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

Thymic lymphoma development is a multistage process in which genetic and ep igenetic events cooperate in the emergence of a malignant clone. The notion that signaling via TCR-ligand interactions plays a role in promoting the e xpansion of developing neoplastic clones is a matter of debate. To investig ate 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 d isplayed 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-in duced lymphomas, V(beta)8, V(beta)7, V(beta)13 and V(beta)14 were over-repr esented on spontaneous lymphomas, The dissimilar TCR V-beta profiles indica te that different endogenous ligands promote neoplastic clonal expansion in untreated and MNU-treated mice. Although the nature of these ligands is no t clear, the lack of conservation in TCR beta chain CDR3 regions among lymp homas that express the same V-beta segment suggests that endogenous superan tigens (SAG), as opposed to conventional peptide ligands, are likely to be involved in the selection process. The biased representation of lymphomas e xpressing 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 i s expressed at high levels in spontaneous and MNU-induced lymphomas suggest s that preneoplastic thymocytes may be resistant to SAG-induced clonal dele tion. A working model is presented in which preneoplastic clones expressing TCRs that recognize endogenous SAG are selectively expanded as a consequen ce of sustained TCR-mediated signaling.