scholarly journals Allelic Exclusion of the T Cell Receptor β Locus Requires the Sh2 Domain–Containing Leukocyte Protein (Slp)-76 Adaptor Protein

1999 ◽  
Vol 190 (8) ◽  
pp. 1093-1102 ◽  
Author(s):  
Iannis Aifantis ◽  
Vadim I. Pivniouk ◽  
Frank Gärtner ◽  
Jacqueline Feinberg ◽  
Wojciech Swat ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Allelic Exclusion ◽  
Double Positive ◽  
Thymic Development ◽  
Developmental Progression

Signaling via the pre-T cell receptor (TCR) is required for the proliferative expansion and maturation of CD4−CD8− double-negative (DN) thymocytes into CD4+CD8+ double-positive (DP) cells and for TCR-β allelic exclusion. The adaptor protein SH2 domain–containing leukocyte protein (SLP)-76 has been shown to play a crucial role in thymic development, because thymocytes of SLP-76−/− mice are arrested at the CD25+CD44− DN stage. Here we show that SLP-76−/− DN thymocytes express the pre-TCR on their surfaces and that introduction of a TCR-α/β transgene into the SLP-76−/− background fails to cause expansion of DN thymocytes or developmental progression to the DP stage. Moreover, analysis of TCR-β rearrangement in SLP-76−/− TCR-transgenic mice or in single CD25+CD44− DN cells from SLP-76−/− mice indicates an essential role of SLP-76 in TCR-β allelic exclusion.

scholarly journals T Cell Receptor (TCR) Interacting Molecule (TRIM), A Novel Disulfide-linked Dimer Associated with the TCR–CD3–ζ Complex, Recruits Intracellular Signaling Proteins to the Plasma Membrane

1998 ◽  
Vol 188 (3) ◽  
pp. 561-575 ◽  
Author(s):  
Eddy Bruyns ◽  
Anne Marie-Cardine ◽  
Henning Kirchgessner ◽  
Karin Sagolla ◽  
Andrej Shevchenko ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Intracellular Signaling ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Pi3 Kinase ◽  
Signaling Proteins

The molecular mechanisms regulating recruitment of intracellular signaling proteins like growth factor receptor–bound protein 2 (Grb2), phospholipase Cγ1, or phosphatidylinositol 3-kinase (PI3-kinase) to the plasma membrane after stimulation of the T cell receptor (TCR)– CD3–ζ complex are not very well understood. We describe here purification, tandem mass spectrometry sequencing, molecular cloning, and biochemical characterization of a novel transmembrane adaptor protein which associates and comodulates with the TCR–CD3–ζ complex in human T lymphocytes and T cell lines. This protein was termed T cell receptor interacting molecule (TRIM). TRIM is a disulfide-linked homodimer which is comprised of a short extracellular domain of 8 amino acids, a 19–amino acid transmembrane region, and a 159–amino acid cytoplasmic tail. In its intracellular domain, TRIM contains several tyrosine-based signaling motifs that could be involved in SH2 domain–mediated protein–protein interactions. Indeed, after T cell activation, TRIM becomes rapidly phosphorylated on tyrosine residues and then associates with the 85-kD regulatory subunit of PI3-kinase via an YxxM motif. Thus, TRIM represents a TCR-associated transmembrane adaptor protein which is likely involved in targeting of intracellular signaling proteins to the plasma membrane after triggering of the TCR.

scholarly journals SH2 Domain Function Is Essential for the Role of the Lck Tyrosine Kinase in T Cell Receptor Signal Transduction

1996 ◽  
Vol 271 (17) ◽  
pp. 9976-9981 ◽  
Author(s):  
David B. Straus ◽  
Andrew C. Chan ◽  
Barbara Patai ◽  
Arthur Weiss
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Receptor Signal

scholarly journals Contributions of the T Cell Receptor–associated CD3γ–ITAM to Thymocyte Selection

