Canonical Wnt Signaling Negatively Modulates Regulatory T Cell Function

Abstract

Foxp3 is crucial for both the development and function of regulatory T (Treg) cells; however, the posttranslational mechanisms regulating Foxp3 transcriptional output remain poorly defined. Here, we demonstrate that T cell factor 1 (TCF1) and Foxp3 associates in Treg cells and that active Wnt signaling disrupts Foxp3 transcriptional activity. A global chromatin immunoprecipitation sequencing comparison in Treg cells revealed considerable overlap between Foxp3 and Wnt target genes. The activation of Wnt signaling reduced Treg-mediated suppression both in vitro and in vivo, whereas disruption of Wnt signaling in Treg cells enhanced their suppressive capacity. The activation of effector T cells increased Wnt3a production, and Wnt3a levels were found to be greatly increased in mononuclear cells isolated from synovial fluid versus peripheral blood of arthritis patients. We propose a model in which Wnt produced under inflammatory conditions represses Treg cell function, allowing a productive immune response, but, if uncontrolled, could lead to the development of autoimmunity.

Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus

“…Unlike these TNFR family members that support Treg differentiation by lowering the required TCR threshold, TCF7 could act antagonistically to restrict generation, exclude low TCR affinities, and, thereby, help to shape the Treg TCR repertoire toward higher-affinity clones. Interestingly, a recent study demonstrated that Tregs from Tcf7-deficient mice are perfectly functional and, if anything, were even more potent in suppression assays (50).…”

TIGIT predominantly regulates the immune response via regulatory T cells

“…The upregulation of CCR8 and CCL4 indicates that TIGIT signaling may promote Treg migration and retention in tumor tissue (28,29). Interestingly, TIGIT signaling decreased expression of TCF7, which has recently been shown to antagonize the FOXP3-driven transcriptional program in Tregs (30). Thus, TIGIT signaling in Tregs may favor Treg stability.…”

Lrp5/β-Catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis

“…Although lung epithelial-and fibroblast-specific roles of Wnt signaling relevant to fibrosis have been described (16,17), less is understood about how Wnt signaling affects the immune system of the lung. Recent reports suggest that Wnt/b-catenin signaling may have opposing effects in different immune cell types (18)(19)(20)(21). In a mouse model of inflammatory bowel disease, activation of b-catenin signaling in CD11c 1 CD11b…”