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Molecular identification of an MHC-independent ligand recognized by a human {alpha}/{beta} T-cell receptor.

ABSTRACT: During an analysis of T-cell responses against human renal cell carcinoma (RCC), we identified a CD4(+) T-cell line that showed TCR-mediated recognition and lysis of nearly all RCC lines regardless of MHC type. We have now elucidated the nature of the ligand for this ?/? TCR, and it contains no MHC-related moiety and does not involve classic peptide processing. First, matrix metalloproteinase 14 (MMP14) expressed on RCC cells releases membrane-bound TRAIL expressed by the T cell; then, soluble TRAIL binds to its receptor DR4 (TRAIL-R1), which is expressed on tumor cells, and this TRAIL-DR4 complex is recognized by the TCR through a complementarity-determining region 3? (CDR3?)-mediated interaction. Direct and specific antigen-TCR interaction was demonstrated when the immobilized recombinant TRAIL/DR4 complex stimulated the TCR. In addition, amino acid substitutions in the CDR3? of the TCR either obliterated or enhanced target-specific recognition. This description of the molecular nature of a non-MHC target structure recognized by a naturally occurring ?/? TCR not only broadens our concept of what the TCR can recognize, but also raises the question of whether such a T cell could be of clinical utility against RCC.

SUBMITTER: Hanada K

PROVIDER: S-EPMC3100692 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Molecular identification of an MHC-independent ligand recognized by a human {alpha}/{beta} T-cell receptor.

Hanada Ken-ichi K Wang Qiong J QJ Inozume Takashi T Yang James C JC

Blood 20110207 18

During an analysis of T-cell responses against human renal cell carcinoma (RCC), we identified a CD4(+) T-cell line that showed TCR-mediated recognition and lysis of nearly all RCC lines regardless of MHC type. We have now elucidated the nature of the ligand for this α/β TCR, and it contains no MHC-related moiety and does not involve classic peptide processing. First, matrix metalloproteinase 14 (MMP14) expressed on RCC cells releases membrane-bound TRAIL expressed by the T cell; then, soluble T ...[more]

PMID: 21300979

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Project description:We studied potential modulators of antithrombin gene expression. A putative hormone response element (HRE) was identified by sequence similarity analysis of the antithrombin promoter, situated between nucleotides -92 and -54 relative to the transcription start site. This HRE contains three hexa-nucleotide motifs with an AGGTCA consensus, which are potential targets of members of the steroid/thyroid superfamily of nuclear receptors. Stimulation of the hepatoma cell line HepG2 with the receptor ligands L-3,5,3'-tri-iodothyronine, all-trans retinoic acid, or their combination, increased production of antithrombin into the culture medium by 1.3-, 1.6-, and 2.0-fold, respectively. In contrast, the receptor ligand 1,25-dihydroxy-cholecalciferol[1,25-(OH)2VitD3] did not influence antithrombin production. Analysis of promoter chloramphenicol acetyl-transferase (CAT) constructs, showed that the first 86 bp of the antithrombin promoter region are sufficient for basal transcription. The DNA length polymorphism of 32 bp or 108 bp, located upstream of position -276, did not influence anti-thrombin promoter activity. The antithrombin promoter activity dropped to background values when deleting the region -97/-49 of promoter fragment -453/+57. Transactivation of the antithrombin promoter by retinoid X receptor alpha (RXR alpha) (5-7-fold) or thyroid hormone receptor beta (TR beta) (4-5-fold) was only observed when at least -167/+57 bp of the promoter region is present in CAT constructs, and when the appropriate ligand of the nuclear receptor was added. This transactivation was not observed upon deletion of the antithrombin promoter region -97/-49. With three copies of the antithrombin promoter fragment -109/-42 in front of the thymidine kinase minimal promoter, transactivation was only obtained with RXR alpha, and not with TR beta. In conclusion, these results indicate that the ligand-dependent enhancement of antithrombin gene expression is regulated by RXR alpha as well as by TR beta. Transactivation of antithrombin gene expression by RXR alpha and TR beta appears to be dependent upon the presence of promoter region up to nucleotide -167. The HRE segment (-109/-42) only confers RXR alpha responsiveness to a heterologous promoter. Further study is needed to unravel the exact nature of this HRE and its 5'-flanking sequences.

Dataset Information

Molecular identification of an MHC-independent ligand recognized by a human {alpha}/{beta} T-cell receptor.

Publications

Molecular identification of an MHC-independent ligand recognized by a human {alpha}/{beta} T-cell receptor.

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