Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence implicates PI 3-kinase in TCR signal transduction. The fungal metabolite wortmannin is a specific inhibitor of PI 3-kinase both in vitro and in vivo when used at nanomolar concentrations. Therefore, we examined the effect of wortmannin on stimulation of primary T cells and T cell lines. Wortmannin had a dose-dependent inhibitory effect on TCR-dependent primary T cell proliferation with IC50 in the nanomolar range. Furthermore, activation of T cell lines independently of antigen presenting cells and, therefore of any CD28 co-stimulatory signaling, was also sensitive to wortmannin. As expected, phorbol ester stimulation bypassed PI 3-kinase signal transduction. Importantly, the effect of wortmannin correlated with inhibition of activation of PI 3-kinase in stimulated T cells. The earliest step in T cell activation, tyrosine kinase activation, was not significantly affected by wortmannin. We conclude that a wortmannin-sensitive enzyme, probably PI 3-kinase, acting downstream of tyrosine kinases, but independently of the phorbol ester activated pathway, is necessary for stimulation of T cells via the TCR, and that this requirement is independent of any role of PI 3-kinase in co-stimulation via CD28 coreceptor. PI 3-kinase is most probably involved in generation of 3-phosphorylated lipid products, and is not merely an adaptor.
Mol Immunol 1997 Feb
PMID:Evidence for phosphatidylinositol 3-kinase-dependent T cell antigen receptor (TCR) signal transduction. 922 64

Superantigens are microbial products which bind both to the TCR beta-chain and, with moderate affinity, to MHC class II molecules. Class II-bearing cells bind the superantigen and present the superantigen to T cells expressing certain TCR beta-chain variable region alleles. We have previously reported that the superantigen staphylococcal enterotoxin B (SEB) binds with moderate affinity to the protein p85 expressed on COS-1, an African Green Monkey kidney fibroblast-like cell line. In the present report we carry out a structural analysis to examine the basis for the interaction of superantigen to p85. We show that SEC1, SEC2, and SEC3 also bind to p85 based on inhibition of the binding of radiolabeled SEB. On the other hand, SEA, SED, SEE and toxic shock syndrome toxin-1 do not exhibit detectable binding. In an effort to characterize the structural basis for the SEB binding to p85, we have generated both amino- and carboxy-terminal truncations of SEB expressed as fusion proteins with the maltose-binding protein of Escherichia coli. Our results show that the full-length SEB fusion protein and a truncation missing the 81 amino-terminal amino acids both compete successfully with native SEB for binding. On the other hand, carboxy-terminal truncations in which 19 or 34 residues are deleted both fail to compete for binding. These results are consistent with results which show that monoclonal anti-SEB antibodies specific for carboxy-terminal determinants block SEB binding to p85, but an amino-terminal mAb fails to exhibit any alteration in binding. These results suggest that residues at or near the carboxy-terminus of SEB play a role in binding to p85.
Mol Immunol 1997 Feb
PMID:Structural basis for the interaction of superantigen with the alternative superantigen-binding receptor p85. 922 68

Rearrangement of the T cell antigen receptor genes is a complex, highly regulated process. To gain a better understanding of the extracellular factors involved in the regulation of TCR beta and gamma gene rearrangement in adult murine bone marrow-resident precursor T cells, several cytokines were tested for their ability to induce gene recombination. A selected population of C58/J bone marrow cells (Thy 1(low), CD3, CD8, B220) that is enriched for pre-T cell activity was propagated in vitro in medium supplemented with IL-3 and mast cell growth factor (MGF, also referred to as stem cell factor, Steele factor and c-kit ligand). These cytokines were required for the maintenance of pre-T cell activity in culture, but had no effect on TCR gene expression. Several additional cytokines were added to the culture medium. Of all those tested, only IL-7 induced complete rearrangement of the TCR gamma locus. Complete rearrangement of the TCR beta locus was not induced under any of the culture conditions analysed here. The bone marrow cells cultured in IL-3, MGF and IL-7 did not begin to express mature T cell proteins and maintained their in vivo progenitor potential. Furthermore, IL-7 cultured bone marrow cells were capable of differentiation in vivo into all phenotypic subpopulations of T cells, without an apparent bias toward the gammadelta lineage. The data presented here suggest that TCR gamma gene rearrangement in adult pre-T cells is regulated by IL-7, but that the TCR beta locus requires additional or alternative signals for the induction of complete rearrangement.
Mol Immunol 1997 Apr
PMID:Interleukin 7 induces TCR gene rearrangement in adult marrow-resident murine precursor T cells. 930 61

