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At least 19 recordsLinked to original sources

PubMed1994

Refined crystal structure of rat parvalbumin, a mammalian alpha-lineage parvalbumin, at 2.0 A resolution.

We present here the X-ray crystal structure of the rat alpha-parvalbumin from fast twitch muscle. This protein (M(r) 11.8 kDa) crystallizes in space group P2(1)2(1)2(1) with unit cell dimensions of a = 34.3 A, b = 55.0 A, c = 156.1 A and three molecules in the asymmetric unit. The protein structure was solved by the molecular replacement method and has been refined to a crystallographic R-factor [formula: see text] of 0.181 for all reflections with I/sigma(I) > or = 2 (I = intensity) between 8.0 and 2.0 A resolution. The molecules located most easily in the molecular replacement rotation function had lower overall thermal motion parameters and higher numbers of intermolecular crystal packing contacts. The overall fold of the polypeptide chain for the rat alpha-parvalbumin is similar to other known parvalbumin structures (root-mean-square deviations in alpha-carbon atom positions range from 0.60 to 0.87 A). There are two Ca(2+)-binding sites in parvalbumins, and there is some evidence for a third ion-binding site, adjacent to the CD site, in the rat species. The level of structural variability among the best-ordered regions of the three independent rat alpha-parvalbumin molecules in the crystallographic asymmetric unit is two to three times higher than the mean coordinate error (0.10 A), indicating flexibility in the molecule. Sequence differences between alpha and beta-lineage parvalbumins result in repacking of the hydrophobic core and some shifts in the protein backbone. The shifts are localized, however, and entire helices do not shift as rigid units.

Animals↗

PubMed2004

Self-reactivity in thymic double-positive cells commits cells to a CD8 alpha alpha lineage with characteristics of innate immune cells.

Thymocytes displaying self-reactive T cell receptors usually undergo negative selection in the thymus. Here we demonstrate that agonist peptides can promote positive selection of immature double-positive thymocytes into distinct lineages, varying with the agonist concentration and the animal's age. Microarray gene expression analyses showed broad transcriptional alterations in a set of transcripts associated with the innate immune system, as well as silencing of CD8 beta expression. The resulting CD8 alpha alpha T cells showed a rapid effector cytokine response. Hence, T cells displaying self-reactive receptors can have the gene expression profile and phenotypic characteristics of innate immune cells.

Animals↗

PubMed1996

T cell receptor delta gene rearrangement and T early alpha (TEA) expression in immature alpha beta lineage thymocytes: implications for alpha beta/gamma delta lineage commitment.

Mature T cells comprise two mutually exclusive lineages expressing heterodimeric alpha beta or gamma delta antigen receptors. During development, beta, gamma, and delta genes rearrange before alpha, and mature gamma delta cells arise in the thymus prior to alpha beta cells. The mechanism underlying commitment of immature T cells to the alpha beta or gamma delta lineage is controversial. Since the delta locus is located within the alpha locus, rearrangement of alpha genes leads to deletion of delta. We have examined the rearrangement status of the delta locus immediately prior to alpha rearrangement. We find that many thymic precursors of alpha beta cells undergo VDJ delta rearrangements. Furthermore, the same cells frequently coexpress sterile T early alpha (TEA) transcripts originating 3' of C delta and 5' of the most upstream J alpha, thus implying that individual alpha beta lineage cells undergo sequential VDJ delta and VJ alpha rearrangements. Finally, VDJ delta rearrangements in immature alpha beta cells appear to be random, supporting models in which alpha beta lineage commitment is determined independently of the rearrangement status at the TCR delta locus.

Amino Acid Transport Systems, Basic↗

PubMed1995

Interhomologue sequence variation of alpha satellite DNA from human chromosome 17: evidence for concerted evolution along haplotypic lineages.

