7. Project Summary/AbstractThe development of resistance to immunomodulatory and tolerogenic effects of TGF in the immune cells is ofkey importance in the pathogenesis of auto-inflammatory disorders including Inflammatory Bowel Diseases(IBD). While most effort has been directed towards understanding of such resistance in the cells of theadaptive immune system similar phenomenon has not yet been described in the innate immune cells. Mucosaldendritic cells (DCs) play a crucial role in both immunity and tolerance and by extension in the pathogenesisof autoimmune disorders including IBD. We provide new evidence to show that DC activation leads to adevelopment of TGF resistance and identify two putative mediators of this phenomenon IL15/IL15Rcomplex and DAB2 protein. We developed a mouse model mimicking DC-specific TGF resistance(TGFbR2DC mice) in which we demonstrate severe consequences in form of gastrointestinal auto-inflammatory disorder. Both CD4+ and CD8+ T cells are required for the pathogenesis of colitis in TGFbR2DCmice which is accompanied with altered regulatory T cell compartment (Treg; expansion of CD4+CD25-FoxP3+Tregs and reduction of CD8+CD103+ Tregs). With the developed mouse models and molecular tools we willpurse the hypothesis that DC activation by inflammatory and/or infectious insults result in elevatedexpression of IL15/IL15R complexes and downregulation of Dab2 that lead to TGF resistance indendritic cells a phenomenon resulting in impaired Treg development and function and anestablishment of chronic intestinal inflammation. We propose to address this hypothesis in the followingthree specific aims: (1) To define the primary subset(s) of intestinal DCs affected with refractory TGFresponse during intestinal inflammation; (2) To characterize the mechanism responsible for the refractoryresponse to TGF in activated DCs; (3) To define the phenotypic and functional impairment of CD4+ and CD8+Treg phenotype and function that develops as a consequence of TGF resistance in dendritic cells. Our workwill address a physiologically and clinically important yet unexplored phenomenon of TGF resistanceacquired by activated dendritic cells. It will identify the molecular and cellular mechanisms responsible anddescribe the consequences of such resistance in the context of autoinflammatory disorders.