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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this study was to explore the nature of the antigen-specific T cell response in giant cell arteritis by analyzing clonally expanded T cells in temporal artery specimens. In temporal artery tissue from eight patients, 10% of the T cell receptor beta chain repertoire was systematically screened for clonal T cells by reverse-transcriptase polymerase chain reaction with selected BV, BJ, and BC specific primers and by direct sequencing of the amplified product. In five additional patients tissue-derived T cell clones were characterized. All expanded clonotypes were analyzed for their presence at different sites of the inflamed artery. T cell lines were tested for their proliferation to autologous monocytes pulsed with temporal artery extracts from patients with giant cell arteritis, polymyalgia rheumatica, and unrelated diseases. Clonally expanded T cells were identified in 30% of the BV-J combinations of the sampled repertoire. A subset of these clones were encountered at different sites of the inflammation, but not in the peripheral blood. The T cell receptor beta chain sequences were diverse. The patients had between none and five such clonotypes in the sampled repertoire, suggesting that only few T cell specificities in each patient are involved in antigen recognition. One of these T cell clonotypes was shown to proliferate in response to an antigen selectively expressed in temporal artery specimens from giant cell arteritis and from polymyalgia rheumatica patients. Clonotypes with identical T cell receptor beta chain sequences can be found at distinct sites of the inflammation in giant cell arteritis, suggesting recognition of the same antigen at different locations. At least for some of these T cell clones the antigen is shared between different giant cell arteritis and polymyalgia rheumatica patients but not expressed in temporal arteries of patients with unrelated diseases. While different HLA-DR4+ patients utilize distinct T cell specificities, the actual number of responding T cells in individual patients is small and may be disease limiting.
J Mol Med (Berl) 1996 Nov
PMID:Recognition of tissue residing antigen by T cells in vasculitic lesions of giant cell arteritis. 895 56

We have analysed the T cell receptor (TCR) alpha and beta chain sequences of 16 human CD4+ T cell clones (TCCs) specific for three important epitopes of the major birch pollen allergen Bet v 1. The TCCs were raised from the peripheral blood of eight patients with birch pollen allergy, showing allergic rhino-conjunctivitis and allergic asthma. The TCCs from these individuals were specific for Bet v 1-derived peptides: amino acids (aa)77-92 (epitope 1), aa93-108 (epitope 2) and aa113-126 (epitope 3). The DNA sequence analysis of the TCRAV and BV regions revealed heterogeneous repertoires for recognition of the peptides. Multiple combinations of AV/AJ and BV/BJ were used. However, some inter-individual restriction was evident. A limited selection of AVS and the normally infrequently used BV1S4 was obvious in TCCs specific for epitope 1. The TCRBV13 was more frequent in TCCs recognizing epitope 3. A very narrow distribution in length could be seen in the CDR3 sequences of the beta chain of TCRs with specificity for epitopes 1 and 2. Inter-individual positional micro-restriction was observed for the aa motif LR in the tCDR3 (epitope 1), for the aa residue M in the alphaCDR3 and for the aa residue G in the betaCDR3 (epitope 3). Our results illustrate clearly that each antigenic peptide derived from a single allergen, is capable of selecting different characteristics in the responding repertoire of TCRs, thus increasing the complexity of allergen-recognition by T lymphocytes. Therefore, our findings limit the potential use of TCR targeted therapeutical strategies in Type I allergy.
Mol Immunol 1996 Sep
PMID:Sequence comparisons of the CDR3 hyper-variable loops of human T cell receptors specific for three major T cell epitopes of the birch pollen allergen Bet v 1. 901 Feb 43

When human T cell receptor for antigen (TCR) alpha chain V-genes were compared pair-wise, the numbers of nucleotide differences showed a characteristic distribution; most were in the range of 100 to 200 differences out of a total of about 300 bases. The same distribution was observed for mouse TCR alpha chains. Even more interesting was that comparing human alpha chains and mouse alpha chains gave essentially the same nucleotide difference pattern. It is inferred from the large number of differences and from the nonspecificity of trans-species (human and mouse) nucleotide sequence differences of TCR V-genes that TCR alpha chains probably diverged early during evolution. The same feature was also observed for human and mouse TCR beta chains, although the alpha and beta chain V-genes were distinct. This evolutionary preservation could be of vital importance to the fidelity of the complicated trimolecular interactions among TCR alpha and beta chains, the processed peptide, and the major histocompatibility complex (MHC) class I or II molecules.
J Mol Evol 1997 Mar
PMID:Profile of numbers of sequence differences among V-genes coding for the variable regions of T cell receptor for antigen alpha and beta chains. 906 Mar 91