Alpha satellite DNA is a family of tandemly repeated DNA found at the centromeres of all primate chromosomes. Different human chromosomes 17 in the population are characterized by distinct alpha satellite haplotypes, distinguished by the presence of variant repeat forms that have precise monomeric deletions. Pair-wise comparisons of sequence diversity between variant repeat units from each haplotype show that they are closely related in sequence. Direct sequencing of PCR-amplified alpha satellite reveals heterogeneous positions between the repeat units on a chromosome as two bands at the same position on a sequencing ladder. No variation was detected in the sequence and location of these heterogeneous positions between chromosomes 17 from the same haplotype, but distinct patterns of variation were detected between chromosomes from different haplotypes. Subsequent sequence analysis of individual repeats from each haplotype confirmed the presence of extensive haplotype-specific sequence variation. Phylogenetic inference yielded a tree that suggests these chromosome 17 repeat units evolve principally along haplotypic lineages. These studies allow insight into the relative rates and/or timing of genetic turnover processes that lead to the homogenization of tandem DNA families.

Base Sequence↗

PubMed1995

V-D-J rearrangements at the T cell receptor delta locus in mouse thymocytes of the alpha beta lineage.

The T cell receptor (TCR) delta locus lies within the TCR alpha locus and is excised from the chromosome by V alpha-J alpha rearrangement. We show here that delta sequences persist in a large fraction of the DNA from mature CD4+CD8- alpha beta+ mouse thymocytes. Virtually all delta loci in these cells are rearranged and present in extrachromosomal DNA. In immature alpha beta lineage thymocytes (CD3-/loCD4+CD8+) and in CD4+CD8- alpha beta+ thymocytes expressing a transgene-encoded alpha beta receptor, rearranged delta genes are present both in chromosomal and extrachromosomal DNA. Thus, contrary to earlier proposals, commitment to the alpha beta lineage does not require recombinational silencing of the delta locus or its deletion by a site-specific mechanism prior to V alpha-J alpha rearrangement.

Animals↗

PubMed1994

Lineage specific demethylation of tal-1 gene breakpoint region determines the frequency of tal-1 deletions in alpha beta lineage T-cells.

tal-1 deletions are caused by a site specific recombination, which exclusively occurs in 12-26% of T-cell acute lymphoblastic leukemias (T-ALL). In a previous study on a large series of T-ALL we demonstrated an apparent preferential occurrence of tal-1 deletions in CD3- and CD3+ alpha beta lineage T-ALL with TcR-delta gene deletions on one or both alleles. In the present study we investigated whether accessibility of the tal-1 deletion breakpoint regions influences the preferential occurrence in specific T-ALL subgroups. Because DNA methylation is assumed to determine accessibility of DNA for recombination, the methylation status of the tal-1 deletion type 1 breakpoint regions (sildb and taldb1) was studied. Although the sildb were completely demethylated in all T-ALL, preferential (de)methylation configurations of the taldb1 were observed in the analysed 119 T-ALL. Most TcR-alpha beta + T-ALL contained completely demethylated taldb1 (77%), whereas in most TcR-gamma delta + T-ALL partial or complete methylation occurred (42% and 47%, respectively). In T-ALL subgroups defined by different TcR-delta gene configurations also preferential taldb1 (de)methylation patterns were seen, which was most prominent in T-ALL with both TcR-delta genes deleted (84% complete demethylation). The previously observed preferential occurrence of tal-1 deletion type 1 in TcR-alpha beta + vs CD3- T-ALL and in T-ALL with both vs one TcR-delta genes deleted, disappeared when we retricted to T-ALL with completely demethylated taldb1. Moreover, all T-ALL with a tal-1 deletion type 1 (n = 15) contained completely demethylated taldb1. We therefore conclude that complete demethylation of taldb1 is a prerequisite for tal-1 deletions type 1 and that the differences in tal-1 deletion frequencies observed in the various T-ALL subgroups are caused by differences in the (de)methylation status of taldb1 in these subgroups.

Base Sequence↗

PubMed1995

Efficient maturation of alpha beta lineage thymocytes to the CD4+CD8+ stage in the absence of TCR-beta rearrangement.

