Therapeutic Blockade of TCR Signal Transduction and Co-Stimulation in Autoimmune Disease

2005 ◽  
Vol 4 (2) ◽  
pp. 205-216 ◽  
Author(s):  
Laurence Howard ◽  
Adam Kohm ◽  
Carol Castaneda ◽  
Stephen Miller
Keyword(s):  
Signal Transduction ◽  
Autoimmune Disease ◽  
Therapeutic Blockade ◽  
Tcr Signal Transduction

scholarly journals Selective Accumulation of Raft-Associated Membrane Protein Lat in T Cell Receptor Signaling Assemblies

2000 ◽  
Vol 151 (2) ◽  
pp. 199-208 ◽  
Author(s):  
Thomas Harder ◽  
Marina Kuhn
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
T Cell ◽  
Membrane Protein ◽  
Transmembrane Protein ◽  
Leukemic Cells ◽  
Signaling Proteins ◽  
Dependent Manner ◽  
Tcr Signal Transduction ◽  
Signal Transduction Proteins

Activation of T cell antigen receptor (TCR) induces tyrosine phosphorylations that mediate the assembly of signaling protein complexes. Moreover, cholesterol-sphingolipid raft membrane domains have been implicated to play a role in TCR signal transduction. Here, we studied the assembly of TCR with signal transduction proteins and raft markers in plasma membrane subdomains of Jurkat T leukemic cells. We employed a novel method to immunoisolate plasma membrane subfragments that were highly concentrated in activated TCR–CD3 complexes and associated signaling proteins. We found that the raft transmembrane protein linker for activation of T cells (LAT), but not a palmitoylation-deficient non-raft LAT mutant, strongly accumulated in TCR-enriched immunoisolates in a tyrosine phosphorylation–dependent manner. In contrast, other raft-associated molecules, including protein tyrosine kinases Lck and Fyn, GM1, and cholesterol, were not highly concentrated in TCR-enriched plasma membrane immunoisolates. Many downstream signaling proteins coisolated with the TCR/LAT-enriched plasma membrane fragments, suggesting that LAT/TCR assemblies form a structural scaffold for TCR signal transduction proteins. Our results indicate that TCR signaling assemblies in plasma membrane subdomains, rather than generally concentrating raft-associated membrane proteins and lipids, form by a selective protein-mediated anchoring of the raft membrane protein LAT in vicinity of TCR.

scholarly journals Normal TCR Signal Transduction in Mice That Lack Catalytically Active PTPN3 Protein Tyrosine Phosphatase

2007 ◽  
Vol 178 (6) ◽  
pp. 3680-3687 ◽  
Author(s):  
Timothy J. Bauler ◽  
Elizabeth D. Hughes ◽  
Yutaka Arimura ◽  
Tomas Mustelin ◽  
Thomas L. Saunders ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Tcr Signal Transduction ◽  
Catalytically Active

scholarly journals Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

JCI Insight ◽  
2019 ◽  
Vol 4 (11) ◽  
Author(s):  
Oscar Okwudiri Onyema ◽  
Yizhan Guo ◽  
Bayan Mahgoub ◽  
Qing Wang ◽  
Amir Manafi ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tcr Signal Transduction

scholarly journals Association of the Adaptor Molecule Lat with Cd4 and Cd8 Coreceptors Identifies a New Coreceptor Function in T Cell Receptor Signal Transduction

1999 ◽  
Vol 190 (10) ◽  
pp. 1517-1526 ◽  
Author(s):  
Rémy Bosselut ◽  
Weiguo Zhang ◽  
Jennifer M. Ashe ◽  
Jeffrey L. Kopacz ◽  
Lawrence E. Samelson ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
T Cell Receptor ◽  
Protein Tyrosine Kinase ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Downstream Signaling ◽  
Cysteine Motif ◽  
Receptor Signal ◽  
Tcr Signal Transduction

Linker for activation of T cells (LAT) is an adaptor protein whose tyrosine phosphorylation is critical for transduction of the T cell receptor (TCR) signal. LAT phosphorylation is accomplished by the protein tyrosine kinase ZAP-70, but it is not at all clear how LAT (which is not associated with the TCR) encounters ZAP-70 (which is bound to the TCR). Here we show that LAT associates with surface CD4 and CD8 coreceptors and that its association is promoted by the same coreceptor cysteine motif that mediates Lck binding. In fact, LAT competes with Lck for binding to individual coreceptor molecules but differs from Lck in its preferential association with CD8 rather than CD4 in CD4+CD8+ thymocytes. Importantly, as a consequence of LAT association with surface coreceptors, coengagement of the TCR with surface coreceptors induces LAT phosphorylation and the specific recruitment of downstream signaling mediators to coreceptor-associated LAT molecules. These results point to a new function for CD4 and CD8 coreceptors in TCR signal transduction, namely to promote LAT phosphorylation by ZAP-70 by recruiting LAT to major histocompatibility complex–engaged TCR complexes.

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