In determining the T cell receptor (TcR) usage of various T cell clones that recognize peptide antigens derived from allergens, a particular clone (AC20) was found, that apparently expressed three different species of mRNA encoding alpha chains. The logical conclusion that the cells were not clonal was refuted by the finding of only a single beta chain rearrangement. One of the alpha chains (V alpha20), was not in frame, but two V alpha8 transcripts of different lengths were both potentially translatable. Sequence analysis suggested that the shorter transcript was generated by a secondary splice event from the longer, through the use of a splice donor sequence encoded by the J alpha38 gene segment. The efficiency of excision of the intervening sequence is such that approximately equal amounts of the long and short transcripts occur in the steady state pool of mRNA. This phenomenon has been reported previously in TcR alpha rearrangements, but it has never been made clear whether these truncated chains can form a functional TcR. Reconstitution of a TcR negative cell line with these transcripts showed that only the full length alpha chain was able to pair efficiently with the beta chain to generate a functional receptor at the cell surface.
Mol Immunol 1996 Oct
PMID:A T cell clone with three potential TCR alpha chain rearrangements expresses only one receptor combination at the cell surface. 907 Jun 66

Diversity of vertebrate antigen receptors is accomplished in large part by a somatic gene rearrangement process known as V(D)J recombination. The first step of the reaction appears to be the creation of a double strand break immediately between the recombination signal sequence (RSS) and the coding gene segment to generate a signal end and a coding end. Signal ends have been shown, both in vitro and in vivo, to be precise and blunt, while coding ends generated in vitro are covalently sealed hairpins. It has been difficult to document the existence of coding ends in vivo in normal lymphoid precursors, presumably because of their low abundance. To date, they have been identified in vivo only in a transformed pre-B cell line and in cells from the mutant scid mouse, where they largely conform to the hairpin structure found in vitro. Here, we identify T cell receptor J alpha gene coding ends in normal murine thymocytes. We demonstrate that these ends are processed, not blunt, and that most are not hairpin terminated, in sharp contrast to previous in vivo and in vitro observations. These results provide the first direct demonstration of this important intermediate of V(D)J recombination in normal lymphoid precursors and have implications for the mechanism of coding joint formation in vivo.
J Mol Biol 1997 Mar 21
PMID:Identification of V(D)J recombination coding end intermediates in normal thymocytes. 909 2

Cytotoxic T lymphocytes possess the capacity to lyse target cells which express antigens on their surface recognized by the T cell receptor. These cells are crucial in the body's defense against foreign antigens. It has long been a goal of tumor biology to utilize T cells specialized in the elimination of unwanted cells for the treatment of cancer. The killing activity of T lymphocytes is restricted to specific antigen-presenting cells. For this reason the use of cytotoxic T cells in the elimination of cancer cells is limited to cancer cells which present neoantigens on their surface. To circumvent this limitation we describe a procedure in which the zeta component of the T cell receptor is genetically manipulated and equipped with an extracellular recognition domain. Introduction of a chimeric gene, consisting of the zeta chain of the T cell receptor and a single-chain antibody domain, into cytotoxic T lymphocytes results in T cells with a predetermined recognition specificity for particular tumor cells. The MHC restriction of target cell recognition can be avoided and tumor cells recognized by the single chain antibody domain can be recognized and lysed. Retroviral-mediated gene transduction was used to introduce chimeric zeta chain constructs into primary T cells of mice. The cocultivation of retrovirus producing helper cells with in vitro activated T lymphocytes led to a high gene transduction efficiency into primary T cells. These primary T cells assumed a predetermined specificity for target cell recognition and lysis. The production and provision of tumor cell specific T lymphocytes might not be sufficient to eradicate large tumors in vivo. Using a Schwannoma cell line, we showed that transplanted tumors secrete transforming growth factor beta and thereby stifle the action of lymphocytes. We suggest that a coordinated strategy including the suppression of tumor cells specific antilymphocyte action and the provision of tumor cell specific T cells might be required to successfully eliminate tumor cells in vivo.
J Mol Med (Berl) 1997 Apr
PMID:Specific cytotoxic T lymphocytes in gene therapy. 915 Dec 12

The T cell response of C57BL/6 mice to human C-reactive protein (hCRP), an inducible acute phase protein, was analysed. Two I-A(b)-restricted epitopes at positions 79 95 (epitope A) and 87-102 (epitope B) were identified using a panel of CD4+ T cell clones. Human C-reactive protein shares considerable homology with mouse C-reactive protein and mouse serum amyloid P component. Interestingly, the two epitopes map to the region of lowest homology between human CRP and its mouse homologues. Human CRP-specific T cell clones express a restricted T cell receptor (TCR) repertoire, both with regard to usage of TCR germline gene segments (V alpha, J alpha, V beta, J beta) and certain TCR alpha beta combinations. Therefore, epitope-A specific clones preferentially use TCR V beta8.3 and V alpha3 J alpha15 V beta8.3-J beta2.3 and epitope-B specific clones use V beta2 and V alpha1-J alpha24/30-V beta2. This bias is even more pronounced when TCR usage is correlated with epitope fine specificity. A role for homology of hCRP to self components in selecting these particular T cell epitopes and TCR is discussed.
Mol Immunol 1997 Feb
PMID:The MHC class II-restricted T cell response of C57BL/6 mice to human C-reactive protein: homology to self and the selection of T cell epitopes and T cell receptors. 918 44

