  
pp. 1801-1806 ◽  
Author(s):  
H Lin ◽  
S F Bolling ◽  
P S Linsley ◽  
R Q Wei ◽  
D Gordon ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Subsequent Treatment ◽  
Third Party ◽  
Cardiac Allografts

Allograft rejection is a T cell-dependent process. Productive T cell activation by antigen requires antigen engagement of the T cell receptor as well as costimulatory signals delivered through other T cell surface molecules such as CD28. Engagement of CD28 by its natural ligand B7 can be blocked using a soluble recombinant fusion protein, CTLA4Ig. Administration of CTLA4Ig blocks antigen-specific immune responses in vitro and in vivo, and we have shown that treatment of rats with a 7-d course of CTLA4Ig at the time of transplantation leads to prolonged survival of cardiac allografts (median 30 d), although most grafts are eventually rejected. Here, we have explored additional strategies employing CTLA4Ig in order to achieve long-term allograft survival. Our data indicate that donor-specific transfusion (DST) plus CTLA4Ig can provide effective antigen-specific immunosuppression. When DST is administered at the time of transplantation followed by a single dose of CTLA4Ig 2 d later, all animals had long-term graft survival (> 60 d). These animals had delayed responses to donor-type skin transplants, compared with normal rejection responses to third-party skin transplants. Furthermore, donor-matched second cardiac allografts were well tolerated with minimal histologic evidence of rejection. These data indicate that peritransplant use of DST followed by subsequent treatment with CTLA4Ig can induce prolonged, often indefinite, cardiac allograft acceptance. These results may be clinically applicable for cadaveric organ and tissue transplantation in humans.

scholarly journals Regulation and Function of the CD3γ DxxxLL Motif: A Binding Site for Adaptor Protein-1 and Adaptor Protein-2 in Vitro

1997 ◽  
Vol 138 (2) ◽  
pp. 271-281 ◽  
Author(s):  
Jes Dietrich ◽  
Jesper Kastrup ◽  
Bodil L. Nielsen ◽  
Niels Ødum ◽  
Carsten Geisler
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tolerance Induction ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Cell Receptor ◽  
Coated Vesicle

Several receptors are downregulated by internalization after ligand binding. Regulation of T cell receptor (TCR) expression is an important step in T cell activation, desensitization, and tolerance induction. One way T cells regulate TCR expression is by phosphorylation/dephosphorylation of the TCR subunit clusters of differentiation (CD)3γ. Thus, phosphorylation of CD3γ serine 126 (S126) causes a downregulation of the TCR. In this study, we have analyzed the CD3γ internalization motif in three different systems in parallel: in the context of the complete multimeric TCR; in monomeric CD4/CD3γ chimeras; and in vitro by binding CD3γ peptides to clathrin-coated vesicle adaptor proteins (APs). We find that the CD3γ D127xxxLL131/132 sequence represents one united motif for binding of both AP-1 and AP-2, and that this motif functions as an active sorting motif in monomeric CD4/ CD3γ molecules independently of S126. An acidic amino acid is required at position 127 and a leucine (L) is required at position 131, whereas the requirements for position 132 are more relaxed. The spacing between aspartic acid 127 (D127) and L131 is crucial for the function of the motif in vivo and for AP binding in vitro. Furthermore, we provide evidence indicating that phosphorylation of CD3γ S126 in the context of the complete TCR induces a conformational change that exposes the DxxxLL sequence for AP binding. Exposure of the DxxxLL motif causes an increase in the TCR internalization rate and we demonstrate that this leads to an impairment of TCR signaling. On the basis of the present results, we propose the existence of at least three different types of L-based receptor sorting motifs.

scholarly journals Deltex Regulates T-Cell Activation by Targeted Degradation of Active MEKK1

2005 ◽  
Vol 25 (4) ◽  
pp. 1367-1378 ◽  
Author(s):  
Wen-Hsien Liu ◽  
Ming-Zong Lai
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Dominant Form

ABSTRACT Deltex is known as a Notch signal mediator, but its physiological action mechanism is poorly understood. Here we identified a new regulatory role of Deltex in T-cell activation. Deltex expression was constitutive in resting T cells and was reduced upon T-cell receptor (TCR)-stimulated activation. The biological role of Deltex is supported by the enhanced T-cell activation when Deltex1 was down-regulated by small interfering RNA. Overexpression of Deltex1 suppressed T-cell activation but not the proximal TCR activation events. The impaired activation of mitogen-activated protein kinase by Deltex could be partly attributed to a selective down-regulation of MEKK1 protein in T cells. We further found that Deltex promoted degradation of the C-terminal catalytic fragment of MEKK1 [MEKK1(C)]. Deltex1 interacted directly with MEKK1(C) and stimulated the ubiquitination of MEKK1(C) as shown by in vivo and in vitro ubiquitination analysis. Therefore, MEKK1(C), the dominant form of MEKK1 in T cells, is a target of Deltex E3 ubiquitin ligase. Our results reveal a novel mechanism as to how Deltex selectively suppresses T-cell activation through degradation of a key signaling molecule, MEKK1.

