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)

The maturation of T-cells depends on V(D)J recombination at the TCR alpha/beta and gamma/delta loci that occurs in the thymus during fetal development. Due to the essential role of the TCRbeta in thymocyte differentiation, it is important to define with precision the temporal emergence of the TCRbeta rearrangement and its expression in normal non-manipulated mouse strains. We studied the onset of the V(D)J recombination and transcription of the TCR Valpha3 and Vbeta11 genes during ontogeny in Balb-c, C57B1/6 and CBA inbred mouse strains. Our data show differences in the emergence of recombination in both TCR alpha and beta loci among strains. The transcriptions of these loci followed respective recombinations and we detected an early germline transcript before TCR beta locus recombination in the CBA strain.
Mol Cell Biochem 1998 Oct
PMID:Emergence of TCR alpha/beta V(D)J recombination and transcription during ontogeny of inbred mouse strains. 978 44

CD1 molecules are MHC-unlinked class Ib molecules consisting of classical (human CD 1a-c) and non-classical subsets (human CD1d and murine CD1). The characterization of non-classical subsets of CD1 is limited due to the lack of reagents. In this study, we have generated two new anti-mouse CD1 monoclonal antibodies, 3H3 and 5C6, by immunization of hamsters with purified CD1 protein. These antibodies recognize CD1-transfected cells and have no reactivity to cells isolated from CD1-/- mice. Both antibodies precipitate the 52 kDa heavy chain and 12 kDa beta2m from thymocytes and splenocytes by radio-immunoprecipitation. Deglycosylation of CD1 reduces molecular mass of the heavy chain by 7.5 kDa, which can be detected by 3H3 but not 5C6. 3H3 and 5C6 detect surface CD1 expression on cells from the thymus, spleen, lymph node and bone marrow, but not on intestinal epithelial cells. Developmentally, CD1 is expressed on thymocytes prior to TCR rearrangement and remains constant throughout thymic development. CD1 is expressed early in the fetal liver (day 14) and remains expressed in hepatocytes postnatally. These data support evidence of a role for CD1 in the selection and/or expansion of NK1- T cells of both thymic origin and extrathymic origin. Unlike classical class I molecules, murine CD1 levels are not affected by IFN-gamma, but like human CD1b can be up-regulated by IL-4 and GM-CSF although only moderately. Similar to human CD1b, murine CD1 is found by immunofluorescence microscopy on the cell surface, and in various intracellular vesicles, including early and late endosomes. Localization in endocytic compartments indicates that murine CD1 may be capable of binding endocytosed antigens.
Mol Immunol 1998 Jun
PMID:Tissue distribution, regulation and intracellular localization of murine CD1 molecules. 980 80

Herein are reported full length cDNA sequences for TCR alpha- and beta-chains of the channel catfish. Included are sequences belonging to four Valpha and six Vbeta families which share hallmarks in common with the Valpha and Vbeta genes of other species. Similar to the situation in other vertebrates, the catfish Calpha and Cbeta sequences exhibit distinct immunoglobulin, connecting peptide, transmembrane and cytoplasmic domains. However, the catfish TCR Calpha and Cbeta regions are shorter than those of mammals and the catfish Cbeta chain lacks a cysteine in its connecting peptide region. Two different catfish Cbeta cDNA sequences were identified, suggesting the existence of either two Cbeta loci or allotypes. Based on Southern blot analyses, each of the catfish TCR gene loci appear to be arranged in a translocon (as opposed to multicluster) organization with multiple V elements and a single or few copies of C region DNA. At the deduced amino acid level, the catfish Cbeta sequence exhibits 42% identity with the Cbeta of Atlantic salmon, 41% identity with the Cbeta of rainbow trout and 26% identity with Cbeta of the horned shark. The catfish Calpha amino acid sequence exhibits 44 and 29% identity with Calpha of the rainbow trout and southern pufferfish, respectively. TCRalpha and beta messages are selectively expressed and rearranged in a catfish clonal cell line that appears to be of the T lineage. This TCR alpha/beta expressing clonal lymphocyte line, designated 28S.1, has T-cell like function in that it constitutively produces a supernatant factor(s) with growth promoting activity. These findings should facilitate functional studies of fish TCRs and T cells in ways not previously possible with other 'lower' vertebrate models.
Mol Immunol 1998 Jun
PMID:T-cell receptors in channel catfish: structure and expression of TCR alpha and beta genes. 980 82

