scholarly journals Selective Induction of Apoptosis in Mature T Lymphocytes by Variant T Cell Receptor Ligands

1998 ◽  
Vol 187 (3) ◽  
pp. 349-355 ◽  
Author(s):  
Behazine Combadière ◽  
Caetano Reis e Sousa ◽  
Ronald N. Germain ◽  
Michael J. Lenardo
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Apoptosis ◽  
Intracellular Signaling ◽  
Fas Ligand ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Cell Receptor ◽  
T Helper 1 ◽  
T Cell Apoptosis

Activation, anergy, and apoptosis are all possible outcomes of T cell receptor (TCR) engagement. The first leads to proliferation and effector function, whereas the others can lead to partial or complete immunological tolerance. Structural variants of immunizing peptide–major histocompatibility complex molecule ligands that induce selective lymphokine secretion or anergy in mature T cells in association with altered intracellular signaling events have been described. Here we describe altered ligands for mature mouse CD4+ T helper 1 cells that lead to T cell apoptosis by the selective expression of Fas ligand (FasL) and tumor necrosis factor (TNF) without concomitant IL-2, IL-3, or interferon γ production. All ligands that stimulated cell death were found to induce FasL and TNF mRNA expression and TCR aggregation (“capping”) at the cell surface, but did not elicit a common pattern of tyrosine phosphorylation of the TCR-associated signal transduction chains. Thus, TCR ligands that uniquely trigger T cell apoptosis without inducing cytokines that are normally associated with activation can be identified.

scholarly journals Qualitative and quantitative contributions of the T cell receptor zeta chain to mature T cell apoptosis.

1996 ◽  
Vol 183 (5) ◽  
pp. 2109-2117 ◽  
Author(s):  
B Combadière ◽  
M Freedman ◽  
L Chen ◽  
E W Shores ◽  
P Love ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Apoptosis ◽  
Cell Receptor ◽  
Single Chain ◽  
Tcr Signaling ◽  
T Cell Apoptosis ◽  
Zeta Chain ◽  
Src Homology ◽  
Src Homology 2 Domain

Engagement of the T cell receptor (TCR) of mature T lymphocytes can lead either to activation/proliferation responses or programmed cell death. To understand the molecular regulation of these two fundamentally different outcomes of TCR signaling, we investigated the participation of various components of the TCR-CD3 complex. We found that the TCR-zeta chain, while not absolutely required, was especially effective at promoting mature T cell apoptosis compared with the CD3 epsilon, gamma, or delta chains. We also carried out mutagenesis to address the role of the immunoreceptor tyrosine-based activation motifs (ITAMs) that are the principal signaling components found three times in the TCR-zeta chain and once in each of the CD3 epsilon, gamma, or delta chains. We found that the ability of the TCR-zeta chain to promote apoptosis results both from a quantitative effect of the presence of multiple ITAMs as well as qualitatively different contributions made by individual ITAMs. Apoptosis induced by single chain chimeras revealed that the first zeta ITAM stimulated greater apoptosis than the third zeta ITAM, and the second zeta ITAM was unable to trigger apoptosis. Because microheterogeneity in the amino acid sequence of the various ITAM motifs found in the TCR-zeta and CD3 chains predicts interactions with distinct src-homology-2-domain signaling proteins, our results suggest the possibility that individual ITAM motifs might play unique roles in TCR responses by engaging specific signaling pathways.

Glucosamine Induces Activated T Cell Apoptosis Through Reduced T Cell Receptor

2013 ◽  
Vol 78 (1) ◽  
pp. 17-27 ◽  
Author(s):  
N.-H. Chen ◽  
K. A. Cheong ◽  
C.-H. Kim ◽  
M. Noh ◽  
A.-Y. Lee
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Apoptosis ◽  
Cell Receptor ◽  
T Cell Apoptosis ◽  
Activated T Cell

scholarly journals Transplantation of SHED Prevents Bone Loss in the Early Phase of Ovariectomy-induced Osteoporosis

2014 ◽  
Vol 93 (11) ◽  
pp. 1124-1132 ◽  
Author(s):  
Y. Liu ◽  
L. Wang ◽  
S. Liu ◽  
D. Liu ◽  
C. Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Cell Apoptosis ◽  
Fas Ligand ◽  
Deciduous Teeth ◽  
Stem Cell Population ◽  
T Helper ◽  
T Helper 1 ◽  
T Cell Apoptosis ◽  
Fas Pathway

Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population, possessing multipotent differentiation capacity and immunomodulatory properties. However, the mechanism by which SHED treat immune diseases is not fully understood. Here we show that systemic transplantation of SHED via the tail vein ameliorates ovariectomy (OVX)-induced osteopenia by reducing T-helper 1 (Th1) and T-helper 17 (Th17) cell numbers in the recipient OVX mice. Mechanistically, SHED transplantation induces activated T-cell apoptosis in OVX mice via Fas ligand (FasL)-mediated Fas pathway activation, leading to up-regulation of regulatory T-cells (Tregs) and down-regulation of Th1 and Th17 cells. This SHED-mediated immunomodulation rescues OVX-induced impairment of bone marrow mesenchymal stem cells (BMMSCs) and activation of osteoclastogenesis, resulting in increased bone mass. In summary, SHED-mediated T-cell apoptosis via a FasL/Fas pathway results in immune tolerance and ameliorates the osteopenia phenotype in OVX mice.

Transgenic mice to study T-cell receptor gene regulation and repertoire formation

Genome ◽  
1989 ◽  
Vol 31 (2) ◽  
pp. 652-655 ◽  
Author(s):  
Michael Steinmetz ◽  
Horst Blüthmann ◽  
Stefan Ryser ◽  
Yasushi Uematsu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Cell Receptor ◽  
Target Cells ◽  
Allelic Exclusion

Transgenic mice have been obtained with genes coding for an αβ T-cell receptor that recognizes the male-specific antigen H-Y in association with the Db class I major histocompatibility complex molecule. Most if not all of the T-cells express the β chain encoded by the transgene and show allelic exclusion of endogenous β genes. In contrast, the expression of the α transgene does not completely block rearrangement and formation of functional endogenous α genes. In H-2b transgenic female mice the transgenic T-cell receptor is functionally expressed on at least 30% of CD8+ peripheral T-lymphocytes as indicated by their ability to lyse male target cells. Also in transgenic H-2b male mice a large proportion of peripheral T-cells appear to express the transgenic receptor. However, these cells do not react with male target cells because they show only low level or no expression of CD8 cell interaction molecules. Tolerance is established in the male transgenic thymus through deletion of CD4+CD8+ immature thymocytes.Key words: transgenic mice, immune system, T-lymphocytes, T-cell receptor, tolerance, CD8 surface antigen, enhancer, gene rearrangement, allelic exclusion.

scholarly journals Evidence of T cell receptor β-chain patterns in inflammatory and noninflammatory bowel disease states

1999 ◽  
Vol 276 (3) ◽  
pp. G613-G621 ◽  
Author(s):  
Lawrence J. Saubermann ◽  
Christopher S. J. Probert ◽  
Andreas D. Christ ◽  
Andreas Chott ◽  
Jerrold R. Turner ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Bowel Disease ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Cell Receptor ◽  
Amino Acid Sequences ◽  
Intestinal Lymphocytes ◽  
Β Chain

T cell activation, as defined by expression of relevant cell surface molecules, such as the interleukin-2 receptor (CD25), is increased in many chronic relapsing diseases, including inflammatory bowel disease (IBD). These T cells are generally activated through contact of their clonotypic T cell receptor (TCR) with a peptide antigen presented by a major histocompatibility complex molecule. One of the putative antigenic contact sites for the TCR is the third complementarity determining region (CDR3) of the TCR β-chain variable region (TCRBV). Therefore, analysis of the TCRBV CDR3 provides insight into the diversity of antigens encountered by a given T cell population. This study evaluated the TCRBV CDR3 usage of the activated intestinal lymphocytes from human subjects with IBD, diverticulitis (inflammatory control), and a normal tissue control. Public patterns, as demonstrated by shared TCRBV CDR3 amino acid sequences of activated intestinal T cell subpopulations, were observed. In particular, a public pattern of TCRBV22, a conserved valine in the fifth position, and use of TCRBJ2S1 or TCRBJ2S5 was present in three of four Crohn’s disease subjects while not present in the ulcerative colitis subjects. However, the private patterns of TCRBV CDR3 region amino acid sequences were far more striking and easily demonstrated in all individuals studied, including a normal noninflammatory control. Thus we conclude that selective antigenic pressures are prevalent among an individual’s activated intestinal lymphocytes.

