TCR V(β) repertoire restriction and lack of CDR3 conservation implicate TCR-superantigen interactions in promoting the clonal evolution of murine thymic lymphomas

Gregorio Gomez, Kimberly Z. Clarkin, Ellen Kraig, Anthony J. Infante, Ellen R. Richie

Research output: Contribution to journalArticle

6 Scopus citations

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(β) 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(β) repertoires. However, whereas V(β)6, V(β)8 and V(β)9 were expressed by a greater than expected frequency of MNU-induced lymphomas, V(β)8, V(β)7, V(β)13 and V(β)14 were over-represented on spontaneous lymphomas. The dissimilar TCR V(β) 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 β chain CDR3 regions among lymphomas that express the same V(β) 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(β)6-, V(β)7- and V(β)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.

Original languageEnglish (US)
Pages (from-to)263-270
Number of pages8
JournalInternational Immunology
Volume12
Issue number3
DOIs
StatePublished - 2000

Keywords

  • AKR/J
  • Bcl-2
  • Carcinogenesis
  • N-methyl-N-nitrosourea
  • Thymocyte

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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