Th168 - The Molecular Mechanisms of Treg Plasticity

Abstract Text: The functional diversity of regulatory T cells (Tregs) is essential for maintaining healthy immunity but is also exploited in disease. We and others have causatively linked the gain of selective Treg proinflammatory functions to the expansion of a Rorγt+ CD4+ Foxp3+ Treg subset. We showed that in patients with inflammatory bowel disease (IBD) and colorectal cancer (CRC), as well as in the APCΔ468 murine polyposis model these cells overexpress β-catenin. Moreover, the expression of a dominant-active β-catenin in Tregs induces RORγt, leading to impaired suppressive function and the acquisition of Th17-like properties, ultimately resulting in a scurfy-like phenotype. Similarly, the loss of TCF-1 also upregulates RORγt but primarily affects the anti-inflammatory functions of Tregs without inducing the full spectrum of dysfunction observed with β-catenin activation. We showed that TCF-1 and HEB work together to regulate T cell development. In Tregs expressing dominant-active β-catenin, the deletion of either TCF-1 or HEB partially restores their function. However, the simultaneous deletion of both TCF-1 and HEB rescues Treg numbers and prevents the development of the scurfy-like phenotype. sc-RNAseq analysis revealed that HEB-deficient Tregs from mesenteric lymph nodes display an enhanced effector phenotype compared to WT and TCF-1KO Tregs, which may contribute to their functional restoration. Additionally, protein interaction predictions using the ARBD algorithm suggest a potential physical interaction between HEB and β-catenin. Collectively, these findings highlight a finely tuned collaboration among β-catenin, TCF-1, HEB, and RORγt to regulate Treg identity and function.