In their study in this issue of the JCI, Filippi et al. examined the mechanisms by which infection with CVB3 or LCMV (which do not directly destroy insulin-producing pancreatic β cells) reduced the incidence and delayed the onset of T1D in NOD mice (2). The authors report that immune cells from both the innate and adaptive immune system are involved in curbing the expansion of autoaggressive T cells that target β cells. They show that IFN-γ produced by adaptive Th1 cells, as well as by various innate immune cells in response to viral infection, upregulates the expression of PD-L1 on a varied population of lymphoid cells. Following interaction with β cell antigen IGRP, activated autoaggressive T cells express the PD-L1 receptor PD-1. PD-1⁺ T cells and PD-L1⁺ cells occupy overlapping habitats. The cognate interaction of PD-1 with PD-L1 inhibits the expansion of IGRP-specific, diabetogenic PD-1⁺ CD8⁺ T cells, which delays the onset of T1D. CD4⁺CD25⁺ Tregs, which are part of the adaptive immune system, are activated by both viruses and autoantigens. These cells produce TGF-β, a potent immunosuppressive cytokine. Filippi et al. also show that after CVB3 or LCMV infection in NOD mice, the populations of Tregs in the pancreatic lymph node and spleen were increased. Production of TGF-β by these cells curbed the expansion of autoaggressive T cells and limited their cytodestructive properties, thereby protecting insulin-producing β cells and reducing the incidence of T1D in these animals. The physical proximity of regulatory and cytodestructive autoimmune cells enables immunoregulation.