Type I IFNs (IFN-I) are cytokines that can mediate both immune suppression and activation. Dendritic cells (DC) are significant producers of IFN-I, and depending on the context (nature of Ag, duration of exposure to Ag), DC-derived IFN-I can have varying effects on CD8+ T cell responses. In this study, we report that in the context of a CD8+ T cell response to a self-Ag, DC-intrinsic expression of IFN regulatory factor 3 is required to induce optimal proliferation and migration of autoreactive CD8+ T cells, ultimately determining their ability to infiltrate a target tissue (pancreas), and the development of glucose intolerance in rat insulin promoter–glycoprotein (RIP-GP) mice. Moreover, we show that signals through the lymphotoxin-β receptor (LTβR) in DC are also required for the proliferation of autoreactive CD8+ T cells, the upregulation of VLA4/LFA1 on activated CD8+ T cells, and their subsequent infiltration into the pancreas both in vitro and in vivo. Importantly, the defects in autoreactive CD8+ T cell proliferation, accumulation of CD8+ T cells in the pancreas, and consequent glucose intolerance observed in the context of priming by LTβR−/− DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LTβR/IFN-I axis is essential for programming of CD8+ T cells to mediate immunopathology in a self-tissue. A further understanding of the IFN-I/LTβR axis will provide valuable therapeutic insights for treatment of CD8+ T cell–mediated autoimmune diseases.