scholarly journals Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes.

1996 ◽  
Vol 183 (3) ◽  
pp. 1053-1062 ◽  
Author(s):  
N S van Oers ◽  
N Killeen ◽  
A Weiss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Tyrosine Kinases ◽  
Cell Receptor ◽  
Protein Tyrosine Kinases ◽  
Peripheral T Cells ◽  
Tcr Signal Transduction ◽  
Deficient Mice

The Src-family and Syk/ZAP-70 family of protein tyrosine kinases (PTK) are required for T cell receptor (TCR) functions. We provide evidence that the Src-family PTK Lck is responsible for regulating the constitutive tyrosine phosphorylation of the TCR zeta subunit in murine thymocytes. Moreover, ligation of the TCR expressed on thymocytes from Lck-deficient mice largely failed to induce the phosphorylation of TCR-zeta, CD3 epsilon, or ZAP-70. In contrast, we find that the TCR-zeta subunit is weakly constitutively tyrosine phosphorylated in peripheral T cells isolated from Lck-null mice. These data suggest that Lck has a functional role in regulation of TCR signal transduction in thymocytes. In peripheral T cells, other Src-family PTKs such as Fyn may partially compensate for the absence of Lck.

T-cell receptor–induced phosphorylation of the ζ chain is efficiently promoted by ZAP-70 but not Syk

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 760-767 ◽  
Author(s):  
Marcos Steinberg ◽  
Oumeya Adjali ◽  
Louise Swainson ◽  
Peggy Merida ◽  
Vincenzo Di Bartolo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Tyrosine Kinases ◽  
Initial Step ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Signaling Cascades ◽  
Leukemia Cells

AbstractEngagement of the T-cell receptor (TCR) results in the activation of Lck/Fyn and ZAP-70/Syk tyrosine kinases. Lck-mediated tyrosine phosphorylation of signaling motifs (ITAMs) in the CD3-ζ subunits of the TCR is an initial step in the transduction of signaling cascades. However, ζ phosphorylation is also promoted by ZAP-70, as TCR-induced ζ phosphorylation is defective in ZAP-70–deficient T cells. We show that this defect is corrected by stable expression of ZAP-70, but not Syk, in primary and transformed T cells. Indeed, these proteins are differentially coupled to the TCR with a 5- to 10-fold higher association of ZAP-70 with ζ as compared to Syk. Low-level Syk-ζ binding is associated with significantly less Lck coupled to the TCR. Moreover, diminished coupling of Lck to ζ correlates with a poor phosphorylation of the positive regulatory tyr352 residue of Syk. Thus, recruitment of Lck into the TCR complex with subsequent ζ chain phosphorylation is promoted by ZAP-70 but not Syk. Importantly, the presence of ZAP-70 positively regulates the TCR-induced tyrosine phosphorylation of Syk. The interplay between Syk and ZAP-70 in thymocytes, certain T cells, and B-chronic lymphocytic leukemia cells, in which they are coexpressed, will therefore modulate the amplitude of antigen-mediated receptor signaling.

scholarly journals The Single Positive T Cells Found in CD3-ζ/η−/− Mice Overtly React with Self–Major Histocompatibility Complex Molecules upon Restoration of Normal Surface Density of T Cell Receptor–CD3 Complex

1997 ◽  
Vol 185 (4) ◽  
pp. 707-716 ◽  
Author(s):  
Shih-Yao Lin ◽  
Laurence Ardouin ◽  
Anne Gillet ◽  
Marie Malissen ◽  
Bernard Malissen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Normal Density ◽  
Cell Receptors ◽  
Peripheral T Cells ◽  
Single Positive ◽  
Deficient Mice

CD3-ζ/η–deficient mice have small thymuses containing cells that show a profound reduction in the surface levels of T cell receptors and terminate their differentiation at the CD4+CD8+ stage. Rather unexpectedly, CD3− or very low single positive T cells accumulate over time in the spleen and lymph nodes of CD3-ζ/η–deficient mice after a process dependent on MHC expression. Fusion of these peripheral T cells with a CD3-ζ–positive derivative of the BW5147 TCR-α−/β− thymoma resulted in hybridomas that do express an heterogeneous set of T cell receptor α/β dimers at their surface and at density comparable to those found in hybridomas derived from wild-type peripheral T cells. We have investigated the specificities of these T cell receptors using spleen cells from congenic and mutant mouse strains, and showed that the majority of them readily recognized self-MHC class I or class II molecules. These results demonstrate that by increasing the density and/or output of the T cell receptors expressed in peripheral T cells, one can confer them with the capacity to respond to normal density of self-MHC molecules.

scholarly journals Itk and Fyn Make Independent Contributions to T Cell Activation

1997 ◽  
Vol 186 (12) ◽  
pp. 2069-2073 ◽  
Author(s):  
X. Charlene Liao ◽  
Dan R. Littman ◽  
Arthur Weiss
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Tyrosine Kinases ◽  
Cell Activation ◽  
Protein Tyrosine Kinases ◽  
Tcr Signaling ◽  
Peripheral T Cells ◽  
Tcr Signal Transduction ◽  
Deficient Mice ◽  
Nonreceptor Protein Tyrosine Kinases

Itk is a member of the Btk/Tec/Itk family of nonreceptor protein tyrosine kinases (PTKs), and has been implicated in T cell antigen receptor (TCR) signal transduction. Lck and Fyn are the Src-family nonreceptor PTKs that are involved in TCR signaling. To address the question of how these members of different families of PTKs functionally contribute to T cell development and to T cell activation, mice deficient for both Itk and either Lck or Fyn were generated. The Itk/Lck doubly deficient mice exhibited a phenotype similar to that of Lck-deficient mice. The phenotype of the Itk/Fyn doubly deficient mice was similar to that of Itk deficient mice. However the Itk/Fyn doubly deficient mice exhibited a more severe defect in TCR-induced proliferation of thymocytes and peripheral T cells than did mice deficient in either kinase alone. These data support the notion that Itk and Fyn both make independent contributions to TCR-induced T cell activation.

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