The development of resistance to immunomodulatory and tolerogenic effects of TGF? in the immune cells is of key 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 the adaptive immune system, similar phenomenon has not yet been described in the innate immune cells. Mucosal dendritic cells (DCs) play a crucial role in both immunity and tolerance, and by extension, in the pathogenesis of autoimmune disorders, including IBD. We provide new evidence to show that DC activation leads to a development of TGF? resistance, and identify two putative mediators of this phenomenon ? IL15/IL15R? complex and DAB2 protein. We developed a mouse model mimicking DC-specific TGF? resistance (TGFbR2?DC 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 TGFbR2?DC mice, 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 will purse the hypothesis that DC activation by inflammatory and/or infectious insults result in elevated expression of IL15/IL15R? complexes and downregulation of Dab2 that lead to TGF? resistance in dendritic cells, a phenomenon resulting in impaired Treg development and function and an establishment of chronic intestinal inflammation. We propose to address this hypothesis in the following three specific aims: (1) To define the primary subset(s) of intestinal DCs affected with refractory TGF? response during intestinal inflammation; (2) To characterize the mechanism responsible for the refractory response 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 work will address a physiologically and clinically important, yet unexplored, phenomenon of TGF? resistance acquired by activated dendritic cells. It will identify the molecular and cellular mechanisms responsible, and describe the consequences of such resistance in the context of autoinflammatory disorders.
Inflammatory Bowel Diseases (IBD), including Crohn's disease and ulcerative colitis remain the most debilitating chronic autoimmune disorders of the gut, affecting an estimated 1.4 million Americans. Despite advances in our understanding of their pathogenesis and treatment, a complete cure is still elusive. Research and medical professionals remain desperate to identify ?druggable? checkpoints in the inflammatory response to the self- and extended-self (commensal bacteria) antigens. The presented novel mechanism of induction of uncontrolled gut inflammation (TGF? resistance developed by activated dendritic cells) is not only relevant to the pathogenesis of IBD and other auto-inflammatory conditions, but also opens new avenues for potential therapeutic strategies which may significantly improve current approaches to disease treatment and/or to significantly reduce the disease relapse rate.
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