We have produced transgenic mice that express rearranged T cell Ag receptor gamma and delta transgenes in the alpha beta lineage of thymocytes. Thymi in these mice contain normal numbers of CD4+CD8+ cells that express low levels of the TCR-gamma delta. Analysis of the delta locus in these thymi indicates that these cells are in the alpha beta lineage even though they express the TCR-gamma delta. This shows that expression of the TCR-gamma delta in early thymocytes can lead to all of the consequences that are normally mediated by the beta-chain. These consequences include maturation to the CD4+CD8+ stage, entry into the cell cycle, and cessation of beta rearrangement. Therefore, the data support a model in which formation of a functional CD3 complex on immature CD4-CD8- thymocytes leads to further development in the absence of extracellular ligand recognition. The data also show that the gamma delta vs alpha beta lineage decision is made in a manner that is independent of gamma and beta gene expression.

Animals↗

PubMed1989

Alpha beta lineage-specific expression of the alpha T cell receptor gene by nearby silencers.

T cells expressing either the alpha beta or gamma delta antigen receptor (TCR) are distinct cell lineages. The single locus encoding the TCR alpha and delta genes requires special regulation to avoid alpha gene expression in gamma delta T cells. We show here that the minimal alpha enhancer is active in the gamma delta T cell lineage but gains alpha beta lineage specificity through negative cis-acting elements 3' of the C alpha gene that silence the enhancer in gamma delta T cells. The negative elements at the C alpha locus consist of several silencers that work in an orientation- and distance-independent fashion. These silencers also act on a retroviral enhancer that is normally ubiquitously expressed, restricting its activity to alpha beta cells. The alpha silencers are active in non-T cell lines, suggesting that the decision of a cell to differentiate into the alpha beta T cell lineage may involve specific relief from these silencers. Silencers are likely to be as important as enhancers in establishing lineage-specific gene expression in many systems.

Animals↗

PubMed1992

Disruption of the SCL locus in T-lymphoid malignancies correlates with commitment to the T-cell receptor alpha beta lineage.

The SCL/tal-1 gene on chromosome 1 is disrupted in up to 30% of immature T-cell malignancies, thus representing the most commonly recognized chromosomal abnormality in this disorder. Abnormalities of the gene occur rarely by chromosomal translocation into the T-cell receptor (TCR) delta locus and commonly by a site-specific 95-kb deletion, SIL-SCL (tald). Analysis of the SIL-SCL deletion by Southern blotting and polymerase chain reaction (PCR) in a series of 52 immature T-cell malignancies showed a type A deletion in 21% of cases, but no type B deletions. The type A deletion correlated with malignancies of the TCR alpha beta lineage, either on the basis of TCR alpha beta expression or bilateral TCR delta deletion. Fifty percent (5 of 10) of TCR alpha beta-expressing cells demonstrated the abnormality, whereas 0% (0 of 11) of TCR gamma delta-expressing cells did so. Six of eight SIL-SCL type A cases had undergone bilateral delta deletion, whereas only one of 31 cases with an apparently normal SCL gene had done so. These data demonstrate an association between SCL disruption and TCR alpha beta lineage differentiation and suggest that the SIL-SCL deletion occurs at the same stage of ontogeny as TCR delta deletion.

Adolescent↗

PubMed2025

Analysis of Variants' Dynamic Using the CLIMB Database in COVID-19 Patients Admitted to Hospitals of Barts Health NHS Trust.

The COVID-19 pandemic, caused by SARS-CoV-2, has led to significant global health challenges. This study analyzes the dynamics of SARS-CoV-2 variants among patients admitted to Barts Health National Health Service (NHS) Trust hospitals using data from the CLIMB-COVID decentralized digital infrastructure allowing precise identification of SARS-CoV-2 variants. A total of 423 patients admitted between October 2020 and March 2021 were included in the study and divided into two groups: the alpha lineage group, which comprised the B.1.1.7 variant, and the other lineages group, which included all other variants. Whole-genome sequencing of SARS-CoV-2 genomes was conducted using the COVID-CLIMB pipelines. Clinical outcomes, such as mortality rates and deterioration within 28 days, were analyzed. To ensure robust findings, analyzes were adjusted for confounding factors, including age and comorbidities. Our findings revealed a significant increase in mortality with age for the alpha lineage and other lineages. The study underscores the importance of age adjustment in clinical studies to accurately assess the impact of different variants. Consistent genomic sequencing and data completeness are crucial for obtaining reliable results and guiding public health responses. These insights are vital for improving patient outcomes and providing a truthful picture of the pandemic, informing both current and future healthcare strategies.