To study how the T cell receptor interacts with its cognate ligand, the MHC/peptide complex, we used site directed mutagenesis to generate single point mutants that alter amino acids in the CDR3beta loop of a H-2Kb restricted TCR (N30.7) specific for an immunodominant peptide N52-N59 (VSV8) derived from the vesicular stomatitis virus nucleocapsid. The effect of each mutation on antigen recognition was analyzed using wild type H-2Kb and VSV8 peptide, as well as H-2Kb and VSV8 variants carrying single replacements at residues known to be exposed to the TCR. These analyses revealed that point mutations at some positions in the CDR3beta loop abrogated recognition entirely, while mutations at other CDR3beta positions caused an altered pattern of antigen recognition over a broad area on the MHC/peptide surface. This area included the N-terminus of the peptide, as well as residues of the MHC alpha1 and alpha2 helices flanking this region. Assuming that the N30 TCR docks on the MHC/peptide with an orientation similar to that recently observed in two different TCR-MHC/peptide crystal structures, our findings would suggest that single amino acid alterations within CDR3beta can affect the interaction of the TCR with an MHC surface region distal from the predicted CDR3beta-Kb/VSV8 interface. Such unique recognition capabilities are generated with minimal alterations in the CDR3 loops of the TCR. These observations suggest the hypothesis that extensive changes in the recognition pattern due to small perturbations in the CDR3 structure appears to be a structural strategy for generating a highly diversified TCR repertoire with specificity for a wide variety of antigens.
Mol Immunol 1998 Jul
PMID:Point mutations in the beta chain CDR3 can alter the T cell receptor recognition pattern on an MHC class I/peptide complex over a broad interface area. 982 58

We recently described the generation and expression of a chimeric T cell receptor with specificity for the tumor antigen TAG72 consisting of the single chain antibody (scFv) B72.3-scFv and the gamma chain of the FcepsilonRI receptor. The corresponding chimeric receptor containing the zeta chain of the TCR as signalling unit is not functionally expressed reflecting that the requirements for functional expression of chimeric receptors containing the gamma signalling chain are apparently different compared to those containing the CD3zeta signalling chain of the TCR. We describe a novel set of chimeric anti-TAG72 receptors including in their extracellular moiety the constant immunoglobulin CH2/3 domains that allow stable expression of chimeric gamma as well as zeta receptors. We designed anti-TAG72 receptors that consist of a scFv fragment derived from an anti-TAG72 second generation antibody (CC49) and of the CH2/3 domains of the human IgG and intracellularily either of the zeta or gamma signalling chain. The recombinant CC49-CH2/3-zeta and CC49-CH2/3-gamma DNA, respectively, was transfected into MD45 T cells and expressed under control of the RSV LTR. Both receptors were found on the cell membrane of transfected cells as demonstrated by flow cytometry analysis using an anti-human IgG Fc antibody directed to the CH2/3 immunoglobulin domains of the chimeric receptor. Specific cross-linking of the chimeric zeta as well as the gamma receptor by antigen or anti-human Ig antibodies resulted in specific activation of transfected cells. Our results demonstrate that both the gamma chain and the zeta chain++ containing receptor are stably expressed and convert T cells to specificity for the TAG72 antigen. This receptor design will facilitate efficient generation of genetically modified peripheral T cells and may provide valuable tools for the cellular immunotherapy of TAG72+ tumors.
Int J Mol Med 1998 Jul
PMID:Chimeric anti-TAG72 receptors with immunoglobulin constant Fc domains and gamma or zeta signalling chains. 985 51

The T cell antigen receptor-CD3 (TCR/CD3) complex is assembled in the endoplasmic reticulum (ER) of T cells after synthesis of individual chains, and is transported to the cell surface for immune recognition and regulation. Partially assembled or unassembled TCR chains are retained and rapidly degraded in the ER. These processes are strictly regulated in the ER at post-translational level for the maintenance of cellular homeostasis. In order to identify the region responsible for the ER retention and rapid degradation of the TCR beta chain, number of mutants were engineered and their fates, after synthesis in the ER of the HeLa cells, were investigated. Extensive mutagenic analysis of TCR beta chain, including changing the charged amino acid residues and two tyrosine residues of the transmembrane region into hydrophobic amino acid residues, did not alter the ER retention and rapid degradation. Soluble TCR beta chain and cytoplasmic tail truncation mutant were also rapidly degraded in the ER. However, N-glycosylation rate of soluble TCR beta chain in the ER was significantly increased possibly due to the increased exposure of the N-glycosylation site. These results suggest that the ER retention of TCR beta chain is mediated through its extracellular and transmembrane-cytoplasmic regions and that the rapid ER degradation can be caused by an exposure of unassembled subregion of TCR beta chain, either extracellular domain or hydrophobic transmembrane region to the hydrophilic environment (lumen of the ER) rather than by presence of a specific degradation signal.
Exp Mol Med 1998 Sep 30
PMID:Endoplasmic reticulum retention and degradation of T cell antigen receptor beta chain. 987 38

