CD200 Receptor 1 (CD200R) is an established inhibitory immune receptor that inhibits TLRinduced cytokine production through Dok2 and RasGAP. RasGAP can be cleaved under certain conditions of mild cellular stress. We found that in the presence of cleaved RasGAP, CD200R loses its capacity to inhibit rpS6 phosphorylation. Furthermore, IFNα prestimulation of human mononuclear cells results in increased amounts of cleaved RasGAP.Coherently, upon pretreatment with increasing concentrations of IFNα, CD200R gradually shifts from an inhibitor to a potentiator of TLR7/8-induced IFNG mRNA production. In peripheral blood mononuclear cells from Systemic Lupus Erythematosus (SLE) patients, a prototypic type I IFN disease, we found an increased proportion of cleaved RasGAP compared to healthy controls. In line with this, in subsets of SLE patients the inhibitory function of CD200R is lost or converted to a potentiating signal for IFNG mRNA production.Thus, our data show that type I IFN rewires CD200R signaling and suggest that this cellextrinsic regulation of signaling could contribute to perpetuation of inflammation in SLE.