Immunological memory has been ascribed to the presence of long-lived memory cells. The mechanisms underlying their generation are not completely understood, but dependence on antigen persistence has been discussed in this regard. However, in spite of in vivo evidence favoring this model, studies on TCR/CD3 stimulation of T cell lines or unseparated peripheral blood T cell in vitro have failed to demonstrate prolonged survival of preactivated cells. We have examined the dose-dependent effect of TCR/CD3 engagement mimicked by immobilized anti-CD3 antibody. To this end, well-defined populations of CD4+ and CD8+ lymphoblasts isolated from bulk cultures of preactivated PBMCs by flow sorting were examined. These cells were restimulated with immobilized anti-CD3 in the presence or absence of various costimulatory factors, and were analyzed for their viability state, as well as their apoptotic and proliferative behavior. We have shown that inhibition of apoptosis following CD3 stimulation occurs at submitogenic concentrations, while activation-driven apoptosis requires high-density TCR/CD3 activation. Prevention of apoptosis by submitogenic CD3 stimulation was, however, observed only when CD4+ but not when CD8+ cells were investigated, and was not readily influenced by other costimulatory factors present in cultures. This observation points to the importance of antigen persistence in regulating survival of memory CD4+ but not CD8+ cells.
Cytokines Mol Ther 1995 Dec
PMID:Submitogenic concentrations of anti-CD3 monoclonal antibody exert antiapoptotic effects in preactivated CD4+ but not CD8+ human T cells. 938 80

The protein phosphatase calcineurin is known to be an essential intracellular signal transducer involved in the TCR-mediated signal transduction pathway and is the common target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. The catalytic subunit of calcineurin exists in multiple isoforms, but their functional differences are not known. It has been assumed that the alpha isoform of calcineurin is the relevant isoform mediating TCR signaling. Recently, calcineurin alpha was knocked out in mice, but no defect in the TCR-mediated IL-2 production was observed, suggesting that another isoform of calcineurin mediates the TCR signal transduction pathway. We have generated specific polyclonal antibodies against the alpha and the beta2 isoforms of calcineurin and examined their distribution in murine tissues and immune cells by immunohistochemical staining and Western blot analysis. We found that the beta2 isoform of calcineurin is predominant in T and B lymphocytes as well as in thymus compared to the alpha isoform, suggesting that the beta2 isoform may play a key role in TCR signaling. Furthermore, we observed that the two isoforms exhibit distinct expression patterns in both kidney and thymus, indicating that the two isoforms of calcineurin have distinct cellular functions. Together, these findings raise the possibility that the nephrotoxicity associated with CsA and FK506 can be reduced by designing novel inhibitors of calcineurin that target specific isoforms of the enzyme.
Mol Immunol 1997 Jun
PMID:Distinct tissue and cellular distribution of two major isoforms of calcineurin. 939 69

Experimental autoimmune encephalomyelitis (EAE) serves as a rodent model of the autoimmune disease multiple sclerosis. In mice, EAE is induced by immunizing with spinal cord homogenate, components of the myelin sheath, such as myelin basic protein (MBP) or proteolipid protein (PLP), or peptides derived from these components. EAE can be induced in H-2u or (H-2u x H-2s)F1 mice with the N-terminal peptide of MBP, Ac1-11. Coimmunization with Ac1-11 and Ac1-11[4A], an analog in which lysine at position four is substituted with alanine, prevents EAE. The mechanism of inhibition has not been elucidated, but probably does not work through MHC blockade, T cell anergy or clonal elimination of encephalitogenic T cells. We have isolated T cell clones and hybridomas from (PL/J x SJL/J)F1 mice immunized with either Ac1-11 alone or Ac1-11 and Ac1-11[4A] and analysed these cells for differences in their T cell receptor repertoire and in vitro response. Although T cells elicited by coinjection of Ac1-11 and Ac1-11[4A] expressed TCR that used V alpha and Vbeta gene elements similar to those elicited by Ac1-11 alone, they differed in the sequences of the junctional region of the alpha chain. Most of these T cells also responded less well to Ac1-11 in vitro, suggesting that coinjection of Ac1-11 and Ac1-11[4A] preferentially activates T cells bearing TCR of different affinity for Ac1-11 bound to I-A(u), and which may therefore be less encephalitogenic. Furthermore, our results show that a more diverse repertoire of V alpha and Vbeta genes are elicited by Ac1-11 in (PL/J x SJL/J)F1 mice compared to PL/J and B10.PL mice, providing further evidence that a restricted TCR repertoire is not required for the development of autoimmune disease.
Mol Immunol 1997 Aug
PMID:Induction of a heterogeneous TCR repertoire in (PL/JXSJL/J)F1 mice by myelin basic protein peptide Ac1-11 and its analog Ac1-11[4A]. 944 77

The zeta chain is required in the TCR complex to guarantee its surface expression and function. However, an understanding of the interaction(s) between the zeta chain and the other proteins in the TCR/CD3 has not yet been achieved. In this report, we attempt to assign a functional role to the short extracellular (EC) domain of the zeta chain by studying its unique positive charge, a lysine at position 9, because of its interesting location to the interchain disulphide bond of the zeta chain homodimer. We show that amino acid exchanges of lysine 9 to glycine, serine, cysteine or asparagine generate TCR complexes which are clearly defective in antigenic signalling. Interestingly, the non-conservative point mutations were segregating TCR complex signalling pathways. However, lysine 9 is not critical for TCR complex surface expression unless the positively charged lysine is exchanged for the negatively charged amino acid aspartic acid. The zeta chain mutant bearing a lysine to cysteine exchange is the sole mutant to be inefficiently co-precipitated with the TCR/CD3 complex suggesting a loose interaction of the zeta chain within the TCR complex.
Mol Immunol
PMID:The short extracellular domain of the T cell receptor zeta chain is involved in assembly and signal transduction. 946 17