CD40, a cell surface molecule found on B lymphocytes and other antigen presenting cells, can, when engaged by CD40 ligand (CD40L), induce gene rearrangements and isotype switching. We report here that CD40 is also expressed on thymocytes and on up to 50% of peripheral T cells from autoimmune prone strains of mice. In normal animals, CD40 is present on a small population of T cells and thymocytes. CD40 is expressed on most T cell hybridomas. We demonstrate that CD40 engagement on peripheral T cells, T cell hybridomas and thymocytes results in altered TCRValpha expression. That induced expression of different Valpha's results from the activity of the recombinase gene is implied by the observation that CD40 does not induce TCR changes in RAG knock-out mice. Total cell numbers remained unchanged between anti-CD40 treated and untreated populations of thymocytes or T cells indicating that treatment does not induce cell proliferation or cell death. The data presented here suggest a mechanism by which self reactive T cells accumulate peripherally and independently of selective processes of the thymus.
Int J Mol Med 1999 Sep
PMID:Increased expression of CD40 on thymocytes and peripheral T cells in autoimmunity: a mechanism for acquiring changes in the peripheral T cell receptor repertoire. 1042 71

The Id proteins are inhibitors of basic-Helix-Loop-Helix transcription factor function that have been implicated in the control of cell differentiation and proliferation. To study the role of Id proteins in the control of T cell development, we generated transgenic mice that overexpress the Id2 protein in thymocytes. We detect a significant expansion of the early CD4(-)CD8(+)TCR(-) thymocyte stage and a depletion of the thymocytes of the subsequent developmental stages. These data indicate that the overexpression of Id2 leads to a stage-specific developmental block early in thymopoiesis. In addition, progeny mice from five of the six Id2 transgenic founder lines succumb to aggressive T cell hyperproliferation that resembles lymphoma. Thus, overexpression of the Id2 protein has profound effects on T cell development and oncogenesis, consistent with the hypothesis that the bHLH proteins play critical roles in these processes.
Mol Immunol 1999 Jun
PMID:Overexpression of the Helix-Loop-Helix protein Id2 blocks T cell development at multiple stages. 1047 4

Local stimulation by Helicobacter pylori (HP), autoantigen, and a concurrent T-cell-mediated stimulation of B cells are believed to play an important role in gastric mucosa-associated lymphoid tissue (MALT) type B cell lymphomagenesis. Many autoimmune diseases have shown to lead to a skewed T-cell repertoire with autoantigen specific expansions and deletions. Characterization of lymphoma and gastritis areas of seven gastrectomy specimens using a T-cell receptor beta variable chain (TCR betaV) family-specific reverse transcriptase (RT)-polymerase chain reaction (PCR) assay and fluorescence-activated cell sorter (FACS) analysis revealed a local chronic and acute activation of T cells in lymphoma and an oligoclonal T-cell repertoire in gastritis and in lymphoma, partially sharing the same clones. Local activation and a partial identity suggest that an antigenic challenge caused by a common local pathogen may still continue to take place in MALT type lymphoma as in gastritis, consistent with the view that gastritis may be a precursor lesion of MALT type lymphoma. Expansions that were found only in one of the compartments suggest that also an immune hyperstimulation may contribute to the T-cell repertoire, possibly because of certain tissue antigens. Deletions of TCR betaV families found only in gastritis underline the view that autoantigen may play an important role in its pathogenesis.
Diagn Mol Pathol 1999 Sep
PMID:Oligoclonal expansions of T-cell repertoire in gastric mucosa associated lymphoid tissue type B-cell lymphoma and adjacent gastritis. 1056 85

Autoimmune lymphoproliferative syndrome (ALPS) is a rare, newly recognized, chronic lymphoproliferative disorder in children and is characterized by lymphadenopathy, splenomegaly, pancytopenia, autoimmune phenomena and expansion of double-negative (DN) T lymphocytes (TCR alpha beta+, CD4-, CD8-). Defective lymphocyte apoptosis caused by mutations of the Fas (CD95) gene has been linked in the pathogenesis of ALPS, as binding of Fas-ligand to Fas can trigger apoptosis. Of the ALPS cases reported to date, point mutations, frameshifts and silent mutations in Fas all have been identified. We report two new point mutations in Fas in a child with ALPS and eosinophilia; studies on other family members established the pattern of inheritance for these mutations. Flow cytometric analysis of blood and tissues (spleen, lymph node, bone marrow) revealed abnormally expanded populations of DN T lymphocytes. Furthermore, activated lymphocytes and IFN gamma-activated eosinophils were resistant to Fas-mediated apoptosis. Eosinophil resistance to Fas-mediated apoptosis has not been previously described in ALPS. Sequencing of Fas revealed two separate mutations not previously reported. One mutation, a C to T change at base 836, was a silent mutation inherited from the mother, while the second mutation, a C to A change at base 916, caused a non-conservative amino acid substitution in the death domain of Fas, changing a threonine to a lysine. This mutation is associated with a predicted change in the structure of a part of the death domain from a beta-pleated sheet to an alpha-helix. We speculate that the mutation in the death domain prevents the interaction of Fas with intracellular mediators of apoptosis and is responsible for the autoimmune manifestations of ALPS and the abnormal lymphocytosis and eosinophilia in this patient.
Blood Cells Mol Dis
PMID:Identification of new Fas mutations in a patient with autoimmune lymphoproliferative syndrome (ALPS) and eosinophilia. 1057 48


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