title: TCR v(beta) repertoire restriction and lack of CDR3 conservation implicate TCR-superantigen interactions in promoting the clonal evolution of murine thymic lymphomas.
abstract: Thymic lymphoma development is a multistage process in which genetic and epigenetic events cooperate in the emergence of a malignant clone. The notion that signaling via TCR-ligand interactions plays a role in promoting the expansion of developing neoplastic clones is a matter of debate. To investigate this issue, we determined the TCR V(beta) repertoire of thymic lymphomas induced in AKR/J mice by either endogenous retroviruses or the carcinogen, N-methyl-N-nitrosourea (MNU). Both spontaneous and MNU-induced lymphomas displayed restricted V(beta) repertoires. However, whereas V(beta)6, V(beta)8 and V(beta)9 were expressed by a greater than expected frequency of MNU-induced lymphomas, V(beta)8, V(beta)7, V(beta)13 and V(beta)14 were over-represented on spontaneous lymphomas. The dissimilar TCR V(beta) profiles indicate that different endogenous ligands promote neoplastic clonal expansion in untreated and MNU-treated mice. Although the nature of these ligands is not clear, the lack of conservation in TCR beta chain CDR3 regions among lymphomas that express the same V(beta) segment suggests that endogenous superantigens (SAG), as opposed to conventional peptide ligands, are likely to be involved in the selection process. The biased representation of lymphomas expressing V(beta)6-, V(beta)7- and V(beta)9-containing TCRs that recognize endogenous SAG is consistent with this hypothesis. The finding that Bcl-2 is expressed at high levels in spontaneous and MNU-induced lymphomas suggests that preneoplastic thymocytes may be resistant to SAG-induced clonal deletion. A working model is presented in which preneoplastic clones expressing TCRs that recognize endogenous SAG are selectively expanded as a consequence of sustained TCR-mediated signaling.
authors.affiliation: Department of Carcinogenesis, and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78724, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gomez
authors.forename: K Z
authors.initials: KZ
authors.lastname: Clarkin
authors.forename: E
authors.initials: E
authors.lastname: Kraig
authors.forename: A J
authors.initials: AJ
authors.lastname: Infante
authors.forename: E R
authors.initials: ER
authors.lastname: Richie
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000473:pathology; D017637:Clonal Deletion; D003043:Cocarcinogenesis; D022801:Complementarity Determining Regions; D020077:Endogenous Retroviruses / Q000276:immunology* / Q000472:pathogenicity; D005260:Female; D017988:Gammaretrovirus / Q000276:immunology* / Q000472:pathogenicity; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D019254:Genes, bcl-2; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008223:Lymphoma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D008770:Methylnitrosourea; D051379:Mice; D008806:Mice, Inbred AKR; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011230:Precancerous Conditions / Q000276:immunology / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D018089:Superantigens / Q000276:immunology*; D013953:Thymus Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000821:virology
chemical_list: D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D022801:Complementarity Determining Regions; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; C095378:Mtv-7 superantigen, Mouse mammary tumor virus; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; D008770:Methylnitrosourea