The nature (Th1 versus Th2) and dynamics of the autoimmune response during the development of insulin-dependent diabetes mellitus (IDDM) and after immunotherapy are unclear. Here, we show in nonobese diabetic (NOD) mice that the autoreactive T cell response starts and spreads as a pure Th1 type autoimmunity, suggesting that a spontaneous Th1 cascade underlies disease progression. Surprisingly, induction of antiinflammatory Th2 responses to a single β cell antigen (βCA) resulted in the spreading of Th2 cellular and humoral immunity to unrelated βCAs in an infectious manner and protection from IDDM. The data suggest that both Th1 and Th2 autoimmunity evolve in amplificatory cascades by generating site-specific, but not antigen-specific, positive feedback circuits. Determinant spreading of Th2 responses may be a fundamental mechanism underlying antigen-based immunotherapeutics, explaining observations of infectious tolerance and providing a new theoretical framework for therapeutic intervention.