Inhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-B, are not well understood. Here, we show that the nuclear receptor PPAR plays a critical role in blocking NF-B activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF-B activation in WT, but not PPAR-deficient, APCs. Forced restoration of H2O2 in PPAR-deficient cells suppressed IB degradation and NF-B activation. Conversely, scavenging reactive oxygen species from mitochondria promoted IB degradation with loss of regulatory and promotion of inflammatory Tcell responses invivo. Thus, communication between PPAR and the mitochondria maintains immune quiescence in the airways.