We recently published a novel CD40-mediated mouse model of spontaneous colitis, where CD11c-specific constitutive CD40-signaling leads to migration of CD103+ DCs from the colonic LP to draining lymph nodes followed by DC-apoptosis.24 Loss of tolerogenic CD103+ DCs caused a lack of RORγt+Helios− iTregs and an increase of inflammatory IL-17+IFN-γ+ Th17/Th1 and IFN-γ+ Th1 cells in the colon, resulting in the breakdown of mucosal tolerance and fatal colitis.24–26 Of note, this model mimics the human IBD situation, as CD40-CD40L interactions are of relevance to the pathogenesis of IBD.27–33. The gene discussed is CD40LG; the disease is colitis.