Pathogenic conversion of RORγt+/Foxp3+ double positive regulatory T cells involves β-catenin up-regulation

Abstract

Abstract The nature of regulatory T cells (Tregs) in cancer is ambivalent. In Colon Cancer (CC) patients and animal models of CC, we previously described a distinct subset of Tregs that suppresses anti-tumor effector T cell functions but simultaneously maintains inflammation. These Tregs co-express the Th17 lineage transcription factor RORγt along with Foxp3. Moreover, we causatively linked the pro-inflammatory skewing of T cells to Wnt/β-catenin-signaling. To elucidate how Wnt/β-catenin signaling orchestrates the induction of pathologic properties in Tregs we analyzed inflammatory bowel disease (IBD) patients. As IBD can progress to CC, this disease presents a unique platform to study the mechanisms underlying the emergence of RORγt+/Foxp3+Tregs. Indeed, in a sub-population of IBD patients we were able to detect RORγt+/Foxp3+Tregs, expressing high levels of β-catenin in the patients’ blood and tissue. To further establish that activated Wnt/β-catenin signaling is responsible for the pro-inflammatory skewing of Foxp3+ Tregs we over-expressed β-catenin Treg-specifically in a conditional Foxp3-Cre driven mouse model. Mice expressing constitutively active β-catenin in Tregs show striking X-linked immune pathology. Males die 4 weeks after birth of a severe scurfy-like phenotype. Although their Tregs are highly activated, they fail to suppress the proliferation of effector T cells. In heterozygous Foxp3-Cre mice, representing natural chimeras harboring wildtype and β-catenin over-expressing Tregs, the relative fitness of genetically altered Tregs is decreased. By further elucidating how Wnt/β-catenin signaling mediates the pathogenic conversion of Tregs, we hope to reveal novel targets for cancer immuno-therapy.