Humans↗

PubMed2002

Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes.

Notch proteins influence cell fate decisions in many developmental systems. During lymphoid development, Notch1 signaling is essential to direct a bipotent T/B precursor toward the T cell fate, but the role of Notch1 at later stages of T cell development remains controversial. We have recently reported that tissue-specific inactivation of Notch1 in immature (CD44(-) CD25(+)) thymocytes does not affect subsequent T cell development. Here, we demonstrate that loss of Notch1 signaling at an earlier (CD44(+)CD25(+)) developmental stage results in severe perturbation of alpha beta but not gamma delta lineage development. Immature Notch1(-/-) thymocytes show impaired VDJ beta rearrangement and aberrant pre-TCR-independent survival. Collectively, our data demonstrate that Notch1 controls several nonredundant functions necessary for alpha beta lineage development.

Animals↗

PubMed1999

Ig heavy chain gene rearrangements in T-cell acute lymphoblastic leukemia exhibit predominant DH6-19 and DH7-27 gene usage, can result in complete V-D-J rearrangements, and are rare in T-cell receptor alpha beta lineage.

Rearranged IGH genes were detected by Southern blotting in 22% of 118 cases of T-cell acute lymphoblastic leukemia (ALL) and involved monoallelic and biallelic rearrangements in 69% (18/26) and 31% (8/26) of these cases, respectively. IGH gene rearrangements were found in 19% (13/69) of CD3(-) T-ALL and in 50% of TCRgammadelta+ T-ALL (12/24), whereas only a single TCRalpha beta+ T-ALL (1/25) displayed a monoallelic IGH gene rearrangement. The association with the T-cell receptor (TCR) phenotype was further supported by the striking relationship between IGH and TCR delta (TCRD) gene rearrangements, ie, 32% of T-ALL (23/72) with monoallelic or biallelic TCRD gene rearrangements had IGH gene rearrangements, whereas only 1 of 26 T-ALL with biallelic TCRD gene deletions contained a monoallelic IGH gene rearrangement. Heteroduplex polymerase chain reaction (PCR) analysis with VH and DH family-specific primers in combination with a JH consensus primer showed a total of 39 clonal products, representing 7 (18%) VH-(DH-)JH joinings and 32 (82%) DH-JH rearrangements. Whereas the usage of VH gene segments was seemingly random, preferential usage of DH6-19 (45%) and DH7-27 (21%) gene segments was observed. Although the JH4 and JH6 gene segments were used most frequently (33% and 21%, respectively), a significant proportion of joinings (28%) used the most upstream JH1 and JH2 gene segments, which are rarely used in precursor-B-ALL and normal B cells (1% to 4%). In conclusion, the high frequency of incomplete DH-JH rearrangements, the frequent usage of the more downstream DH6-19 and DH7-27 gene segments, and the most upstream JH1 and JH2 gene segments suggests a predominance of immature IGH rearrangements in immature (non-TCRalpha beta+) T-ALL as a result of continuing V(D)J recombinase activity. More mature alpha beta-lineage T-ALL with biallelic TCRD gene deletions apparently have switched off their recombination machinery and are less prone to cross-lineage IGH gene rearrangements. The combined results indicate that IGH gene rearrangements in T-ALL are postoncogenic processes, which are absent in T-ALL with deleted TCRD genes and completed TCR alpha (TCRA) gene rearrangements.

Adult↗

PubMed1998

Intestinal intraepithelial lymphocytes include precursors committed to the T cell receptor alpha beta lineage.

