A major focus of our studies has been the elucidation of genetic pathways regulating tolerance and to identify human diseases resulting from defects along those pathways. We have approached this issue from the perspective of Mendelian traits associated with allergic and immunological dysregulatory disorders. Our earlier studies have led to the identification of human mutations in the transcription factor Foxp3, later revealed to be critical for regulatory T (Treg) cell differentiation and effector function. Treg cell deficiency disorders are associated with myriad allergic and autoimmune manifestations, pursuant to the prevailing intense immune dysregulation. Our recent studies have mobilized mouse and human genetic and functional approaches to elucidate the precise molecular mechanisms of the breakdown in Treg cell function in these disorders. We also seek to reprogram regulatory function in impaired Treg cells (e.g. those lacking Foxp3, reference 1 below) in a manner that can then be broadly applied to a variety of Treg deficiency-related disorders. We are also interested in the mechanisms by which Treg cells can differentially regulate distinct checkpoints governing allergy and autoimmunity, such as those involving Treg cell-derived transforming growth factor beta 1(TGF-β1 ) (reference2). We are also interested in understand the role of Treg cell-mediated immune regulation in common allergic inflammatory diseases including allergic airway inflammation in asthma (reference 3 and 4) and oral tolerance breakdown in food allergy (reference 5 and 6), Having established a critical role for tissue Treg cells in the pathogenesis of the respective disorder, we are particularly interested in the molecular and cellular mechanisms by which Treg cells end up licensing tissue inflammation,. Key concepts include the pathological  reprogramming of Treg cells to promote T helper cell type 1, 2 and 17 (Th1, Th2 2 and Th17)-dependent inflammation, the nature of the molecular signals that license Treg cell-dependent tissue inflammation (e.g. Notch4 expression on lung Treg cells) and the role of environmental factors in the process (e.g. air pollutants, microbiota). These these studies are then leveraged to the design of precision therapies for restoring tissuespecific immune tolerance,such as therapy with immunomodulatory commensal bacteria for food allergy (reference 6).