Macrophage IFN-I signaling promotes autoreactive T cell infiltration into islets in type 1 diabetes model.

Here, we report a pathogenic role for type I IFN (IFN-I) signaling in macrophages, and not beta cells in the islets, for the development of type 1 diabetes (T1D). Following lymphocytic choriomeningitis (LCMV) infection in the Rip-LCMV-GP T1D model, macrophages accumulated near islets and in close contact to islet-infiltrating GP-specific (autoimmune) CD8(+) T cells. Depletion of macrophages with clodronate liposomes or genetic ablation of Ifnar in macrophages aborted T1D, despite proliferation of GP-specific (autoimmune) CD8(+) T cells. Histopathologically, disrupted IFN alpha/beta receptor (IFNAR) signaling in macrophages resulted in restriction of CD8(+) T cells entering into the islets with significant lymphoid accumulation around the islet. Collectively, these results provide evidence that macrophages via IFN-I signaling, while not entering the islets, are directly involved in interacting, directing, or restricting trafficking of autoreactive-specific T cells into the islets as an important component in causing T1D.