scholarly journals Force-dependent transition in the T-cell receptor β-subunit allosterically regulates peptide discrimination and pMHC bond lifetime

2015 ◽  
Vol 112 (5) ◽  
pp. 1517-1522 ◽  
Author(s):  
Dibyendu Kumar Das ◽  
Yinnian Feng ◽  
Robert J. Mallis ◽  
Xiaolong Li ◽  
Derin B. Keskin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Optical Tweezers ◽  
T Lymphocyte ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Cell Receptor ◽  
Mammalian Host ◽  
Β Subunit ◽  
Self Peptides

The αβ T-cell receptor (TCR) on each T lymphocyte mediates exquisite specificity for a particular foreign peptide bound to a major histocompatibility complex molecule (pMHC) displayed on the surface of altered cells. This recognition stimulates protection in the mammalian host against intracellular pathogens, including viruses, and involves piconewton forces that accompany pMHC ligation. Physical forces are generated by T-lymphocyte movement during immune surveillance as well as by cytoskeletal rearrangements at the immunological synapse following cessation of cell migration. The mechanistic explanation for how TCRs distinguish between foreign and self-peptides bound to a given MHC molecule is unclear: peptide residues themselves comprise few of the TCR contacts on the pMHC, and pathogen-derived peptides are scant among myriad self-peptides bound to the same MHC class arrayed on infected cells. Using optical tweezers and DNA tether spacer technology that permit piconewton force application and nanometer scale precision, we have determined how bioforces relate to self versus nonself discrimination. Single-molecule analyses involving isolated αβ-heterodimers as well as complete TCR complexes on T lymphocytes reveal that the FG loop in the β-subunit constant domain allosterically controls both the variable domain module’s catch bond lifetime and peptide discrimination via force-driven conformational transition. In contrast to integrins, the TCR interrogates its ligand via a strong force-loaded state with release through a weakened, extended state. Our work defines a key element of TCR mechanotransduction, explaining why the FG loop structure evolved for adaptive immunity in αβ but not γδTCRs or immunoglobulins.

scholarly journals Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

2016 ◽  
Vol 113 (37) ◽  
pp. E5454-E5463 ◽  
Author(s):  
Sophie V. Pageon ◽  
Thibault Tabarin ◽  
Yui Yamamoto ◽  
Yuanqing Ma ◽  
Philip R. Nicovich ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Single Molecule ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Antigen Recognition ◽  
Downstream Signaling ◽  
Nanoscale Clusters

Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used single-molecule localization microscopy to quantify the organization of TCR–CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR–CD3 complexes. We found that only TCR–CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR–pMHC affinity determined the density of TCR–CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR–CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination.

scholarly journals T cell receptor zeta/CD3-p59fyn(T)-associated p120/130 binds to the SH2 domain of p59fyn(T).

1993 ◽  
Vol 178 (6) ◽  
pp. 2107-2113 ◽  
Author(s):  
A J da Silva ◽  
O Janssen ◽  
C E Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
T Complex

Intracellular signaling from the T cell receptor (TCR)zeta/CD3 complex is likely to be mediated by associated protein tyrosine kinases such as p59fyn(T), ZAP-70, and the CD4:p56lck and CD8:p56lck coreceptors. The nature of the signaling cascade initiated by these kinases, their specificities, and downstream targets remain to be elucidated. The TCR-zeta/CD3:p59fyn(T) complex has previously been noted to coprecipitate a 120/130-kD doublet (p120/130). This intracellular protein of unknown identity associates directly with p59fyn(T) within the receptor complex. In this study, we have shown that this interaction with p120/130 is specifically mediated by the SH2 domain (not the fyn-SH3 domain) of p59fyn(T). Further, based on the results of in vitro kinase assays, p120/130 appears to be preferentially associated with p59fyn(T) in T cells, and not with p56lck. Antibody reprecipitation studies identified p120/130 as a previously described 130-kD substrate of pp60v-src whose function and structure is unknown. TCR-zeta/CD3 induced activation of T cells augmented the tyrosine phosphorylation of p120/130 in vivo as detected by antibody and GST:fyn-SH2 fusion proteins. p120/130 represents the first identified p59fyn(T):SH2 binding substrate in T cells, and as such is likely to play a key role in the early events of T cell activation.

Sign in / Sign up

Export Citation Format

Share Document