2002 ◽  
Vol 196 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Mariëlle C. Haks ◽  
Elsa Pépin ◽  
Jeroen H.N. van den Brakel ◽  
Sigrid A.A. Smeele ◽  
Stanley M. Belkowski ◽  
...  
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Dissociation Constants ◽  
Cell Receptor ◽  
Double Positive ◽  
Mutant Receptors

The immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 chains associated with the T cell receptor (TCR) are crucial for TCR signaling. To probe the role of the CD3γ–ITAM in T cell development, we created knock-in mice in which the CD3γ chain of the TCR complex is replaced by a mutant signaling-deficient CD3γ chain, lacking the CD3γ–ITAM. This mutation results in considerable impairment in positive selection in the polyclonal TCR repertoire. When CD3γ–ΔITAM mice are crossed to mice expressing transgenic F5 TCRs, their thymocytes are completely unable to perform positive selection in vivo in response to intrathymic ligands. Also, the in vitro positive selection response of double-positive (DP) thymocytes with F5–CD3γ–ΔITAM mutant receptors to their agonist ligand and many of its variants is severely impaired or abrogated. Yet, the binding and dissociation constants of agonist ligands for the F5 receptor are not affected by the CD3γ–ΔITAM mutation. Furthermore, DP thymocytes with mutant receptors can respond to agonist ligand with normal antigen sensitivity and to normal levels, as shown by their ability to induce CD69 up-regulation, TCR down-regulation, negative selection, and ZAP70 and c-Jun NH2-terminal kinase activation. In sharp contrast, induction of extracellular signal-regulated kinase (ERK) activation and linker for activation of T cells (LAT) phosphorylation are severely impaired in these cells. Together, these findings underscore that intrinsic properties of the TCR–CD3 complex regulate selection at the DP checkpoint. More importantly, this analysis provides the first direct genetic evidence for a role of the CD3γ–ITAM in TCR-driven thymocyte selection.

scholarly journals Essential and Partially Overlapping Role of CD3γ and CD3δ for Development of αβ and γδ T Lymphocytes

1998 ◽  
Vol 188 (7) ◽  
pp. 1375-1380 ◽  
Author(s):  
Baoping Wang ◽  
Ninghai Wang ◽  
Mariolina Salio ◽  
Arlene Sharpe ◽  
Deborah Allen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Gene Knockout ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Γδ T Cell ◽  
Thymic Development ◽  
Gene Knockout Mice

CD3γ and CD3δ are two highly related components of the T cell receptor (TCR)–CD3 complex which is essential for the assembly and signal transduction of the T cell receptor on mature T cells. In gene knockout mice deficient in either CD3δ or CD3γ, early thymic development mediated by pre-TCR was either undisturbed or severely blocked, respectively, and small numbers of TCR-αβ+ T cells were detected in the periphery of both mice. γδ T cell development was either normal in CD3δ−/− mice or partially blocked in CD3γ−/− mice. To examine the collective role of CD3γ and CD3δ in the assembly and function of pre-TCR and in the development of γδ T cells, we generated a mouse strain with a disruption in both CD3γ and CD3δ genes (CD3γδ−/−). In contrast to mice deficient in either CD3γ or CD3δ chains, early thymic development mediated by pre-TCR is completely blocked, and TCR-αβ+ or TCR-γδ+ T cells were absent in the CD3γδ−/− mice. Taken together, these studies demonstrated that CD3γ and CD3δ play an essential, yet partially overlapping, role in the development of both αβ and γδ T cell lineages.

scholarly journals Essential Role of the Pre-T Cell Receptor in Allelic Exclusion of the T Cell Receptor β Locus

Immunity ◽  
1997 ◽  
Vol 7 (5) ◽  
pp. 601-607 ◽  
Author(s):  
Iannis Aifantis ◽  
Jan Buer ◽  
Harald von Boehmer ◽  
Orly Azogui
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Essential Role ◽  
Cell Receptor ◽  
Allelic Exclusion

scholarly journals Normal T lymphocytes can express two different T cell receptor beta chains: implications for the mechanism of allelic exclusion.

