title: 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 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 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 3α (CDR3α)-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 CDR3α 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 α/β 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.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. hanadak@mail.nih.gov
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hanada
authors.forename: Qiong J
authors.initials: QJ
authors.lastname: Wang
authors.forename: Takashi
authors.initials: T
authors.lastname: Inozume
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
mesh_terms: D018801:CD2 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018968:CD58 Antigens / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D022801:Complementarity Determining Regions / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008285:Major Histocompatibility Complex; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D018448:Models, Immunological; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D018801:CD2 Antigens; D018968:CD58 Antigens; D022801:Complementarity Determining Regions; D008024:Ligands; D016693:Receptors, Antigen, T-Cell, alpha-beta; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14