Anti-TOSO antibody treatment promotes T cell activation-induced cell death (AICD) in vitro and in vivo

2014 ◽  
Vol 59 (13) ◽  
pp. 1374-1385
Author(s):  
Yi Tan ◽  
Xue Han ◽  
Xiaoran Wu ◽  
Qiao Xing ◽  
Lieping Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antibody Treatment ◽  
Activation Induced Cell Death

scholarly journals Programmed Cell Death-1 Deficiency Exacerbates T Cell Activation and Atherogenesis despite Expansion of Regulatory T Cells in Atherosclerosis-Prone Mice

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e93280 ◽  
Author(s):  
Clément Cochain ◽  
Sweena M. Chaudhari ◽  
Miriam Koch ◽  
Heinz Wiendl ◽  
Hans-Henning Eckstein ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Regulatory T Cells ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Programmed Cell Death 1

scholarly journals Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4360-4367 ◽  
Author(s):  
Min Chen ◽  
Li Huang ◽  
Jin Wang
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Autoantibody Production ◽  
Systemic Autoimmunity ◽  
Spontaneous Cell Death

Abstract Apoptosis in dendritic cells (DCs) can potentially regulate DC homeostasis and immune responses. We have previously observed that inhibition of the Fas signaling pathway in DCs results in spontaneous T-cell activation and the development of systemic autoimmunity in transgenic mice. However, the role for different apoptosis pathways in DCs in regulating DC homeostasis and immune tolerance remains to be determined. Bim, a BH3-only protein of the Bcl-2 family, was expressed at low levels in DCs and was significantly up-regulated by signaling from CD40 or toll-like receptors (TLRs). Because Bim−/− mice develop spontaneous systemic autoimmunity, we investigated whether Bim−/− DCs contributed to lymphoproliferation and autoimmunity in these mice. Bim−/− DCs showed decreased spontaneous cell death, and induced more robust T-cell activation in vitro and in vivo. Moreover, Bim−/− DCs induced autoantibody production after adoptive transfer. Our data suggest that Bim is important for regulating spontaneous cell death in DCs, and Bim-deficient DCs may contribute to the development of autoimmune diseases in Bim−/− mice.

scholarly journals TAGLN2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse

2015 ◽  
Vol 209 (1) ◽  
pp. 143-162 ◽  
Author(s):  
Bo-Ra Na ◽  
Hye-Ran Kim ◽  
Indre Piragyte ◽  
Hyun-Mee Oh ◽  
Min-Sung Kwon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Actin Dynamics ◽  
Actin Binding

The formation of an immunological synapse (IS) requires tight regulation of actin dynamics by many actin polymerizing/depolymerizing proteins. However, the significance of actin stabilization at the IS remains largely unknown. In this paper, we identify a novel function of TAGLN2—an actin-binding protein predominantly expressed in T cells—in stabilizing cortical F-actin, thereby maintaining F-actin contents at the IS and acquiring LFA-1 (leukocyte function-associated antigen-1) activation after T cell receptor stimulation. TAGLN2 blocks actin depolymerization and competes with cofilin both in vitro and in vivo. Knockout of TAGLN2 (TAGLN2−/−) reduced F-actin content and destabilized F-actin ring formation, resulting in decreased cell adhesion and spreading. TAGLN2−/− T cells displayed weakened cytokine production and cytotoxic effector function. These findings reveal a novel function of TAGLN2 in enhancing T cell responses by controlling actin stability at the IS.

scholarly journals Regulation of c-Jun NH2-terminal Kinase ( Jnk) Gene Expression during T Cell Activation

2000 ◽  
Vol 191 (1) ◽  
pp. 139-146 ◽  
Author(s):  
Linda Weiss ◽  
Alan J. Whitmarsh ◽  
Derek D. Yang ◽  
Mercedes Rincón ◽  
Roger J. Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
T Cell Activation ◽  
Map Kinases ◽  
Cell Activation ◽  
Cell Receptor ◽  
Jnk Pathway ◽  
Gene And Protein Expression

The c-Jun NH2-terminal kinases (JNKs) are a group of mitogen-activated protein (MAP) kinases that participate in signal transduction events mediating specific cellular functions. Activation of JNK is regulated by phosphorylation in response to cellular stress and inflammatory cytokines. Here, we demonstrate that JNK is regulated by a second, novel mechanism. Induction of Jnk gene expression is required in specific tissues before activation of this signaling pathway. The in vivo and in vitro ligation of the T cell receptor (TCR) leads to induction of JNK gene and protein expression. TCR signals are sufficient to induce JNK expression, whereas JNK phosphorylation also requires CD28-mediated costimulatory signals. Therefore, both expression and activation contribute to the regulation of the JNK pathway to ensure proper control during the course of an immune response.

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