1995 ◽  
Vol 181 (4) ◽  
pp. 1587-1591 ◽  
Author(s):  
E Padovan ◽  
C Giachino ◽  
M Cella ◽  
S Valitutti ◽  
O Acuto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Human Peripheral Blood ◽  
Flow Cytometric Analysis ◽  
Cell Receptor ◽  
Allelic Exclusion ◽  
Flow Cytometric ◽  
T Cell Receptor Beta

We have examined the extent of allelic exclusion at the T cell receptor (TCR) beta locus using monoclonal antibodies specific for V beta products. A small proportion (approximately 1%) of human peripheral blood T cells express two V beta as determined by flow cytometric analysis, isolation of representative clones, and sequencing of the corresponding V beta chains. Dual beta T cells are present in both the CD45R0+ and CD45R0- subset. These results indicate that dual beta expression is compatible with both central and peripheral selection. They also suggest that the substantial degree of TCR beta allelic exclusion is dependent only on asynchronous rearrangements at the beta locus, whereas the role of the pre-TCR is limited to signaling the presence of at least one functional beta protein.

scholarly journals Requirement of CD3 Complex–associated Signaling Functions for Expression of Rearranged T Cell Receptor β VDJ Genes in Early Thymic Development

1998 ◽  
Vol 188 (9) ◽  
pp. 1669-1678 ◽  
Author(s):  
Andreas Würch ◽  
Judit Biro ◽  
Alexandre J. Potocnik ◽  
Ingrid Falk ◽  
Horst Mossmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Double Positive ◽  
Thymic Development ◽  
Cell Progression ◽  
Complex Signaling ◽  
Polypeptide Chains

During αβ thymocyte development, the clonotypic αβ–T cell receptor (TCR) is preceded by sequentially expressed immature versions of the TCR–CD3 complex: the pre-TCR, containing a clonotypic TCR-β chain and invariant pre-Tα, is expressed on pre-T cells before rearrangement of the TCR-α locus. Moreover, clonotype-independent CD3 complexes (CIC) appear on pro-T cells before VDJ rearrangements of TCR-β genes. The pre-TCR is known to mediate TCR-β selection, the prerequisite for maturation of CD4−8− double negative (DN) thymocytes to the CD4+8+ double positive stage. A developmental function of CIC has so far not been delineated. In mice single deficient and double deficient for CD3ζ/η and/or p56lck, we observe a pronounced reduction in the proportions of CD25+ DN thymocytes that express intracellular TCR-β chains. TCR-β transcripts are reduced in parallel with TCR-β polypeptide chains whereas no reduction in TCR-β locus rearrangements could be detected. Wild-type levels of TCR-β transcripts and of cells expressing TCR-β polypeptide chains are induced by treatment with anti-CD3ε mAb. The data suggest that the initial expression of rearranged TCR-β VDJ genes in pro-T cell to pre-T cell progression is dependent on CD3 complex signaling, and thus define a putative developmental function for CIC.

scholarly journals Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1

2021 ◽  
Vol 22 (11) ◽  
pp. 5816
Author(s):  
Suresh Velnati ◽  
Sara Centonze ◽  
Federico Girivetto ◽  
Gianluca Baldanzi
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Adaptor Protein ◽  
Diacylglycerol Kinase ◽  
Cell Receptor ◽  
Lymphoproliferative Disease ◽  
Disease Type ◽  
T Cell Response ◽  
Receptor Signalling

Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8+ cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8+ expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach.

scholarly journals Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2713
Author(s):  
Sun-Hye Shin ◽  
Kyung-Ah Cho ◽  
Hee-Soo Yoon ◽  
So-Yeon Kim ◽  
Hee-Yeon Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Acyl Chain ◽  
Signal Strength ◽  
Cell Receptor ◽  
Ceramide Synthase ◽  
Asthmatic Patients

(1) Background: six mammalian ceramide synthases (CerS1–6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22–C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

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.

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