The inflammatory cytokine tumor necrosis factor alpha (TNFalpha) has been linked to the development of several autoimmune diseases. By adapting the tetracycline-regulated gene transcription system, we generated a murine model where islet-specific expression of TNFalpha could be repressed/derepressed within 48 hr following introduction/removal of tetracycline in the drinking water. Here we describe the temporal importance of TNFalpha in diabetes development in mice expressing islet-specific B7-1 and TNFalpha. We show that the duration of TNFalpha-mediated inflammation, not the putative maturity of the immune system at the time of TNFalpha expression, determines diabetes progression. Further, we have described an interval between 21 and 25 days following initiation of TNFalpha expression where the fate of islet-reactive T cells is decided.