De novo differentiation of CD4⁺ T cells was provoked in mice lacking major histocompatibility complex (MHC) class II molecules by intrathymic injection of adenovirus vectors carrying class II genes. This permits a new approach to questions concerning the dynamics of CD4⁺ T cell compartments in the thymus and peripheral lymphoid organs. Here two issues are explored. First, we show that mature CD4⁺CD8⁻ cells reside in the thymus for a protracted period before emigrating to the periphery, highlighting the potential importance of, and our ignorance of, the postselection maturation period. Second, we demonstrate that the survival of CD4⁺ cells in peripheral lymphoid organs is markedly curtailed when class II molecules are absent and is not further reduced in the absence of both class II and class I molecules, raising the possibility that MHC-mediated selection may continue in the periphery.