Role of thymic selection in the development of thymic lymphomas in TCR transgenic mice

Abstract

To investigate the role of antigen receptor-mediated interactions in lymphomagenesis we have analyzed the influence of alpha beta TCR-mediated selection on the development of spontaneous thymic lymphomas, which appear with a high (up to 50%) frequency in mice expressing a transgenic TCR specific for the male antigen (HY) in the context of H-2Db molecules. To this end we compared the kinetics and the incidence of thymic lymphomas developing in females and males with selecting (H-2b) and non-selecting (H-2k) MHC molecules. The kinetics of development of thymic lymphomas was similar in positively selecting (H-2b females) and non-selecting (H-2k females and males) environments but significantly slower (P < 0.01) in the negatively selecting environment (H-2b male). Injection of lymphoma cells derived from a H-2b female into the thymus of a H-2b male resulted in strong, antigen-specific inhibition of growth, indicating that the slower kinetics of lymphomagenesis in H-2b males could be due, at least partially, to the sensitivity of oncogenically transformed thymocytes to TCR-mediated negative selection. Phenotypic and functional analysis of lymphoma cells indicated that they originated from the stage of pre-TCR-dependent transition of immature CD4-CD8- to CD4+ CD8+ thymocytes, which in H-2b females and males developed into tumors under different environmental pressures. These results failed to provide convincing evidence for the role of positive selection but provided a strong indication that self antigen-induced negative selection, in addition to its well established role in self tolerance, can occasionally act as a tumor surveillance mechanism by eliminating or suppressing growth of thymocytes undergoing oncogenic transformation.

Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

“…The current work demonstrates that anti-CD3-mediated activation of endogenous TCR in human T-ALL has an antileukemic function. T-ALL often arises from immature T-cell precursors before the stage of negative selection ( 6,42 ). Consequently, contingent expression of a non-negatively selecting TCR will render T-ALL cells sensitive to TCR-activating apoptotic signals that mimic negative selection, as demonstrated here by anti-CD3 treatment in vitro and in vivo .…”

“…Studies in T-ALL mouse models indicated a prooncogenic role for TCR signaling (39)(40)(41)(42). However, these data were based on transgenic TCR systems, which do not refl ect the expression levels and receptor diversity found among patients with T-ALL where TCR expression is heterogeneous or absent ( 6 ).…”

A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling

“…55 In this regard, TCR/ligand interactions may influence selection events in developing lymphomas. 56,57 To investigate the role of typical TCR/MHC in the development of Stat5-mediated T-ALL, we looked at the effect of Stat5b overexpression on ␤2m Ϫ/Ϫ or TCR␣ Ϫ/Ϫ backgrounds, settings in which normal TCR/MHC interactions do not occur. Stat5b TG ␤2m Ϫ/Ϫ and Stat5b TG TCR␣ Ϫ/Ϫ mice developed lymphomas, strongly suggesting that at least one of the primary events contributing to lymphoma formation in Stat5b TG mice must occur in the DN/DP population, prior to the point at which TCR/MHC interactions play a role in developmental decisions.…”

Synergistic control of T cell development and tumor suppression by diacylglycerol kinase α and ζ

“…Approximately 2-3% HY-TCR transgenic mice develop thymic lymphoma at 5 months of age, with increased tumor occurrence at older ages (28). At 3 to 5 months of age, some DGK␣ ϩ/ϩ ϩ/Ϫ -HY or DGK␣ ϩ/ϩ Ϫ/Ϫ -HY male but not female mice developed thymic lymphomas.…”