CD4 contributes to antigen recognition of T cells by binding to class II MHC molecules. There is heterogeneity in expression of CD4 coreceptor among CD4+CD8+ thymocytes. We have investigated whether the expression level of coreceptor influences positive selection. Thymocytes of mice expressing transgenic lambda2(315)-Ig-light-chain/I-Ed specific TCR are poorly positively selected because they fail to allelically exclude endogenous TCR alpha chain genes and because there is no skewing towards CD4. Transient overexpression of CD4 during thymocyte development, in mice transgenic for both TCR and CD4, resulted in skewing towards CD4 in the periphery, reduced rearrangement and expression of endogenous alpha-chains, and decreased levels of thymocyte RAG-1 transcripts. Kinetic BrdU labeling experiments showed that single CD4+ thymocytes developed faster, representing the predominant population even in the cortex of the double transgenic thymi. These results demonstrate that increased coreceptor expression can compensate for poorly selectable TCR, supporting avidity and instructional models for positive selection of thymocytes.
Mol Immunol 1998 Jan
PMID:Transient overexpression of CD4 enhances allelic exclusion of T-cell receptor (TCR) alpha chains and promotes positive selection of class II-restricted TCR-transgenic thymocytes. 968 61

We have previously shown that prostaglandin E2 (PGE2) and IL-4 inhibit the priming of IFN-gamma-production during the differentiation of naive CD4+ T cells from human cord blood by different signal-transducing mechanisms. To compare and analyse the molecular mechanisms by which PGE2 and IL-4 inhibit the priming of IFN-gamma production, we investigated the effects of PGE2 and IL-4 on the methylation of the IFN-gamma gene during the in vitro differentiation of naive CD4+ T cells. In human naive CD4+ T cells, which produce primarily IL-2 and a little amount of IFN-gamma, the IFN-gamma gene was methylated. After stimulation via TCR, CD4+ T cells produced IFN-gamma and the CpG dinucleotide contained within the TATA proximal regulatory element of the IFN-gamma gene was partially hypomethylated. Both IL-4 and PGE2 inhibited the hypomethylation of this site and the acquisition of IFN-gamma-producing ability. In contrast to the SnaBI site in the TATA proximal regulatory element, the HpalI site in the first intron of the IFN-gamma gene of the CD4+ T cells from cord blood was completely methylated even after stimulation via TCR. 5-azacytidine restored the IFN-gamma-producing ability of these cells treated with IL-4 and PGE2. These findings suggest that, although the signal transduction that inhibits the priming of IFN-gamma-production is different for each reagent, the protection from hypomethylation of the regulatory region of the IFN-gamma gene is involved in the molecular mechanisms by which these reagents inhibit the priming of IFN-gamma-production during the differentiation of human naive CD4+ T cells.
Mol Immunol 1998 Jan
PMID:IL-4 and prostaglandin E2 inhibit hypomethylation of the 5' regulatory region of IFN-gamma gene during differentiation of naive CD4+ T cells. 968 62

Many T cell responses are dominated by restricted TCR expression and can range from repeated usage of particular TCR Vbeta- and/or Valpha-elements, to the preferential usage of both V- and J-elements, often in conjunction with conserved V-D-J or V-J junctional sequences. Cytotoxic T lymphocytes specific for a Kb-restricted determinant from the herpes simplex virus glycoprotein B (gB) preferentially express a dominant TCRBV10 beta-chain with sequence conservation of a tryptophan-glycine located in the V-D junction. Here we have examined whether immunisation of C57BL/6 mice with the gB-peptide can mimic the CTL response seen after HSV-1 infection. Immunisation with the gB-peptide resulted in the generation of gB-specific CTL that showed a similar TCRBV10 bias to that observed after HSV-1 infection. When the gB-determinant was expressed as a part of a fusion protein, immunised mice again exhibited the TCRBV10 bias with the junctional sequence conservation in the responding CTL. C57BL/6 mice were then immunised with variants of the gB-peptide that contained amino acid substitutions at positions previously predicted to contact the TCR beta-chain CDR3. Analysis of the TCRBV usage of variant specific CTL lines showed that substitutions at the TCR-contact positions 4, 6 and 7 of the gB-peptide resulted in a loss of the TCRBV10 bias. These results suggest that the TCRBV10 bias seen in gB-specific CTL after HSV-1 infection is due to antigenic selection by the minimal peptide and is determined by residues proposed to contact the TCR beta-chain CDR3.
Mol Immunol 1998 Apr
PMID:A dominant V beta bias in the CTL response after HSV-1 infection is determined by peptide residues predicted to also interact with the TCR beta-chain CDR3. 974 90


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>