Transgenic αβ TCR tonic signaling is leukemogenic while strong stimulation is leukemia-suppressive

Abstract

The pre-T cell receptor (TCR) and TCR complexes are frequently expressed in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive T cell precursor malignancy. Although mutations in TCR components are infrequent in T-ALL, earlier research indicated that transgenic αβ TCR expression in mouse T cell precursors promoted T-ALL development. However, we recently found that stimulation of TCR signaling in T-ALL induced leukemic cell apoptosis and suppressed leukemia. Our aim was to elucidate if a given αβ TCR complex has a dual role in leukemogenesis depending on the nature of the stimulus. We demonstrate that transgenic expression of the Marilyn αβ TCR, specific for the H-Y male antigen presented by major histocompatibility complex class II, triggers T-ALL development exclusively in female mice. This T-ALL exhibited Notch1 mutations, Cdkn2a copy number loss, immature immunophenotype and infiltrated both lymphoid and non-lymphoid organs. Furthermore, leukemic cells expressed surface CD5, a marker of tonic TCR signaling. T-ALL efficiently developed in Rag2-deficient Marilyn transgenic females, indicating that Rag2-mediated recombination is not implicated in this T-ALL model. T-ALL development was also observed in the OT-I TCR transgenic mouse model, but it did not occur when MHC class I was abrogated through genetic inactivation of β2-microglobulin. Remarkably, exposure of Marilyn female T-ALL cells to endogenous agonist antigen in male recipient mice or exogenous peptide in female recipient mice resulted in T-ALL apoptosis and prolonged mouse survival. These findings underscore the dual role of the same αβ TCR complex in T-ALL, where tonic stimulation is leukemogenic, while strong stimulation suppresses leukemia.

Keywords: Cdkn2a; Notch1; T cells; TCR signaling; leukemia.