The majority of T cells develop in the thymus and exhibit well characterized phenotypic changes associated with their maturation. Previous analysis of intestinal intraepithelial lymphocytes (IEL) from nude mice and a variety of experimentally manipulated models led to the view that at least a portion of these cells represent a distinct T cell population that matures extrathymically. The IEL that are postulated to mature within the intestine include both T cell receptor (TCR) alpha beta- and gamma delta-bearing subpopulations. They can be distinguished from conventional thymically derived T cells in that they express an unusual coreceptor, a CD8alpha homodimer. In addition, they can utilize the Fc receptor gamma-chain in place of the CD3-associated zeta-chain for TCR signaling and their maturation depends on the interleukin 2 receptor beta-chain. Moreover, TCRalpha beta+CD8alpha alpha+ IEL are not subject to conventional thymic selection processes. To determine whether CD3(-)CD8alpha alpha+ IEL represent precursors of T cells developing extrathymically, we examined IEL from knockout mice lacking the recombination activating gene-1 (rag-1), CD3epsilon, or both Lck and Fyn, in which thymic T cell development is arrested. CD3(-)CD8alpha alpha+CD16(+) IEL from all three mutant strains, as well as from nude mice, included cells that express pre-TCRalpha transcripts, a marker of T cell commitment. These IEL from lck-/-fyn-/- animals exhibited TCR beta-gene rearrangement. However, CD3(-)CD8alpha alpha+CD16(+) IEL from epsilon-deficient mice had not undergone Dbeta-Jbeta joining, despite normal rearrangement at the TCRbeta locus in thymocytes from these animals. These results revealed another distinction between thymocytes and IEL, and suggested an unexpectedly early role for CD3epsilon in IEL maturation.

Animals↗

PubMed1998

The role of the T-cell receptor (TCR) in alpha beta/gamma delta lineage commitment: clues from intracellular TCR staining.

T cells belong to two mutually exclusive lineages expressing either alpha beta or gamma delta T-cell receptors (TCR). Although alpha beta and gamma delta cells are known to share a common precursor the role of TCR rearrangement and specificity in the lineage commitment process is controversial. Instructive lineage commitment models endow the alpha beta or gamma delta TCR with a deterministic role in lineage choice, whereas separate lineage models invoke TCR-independent lineage commitment followed by TCR-dependent selection and maturation of alpha beta and gamma delta cells. Here we review the published data pertaining to the role of the TCR in alpha beta/gamma delta lineage commitment and provide some additional information obtained from recent intracellular TCR staining studies. We conclude that a variant of the separate lineage model is best able to accommodate all of the available experimental results.

Animals↗

PubMed2001

Interaction between GC box binding factors and Smad proteins modulates cell lineage-specific alpha 2(I) collagen gene transcription.

Type I collagen is produced predominantly in mesenchymal cells, but molecular mechanisms responsible for cell type-specific expression are virtually unknown. During fibrogenic process in the liver, activated hepatic stellate cells (HSC) are the main producers of type I collagen, whereas parenchymal hepatocytes produce little, if any, of this protein. We have previously reported that Sp1 and an interacting unknown factor(s) bind to the -313 to -255 sequence of the alpha2(I) collagen gene (COL1A2) and play essential roles for basal and TGF-beta-stimulated transcription in skin fibroblasts and HSC. Recently, Smad3 has been shown to bind to this region, and its interaction with Sp1 has been implicated in TGF-beta-elicited COL1A2 stimulation. The present study demonstrates predominant binding of Sp3 rather than Sp1 to this regulatory element in parenchymal hepatocytes. In these cells, this region did not exhibit strong enhancer activity or mediate the effect of TGF-beta. Transfection of HSC with an Sp3 expression plasmid abolished the COL1A2 response to TGF-beta, whereas overexpression of Sp1 in hepatocytes increased basal COL1A2 transcription and conferred TGF-beta responsiveness. Functional and physical interactions between Sp1 and Smad3, but not between Sp3 and Smad3, were demonstrated using the bacterial GAL4 system and immunoprecipitation-Western blot analyses. These results indicate that cell lineage-specific interactions between GC box binding factors and Smad protein(s) may account, at least in part, for differential COL1A2 transcription and TGF-beta responsiveness in HSC and parenchymal hepatocytes.

Animals↗

PubMed1990

A raf/myc virus immortalized macrophage cell line which supports the growth of B-cell and B-cell hybridomas.

