Wednesday, April 24, 2024
4/24/2024
PROJECT SUMMARY/ABSTRACT It is critical that the host immune system does not mount outright inflammatory responses against foreign antigens abundant in the lumen of the intestine (such as dietary antigens exposed through the small intestine mucosa and microbial antigens coming predominantly from the lumen of the large intestine). Failure in this process leads to a significant health threat to the host as evidenced by prevalence of celiac disease and inflammatory bowel diseases. Regulatory T cells (Tregs) have evolved to play a critical role to ensure this tolerance. Dietary antigens are known to generate inducible Tregs (iTregs) and systemic tolerance against those antigens is achieved by circulation of these iTregs throughout the body (oral tolerance). In contrast, it may not be beneficial for the host to establish systemic, Treg-mediated tolerance against antigens from the large intestine since self-replicating microbes, the primary source of antigens in the large intestine, can easily escape and invade tissues outside of the intestine. Our long-term goal is to characterize how Treg-mediated tolerance against antigens from the large intestine is accomplished. Our central hypotheses are that activation of the aryl hydrocarbon receptor (AHR) in T cells induces GPR15 expression and promotes iTreg differentiation simultaneously to produce GPR15+ iTregs and that the GPR15-C10orf99 receptor-ligand pair mediates the retention of Tregs in the large intestine and prevents systemic dissemination of iTregs, accomplishing local tolerance by GPR15+ iTregs. Guided by strong preliminary data, we have generated novel mouse models that will enable us to test these hypotheses. We propose to pursue the following two aims: (1) To characterize Treg-mediated immune tolerance against microbial antigens in the large intestine compared to systemic oral tolerance against dietary antigens from the small intestine, we will check whether GPR15-C10orf99 mediate trafficking of Tregs inside the large intestine lamina propria and Treg retention, in addition to their known function during extravasation. We will also determine the fate of GPR15+ iTregs and the consequences in Treg-mediated tolerance against gut microbial antigens after inducible deletion of GPR15. (2) To characterize the effect of AHR signaling on iTreg differentiation and GPR15 induction, we will test chemicals with reported AHR ligand activity for their ability to induce FOXP3 and GPR15 expression. We will also examine mechanisms underlying AHR-induced increase of GPR15+ Tregs in vivo at the cellular level. To understand the molecular mechanisms for AHR-mediated expression of FOXP3 and GPR15, we will perform CHIPseq analysis in T cells after AHR activation by specific ligands that we will identify. Our findings will significantly advance understanding of Treg-mediated tolerance and will help to develop novel therapeutic strategies to treat various immunological disorders.
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