Dataset Information

Reduced expression of a human V beta 6.1 T-cell receptor allele.

ABSTRACT: We have previously described an allelic polymorphism in the V beta 6.1 T-cell receptor gene. The V beta 6.1B allele is associated with disease in a subgroup of patients with juvenile rheumatoid arthritis. Limited sequence data demonstrated nucleotide differences that resulted in two amino acid changes between the two alleles in positions predicted to be important in major histocompatibility complex/antigen recognition. The present study demonstrates substantially reduced expression of mRNA from the disease-associated allele (V beta 6.1B) in peripheral blood and thymic tissue. The complete genomic sequence of both alleles revealed two additional amino acid changes in the V beta 6.1B gene as well as nucleotide differences in the promoter and intron. A cysteine-to-arginine substitution at position 92 in the disease-associated allele makes this a non-functional beta chain, since this conserved cysteine is involved with disulfide bonding to cysteine-23 to form an immunoglobulin-like domain structure, thus resulting in a potential hole in the T-cell receptor repertoire.

SUBMITTER: Luyrink L

PROVIDER: S-EPMC46512 | biostudies-other | 1993 May

REPOSITORIES: biostudies-other

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Reduced expression of a human V beta 6.1 T-cell receptor allele.

Luyrink L L Gabriel C A CA Thompson S D SD Grom A A AA Maksymowych W P WP Choi E E Glass D N DN

Proceedings of the National Academy of Sciences of the United States of America 19930501 10

We have previously described an allelic polymorphism in the V beta 6.1 T-cell receptor gene. The V beta 6.1B allele is associated with disease in a subgroup of patients with juvenile rheumatoid arthritis. Limited sequence data demonstrated nucleotide differences that resulted in two amino acid changes between the two alleles in positions predicted to be important in major histocompatibility complex/antigen recognition. The present study demonstrates substantially reduced expression of mRNA from ...[more]

PMID: 8506275

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Project description:UnlabelledInnate immunity is the first line of host defense against infections. Many oncogenic viruses can deregulate several immune-related pathways to guarantee the persistence of the infection. Here, we show that the cutaneous human papillomavirus 38 (HPV38) E6 and E7 oncoproteins suppress the expression of the double-stranded DNA sensor Toll-like receptor 9 (TLR9) in human foreskin keratinocytes (HFK), a key mediator of the antiviral innate immune host response. In particular, HPV38 E7 induces TLR9 mRNA downregulation by promoting accumulation of ΔNp73α, an antagonist of p53 and p73. Inhibition of ΔNp73α expression by antisense oligonucleotide in HPV38 E6/E7 HFK strongly rescues mRNA levels of TLR9, highlighting a key role of ΔNp73α in this event. Chromatin immunoprecipitation experiments showed that ΔNp73α is part of a negative transcriptional regulatory complex with IκB kinase beta (IKKβ) that binds to a NF-κB responsive element within the TLR9 promoter. In addition, the Polycomb protein enhancer of zeste homolog 2 (EZH2), responsible for gene expression silencing, is also recruited into the complex, leading to histone 3 trimethylation at lysine 27 (H3K27me3) in the same region of the TLR9 promoter. Ectopic expression of TLR9 in HPV38 E6/E7 cells resulted in an accumulation of the cell cycle inhibitors p21(WAF1) and p27(Kip1), decreased CDK2-associated kinase activity, and inhibition of cellular proliferation. In summary, our data show that HPV38, similarly to other viruses with well-known oncogenic activity, can downregulate TLR9 expression. In addition, they highlight a new role for TLR9 in cell cycle regulation.ImportanceThe mucosal high-risk HPV types have been clearly associated with human carcinogenesis. Emerging lines of evidence suggest the involvement of certain cutaneous HPV types in development of skin squamous cell carcinoma, although this association is still under debate. Oncogenic viruses have evolved different strategies to hijack the host immune system in order to guarantee the persistence of the infection. Their capability to evade the immune system is as important as their ability to promote cellular transformation. Therefore, understanding the viral mechanisms involved in viral persistence is a valid tool to evaluate their potential role in human carcinogenesis. Here, we show that E6 and E7 oncoproteins from the cutaneous HPV38 downregulate the expression of the double-stranded DNA sensor TLR9 of innate immunity. We also present evidence that the HPV38-mediated downregulation of TLR9 expression, in addition to its potential impact on the innate immune response, is linked to cell cycle deregulation.

Dataset Information

Reduced expression of a human V beta 6.1 T-cell receptor allele.

Publications

Reduced expression of a human V beta 6.1 T-cell receptor allele.

Similar Datasets

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