Thesis Project Description:
Thymopoiesis aims to create a repertoire of mature T cells, equipped with a diverse array of functional αβ or γδ T cell receptors (TCR) able to recognize a broad range of foreign antigens. Yet, throughout thymopoiesis, TCRαβ fitness is tested by 2 processes: positive and negative selections. Thymocytes with no, or “unfit” receptors, i.e. displaying too low or too high affinity for self-peptide major histocompatibility complex (p-MHC), are eliminated. While thymocytes with fit TCR (i.e. displaying intermediate affinity for p-MHC) are selected to further differentiate into mature thymocytes, a transition known as positive selection. Therefore, TCR signaling can induce two opposite outcomes during physiological thymocyte development: cell death or survival and differentiation. We sought to address the role of TCRαβ signaling in leukemogenesis and determine whether it is integrated in oncogenic networks and thus facilitate proliferation/survival or, in the contrary, suppresses leukemogenesis by inducing apoptosis. To tackle this issue, we used a conditional mouse model that deletes Pten in thymocytes and gives rise to TCRαβ+ T-ALL. Then, we uncovered that TCRαβ signaling strength directly impacts on leukemia genesis. Indeed, cells harboring fit TCRαβ do not develop leukemia, while cells harboring no or unfit TCRαβ (low signalling strength) are rescued from cell death and can develop leukemia. We hypothesized that Pten loss merely shifts the window of positive and negative selection thresholds. On one hand, Pten loss might substitute for missing TCR signaling, allowing cells with no/low affinity TCR to bypass positive selection and thus to survive. We suggest that further differentiation of those cells carrying unfit TCR is partially blocked, providing an additional opportunity to acquire additional oncogenic mutations. On the other hand, integration of signals resulting from both Pten loss and a fit TCR, might reach over-the-threshold signaling and trigger negative selection (i.e. cell deletional program), eliminating those thymocytes even before malignant transformation.
Interdisciplinary Research Axis:
University of Evry, Paris-Saclay (FR)