TCR-independent T cell development mediated by gain-of-oncogene function or loss-of-tumor-suppressor gene function.

The mechanisms that govern differentiation of T cell precursors during intrathymic development bridge an interdisciplinary research field of immunology, oncology and developmental biology. Critical checkpoints controlling early thymic T cell development and homeostasis are set by the proper signaling function of the IL-7 receptor, c-Kit receptor, and the pre-T cell antigen receptor (pre-TCR). Given the intimate link between cell cycle control and differentiation in T cell development, proto-oncogenes and tumor suppressors participate as physiological effectors downstream of these receptors not only to influence the cell cycle but also to determine differentiation and survival. Gain- or loss-of-function mutations of these downstream effectors uncouples partially or completely T cell precursors from these checkpoints, providing a selective advantage and enabling aberrant development. These effectors can be identified by provirus tagging in normal mice and more readily by complementation tagging in mice with a predefined block in T cell differentiation.