Using a combination of raf and myc oncogenes co-expressed by the recombinant retrovirus J-2 we have generated and characterized a cell line which very efficiently supports the growth of B-cells and B-cell hybridomas. Murine spleen cells were cultured under in vitro immunization conditions favoring the short term proliferation of splenic B lymphocytes and infected with J-2 virus. Screening of immortalized spleen cell pools for the capability to support long term B cell growth in vitro led to the selection of a clonal cell line termed alpha ChyJ2. The presence of macrophage specific features and surface markers suggest that alpha ChyJ2 belongs to the macrophage lineage. alpha ChyJ2 cells constitutively produce low levels of IL-1 like activity and high levels of IL-6. Expression of specific mRNAs as well as production of IL-1 alpha, IL-1 beta and IL-6 are inducible with LPS. Expression or production of other cytokines including IL-2, IL-3, IL-4, IL-5, TGF beta and GM-CSF could not be detected. As the biological effects of alpha ChyJ2 supernatant cannot be fully explained by the described pattern of cytokine production, participation of other, yet uncharacterized, factors is possible. Using alpha ChyJ2 as feeder cells for in vitro as well as in vivo immunizations increased the number of antibody secreting B-cell clones 2 to 15 fold, respectively.

B-Lymphocytes↗

PubMed1991

Delayed activation of phospholipase D by gonadotropin-releasing hormone in a clonal pituitary gonadotrope cell line (alpha T3-1).

Stimulation of cultured pituitary cells from a gonadotrope lineage (alpha T3-1) by the gonadotropin-releasing hormone agonist analog [D-Trp6]GnRH (GnRH-A) resulted in a manifold increase in accumulation of phosphatidylethanol, a specific product of phospholipase D phosphatidyl transferase activity when ethanol is the phosphatidyl group acceptor. Levels of the natural lipid product of phospholipase D, phosphatidic acid, were increased 2-3-fold. Activation of phospholipase D by GnRH-A was dose- and time-dependent and was blocked by a GnRH receptor antagonist [D-pClPhe2,D-Trp3.6]GnRH. GnRH-A stimulated phospholipase D activity after a lag of 1-2 min. We conclude that in alpha T3-1 gonadotropes GnRH receptor occupancy results in delayed activation of phospholipase D which could participate in late phases of gonadotrope regulation by the neurohormone.

Animals↗

PubMed2000

Alpha(v)beta3 expression on blood vessels and melanoma cells in primary lesions: differential association with tumor progression and clinical prognosis.

The alpha(v)beta3 integrin has emerged as a key mediator in angiogenesis. Its role in tumor-induced angiogenesis is supported by its up-regulation in vivo in the vasculature of a number of different types of carcinoma. The potential clinical significance of alpha(v)beta3 expression on blood vessels in carcinomas is suggested by its association with tumor progression. Currently no information is available about the clinical significance of alpha(v)beta3 expression on the vasculature of lesions of melanocytic origin. Since we have previously found that alpha(v)beta3 expression on melanoma cells in primary lesions is associated with a poor prognosis, in the present study we have compared alpha(v)beta3 expression on blood vessels and on cells of melanocytic origin in nevi and in malignant melanoma lesions. In addition we have examined the lesions for expression of the alpha(v) subunit to gain information on the regulation of alpha(v)beta3 expression on endothelial cells and on cells of the melanocyte lineage. alpha(v)beta3 expression on endothelial cells and on melanocytic cells was a relatively sensitive and specific marker for malignant lesions. However, alpha(v)beta3 expression on endothelial cells in primary melanoma lesions was not associated with the prognosis of the disease. The alpha(v) subunit and the alpha(v)beta3 complex were differentially expressed on endothelial cells and on melanocytic cells, implying that different regulatory pathways control their expression. This finding may account for the differential clinical significance of alpha(v)beta3 expression on tumor vasculature and on melanoma cells we observed in our patient cohort. Lastly, alpha(v)beta3 may be a useful target for immunotherapeutic approaches in melanoma because of its high expression on the vasculature of all metastatic lesions tested and its restricted distribution in normal tissues.

Blood Vessels↗