The crystal structure of a mutant T cell receptor (TCR) V alpha domain containing a grafted third complementarity-determining region (CDR3) from a different V alpha was determined at 2.3 A resolution by molecular replacement using the wild-type V alpha structure as a search model. Like the wild-type V alpha domain, the mutant crystallized as a homodimer very similar to TCR V alpha V beta and antibody V(L)V(H) heterodimers, with the CDR loops disposed to form part of the antigen-binding site. However, the relative orientation of the two chains in the mutant V alpha homodimer differs from that in the wild-type by a rotation of 14 degrees such that the buried surface area in the dimer interface of the mutant is 140 A2 less than in the wild-type. While the residues forming the interface are essentially the same in the two structures, there are only four pairs of interface hydrogen bonds in the case of the mutant compared with eight for the wild-type. These results suggest that multiple relative orientations of the V alpha and V beta domains of TCRs may be possible, providing a significant contribution to TCR combining site diversity.
J Mol Biol 1997 Jun 13
PMID:Dual conformations of a T cell receptor V alpha homodimer: implications for variability in V alpha V beta domain association. 919 7

Aplastic anemia (AA) is characterized by multilineage bone marrow failure of unknown etiology. In order to assess the role of immune-mediated mechanisms in hematopoietic suppression, we examined the diversity of T lymphocyte repertoire in terms of variable (V) gene segment usage of the T cell receptor (TCR) beta chain in bone marrow and peripheral blood of six patients with severe untreated AA. Expression of transcripts encoding Vbeta1-Vbeta24 subfamilies was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The results revealed that T lymphocytes in AA utilize highly diverse segments of the beta chain loci. Over the heterogenous Vbeta expression background, transcripts encoding Vbeta3, Vbeta20, Vbeta21, and Vbeta22 subfamilies were enhanced by at least threefold in 5 of 6 patients as compared to normal samples, but a different transcript species was over expressed in each patient. To evaluate clonality of T cells, size diversity within the complementarity determining region 3 (CDR3) and usage of TCRbeta joining (J) gene segments were analyzed in PCR products specific for each of the 24 Vbeta subfamilies. We found that the majority of transcripts display normal CDR3 size patterns, as is characteristic of polyclonal populations. Nevertheless, one or two predominating junctional rearrangements were observed in each patient. They were identified in Vbeta5, Vbeta7, Vbeta8, Vbeta13, Vbeta15, Vbeta16, and Vbeta23 transcripts, which differed from patient to patient and did not correspond to transcripts with an abnormally high expression level. Our results demonstrate that T cell repertoire in AA is random with respect to the TCR beta chain. Unique rearrangements detected in the CDR3 region are suggestive of a limited process of an antigen-driven (oligo)clonal T cell expansion which may take place over the overwhelmingly polyclonal repertoire of T lymphocytes at the onset of severe AA.
Blood Cells Mol Dis 1997
PMID:T-cell receptor beta chain variability in bone marrow and peripheral blood in severe acquired aplastic anemia. 921 56

The set of potential T cell receptor specificities is highly diverse. The relative contributions of T cell receptor (TCR) V beta gene segment polymorphisms, duplications, deletions, and gene conversions to this final T cell receptor protein diversity are unknown. To study these mechanisms, we sequenced and compared closely related primate TCR gene segments from BV8S1, S2, and S5. Interspecies comparisons show that these gene segments have sustained multiple duplication, gene conversion, and deletion events during the last 35 million years of anthropoid primate evolution. BV8 coding sequences are generally conserved with respect to their flanking noncoding sequences, but we find no evidence for positive or negative selection in sequences coding for the first two putative complementarity-determining (ligand-binding) regions. Sequences of TCRBV8 gene segments from unrelated humans demonstrate no nonsynonymous substitutions in nonleader regions of either the BV8S1 or S2 gene segments. We conclude that gene duplication, deletion, and conversion mechanism contribute in a substantial way to the overall diversity of the TCRBV8 gene segment repertoire in primate evolution and that germline substitutions and consequent polymorphisms in CDRs 1 and 2 of these gene segments probably do not play an active role in generating TCR beta chain protein variation.
Mol Phylogenet Evol 1997 Aug
PMID:Evolution and selection of primate T cell antigen receptor BV8 gene subfamily. 924 95


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