A system that allows the study, in a gentle fashion, of the role of MHC molecules in naive T cell survival is described. Major histocompatibility complex class II–deficient mice were engineered to express Eα chains only in thymic epithelial cells in a tetracycline (tet)-controllable manner. This resulted in tet-responsive display of cell surface E complexes, positive selection of CD4⁺8^– thymocytes, and generation of a CD4⁺ T cell compartment in a class II–barren periphery. Using this system, we have addressed two unresolved issues: the half-life of naive CD4⁺ T cells in the absence of class II molecules (3–4 wk) and the early signaling events associated with class II molecule engagement by naive CD4⁺ T cells (partial CD3 ζ chain phosphorylation and ZAP-70 association).