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EMBO workshop report “Lymphocyte antigen receptor and coreceptor signaling”
No full textCommentary EMBO workshop 1999 "Lymphocyte antigen receptor and coreceptor signaling
p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells.
Full text linkp95vav, the product of the vav protooncogene, has been implicated in the T cell receptor (TCR)-mediated signaling cascade p95vav is phosphorylated on tyrosine residues after TCR stimulation by anti-TCR/CD3 antibodies and possesses a number of landmark features of signaling molecules such as a putative guanine nucleotide exchange factor domain, a pleckstrin homology domain, and an Sre homology (SH) 2 and two SH3 domains, which provide the capacity to form multimeric signaling complexes. However, the precise role of p95vav in TCR signaling remains unclear. In this work we show that physiological stimulation of T cell hybridomas with antigen presented by major histocompatibility complex class II molecules leads to a strong tyrosine phosphorylation of p95vav and its association with tyrosine-phosphorylated SLP-76. SLP-76 is a newly described SH2-containing protein that has been previously found to bind to the adapter molecule Grb2. Moreover, we provide evidence that p95vav-SI P-76 association is SH2-mediated by demonstrating that this interaction can be inhibited by a phosphopeptide containing a putative p95vav-SH2-binding motif (pYESP) present in SLP-76. Furthermore, in vitro experiments show that after antigen stimulation, phosphorylated p95vav-SLP-76 can bind to Grb2 in a complex that contains pp36/38 and pp116 proteins. Our data provide a clue to explain recent independent observations that overexpression of p95vav or SLP-76 enhances TCR-mediated gene activation
Antigen receptor signaling: the Tuscan chronicles.
No full textThe fourth EMBO workshop on "Lymphocyte antigen receptor and coreceptor signaling" gathered immunologists to share key findings, new questions and emerging trends in the field of cell signaling
CD28 as a molecular amplifier extending TCR ligation and signaling capabilities.
No full textEvidence has gathered that CD28 costimulation facilitates T cell activation by potentiating TCR intrinsic-signaling. However, the underlying molecular mechanism is largely unknown. Here we show that, by enhancing T cell/APC close contacts, CD28 facilitates TCR signal transduction. Moreover, the signal supplied by CD28 does not lead to increased Zap-70 and Lat phosphorylation, but amplifies PLCgamma1 activation and Ca(2+) response. We provide evidence that the PTK Itk controls the latter function. Our data suggest that CD28 binding to B7 contributes to setting the level of TCR-induced phosphorylated Lat for recruiting signaling complexes, whereas the CD28 signal boosts multiple pathways by facilitating PLCgamma1 activation. These results should provide a conceptual framework for understanding quantitative and qualitative aspects of CD28-mediated costimulation
Molecular dynamics simulations reveal canonical conformations in different pMHC/TCR interactions
Full text linkThe major defense system against microbial pathogens in vertebrates is the adaptive immune response and represents an effective mechanism in cancer surveillance. T cells represent an essential component of this complex system. They can recognize myriads of antigens as short peptides (p) originated from the intracellular degradation of foreign proteins presented by major histocompatibility complex (MHC) proteins. The clonotypic T-cell antigen receptor (TCR) is specialized in recognizing pMHC and triggering T cells immune response. It is still unclear how TCR engagement to pMHC is translated into the intracellular signal that initiates T-cell immune response. Some work has suggested the possibility that pMHC binding induces in the TCR conformational changes transmitted to its companion CD3 subunits that govern signaling. The conformational changes would promote phosphorylation of the CD3 complex ζ chain that initiates signal propagation intracellularly. Here, we used all-atom molecular dynamics simulations (MDs) of 500 ns to analyze the conformational behavior of three TCRs (1G4, ILA1 and ILA1α1β1) interacting with the same MHC class I (HLA-A*02:01) bound to different peptides, and modelled in the presence of a lipid bilayer. Our data suggest a correlation between the conformations explored by the β-chain constant regions and the T-cell response experimentally determined. In particular, independently by the TCR type involved in the interaction, the TCR activation seems to be linked to a specific zone of the conformational space explored by the β-chain constant region. Moreover, TCR ligation restricts the conformational space the MHC class I groove
Proximal changes in signal transduction that modify CD8+ T cell responsiveness in vivo
Full text linkThe antigen dose conditions the functional properties of CD8+ T cells generated after priming.
At relatively low antigen doses, efficient memory T cells may be generated, while high
antigen doses lead to tolerance. To determine the mechanisms leading to such different
functional outcomes, we compared the proximal TCR signal transduction of naive cells, to
that of memory or high-dose tolerant cells generated in vivo. In vivo activation led to the constitutive
phosphorylation of CD3 4 , recruiting Zap70, in both memory and tolerant cells. In tolerant
cells, these phenomena were much more marked, the CD3 4 and ́ chains no longer
associated, and the Src kinases p56Lck and p59Fyn were inactive. Therefore, when the antigen
load overcomes the capacities of immune control, a new mechanism intervenes to block
signal transduction: the recruitment of Zap70 to CD3 4 becomes excessive, leading to TCR
complex destabilization, Src kinase dysfunction, and signal arrest
Preferential Vβ gene usage and lack of junctional sequence conservation among human T cell receptors specific for a tetanus toxln-derived peptide: Evidence for a dominant role of a germline-encoded V region in antigen/major histocompatibility complex recognition
No full textTo investigate the structural and genetic basis of the T cell response to defined peptide/major histocompatibility (MHC) class II complexes in humans, we established a large panel of T cell clones (61) from donors of different HLA-DR haplotypes and reactive with a tetanus toxin-derived peptide (tt830-844) recognized in association with most DR molecules (universal peptide). By using a bacterial enterotoxin-based proliferation assay and cDNA sequencing, we found preferential use of a particular Vβ region gene segment, Vβ2.1, in three of the individuals studied (64%, n = 58), irrespective of whether the peptide was presented by the DR6wcI, DR4w4, or DRw11.1 and DRw11.2 alleles, demonstrating that shared MHC class II antigens are not required for shared Vβ gene use by T cell receptors (TCRs) specific for this peptide. Vα gene use was more heterogeneous, with at least seven different Vα segments derived from five distinct families encoding ot chains able to pair with Vβ2.1 chains to form a tt830-844/DR-specific binding site. Several cases were found of dories restricted to different DR alleles that expressed identical Vβ and (or very closely related) Vα gene segments and that differed only in their junctional sequences. Thus, changes in the putative complementary determining region 3 (CDR3) of the TCR may, in certain cases, alter MHC specificity and maintain peptide reactivity. Finally, in contrast to what has been observed in other defined peptide/MHC systems, a striking heterogeneity was found in the junctional regions of both α and β chains, even for TCRs with identical Vα and/or Vβ gene segments and the same restriction. Among 14 anti-tt830-844 clones using the Vβ2.1 gene segment, 14 unique Vβ-D-Jβ junctions were found, with no evident conservation in length and/or amino acid composition. One interpretation for this apparent lack of coselection of specific junctional sequences in the context of a common V element, Vβ2.1, is that this V region plays a dominant role in the recognition of the tt830-844/DR complex. © 1992, Rockefeller University Press., All rights reserved
Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen presenting cells.
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