Project Details
Description
ABSTRACT
The plasticity and functional diversity of regulatory T cells (Tregs) is essential for the maintenance of healthy
immunity but it is also exploited in disease. We have described a subset of Tregs that express high levels of β-
catenin and promote inflammation. The frequency of these Tregs is increased in inflammatory bowel diseases
(and mouse colitis), colon cancer (and mouse polyposis), as well as in multiple sclerosis (and mouse EAE).
Expression of a dominant active β-catenin, or ablation of Tcf-1 in Tregs both foster expression of Rorγt the
canonical transcription factor of the Th17 lineage, and promote a Th17 differentiation signature. In the
mesenteric lymph nodes (MLN) of healthy mice, we identified at least 5 transcriptionally distinct activated
clusters of Tregs. One of these clusters is defined by expression of Rorγt and has prominent Th17
differentiation characteristics. In Tcf-1 deficient Tregs the Th17 differentiation profile expanded to all other
clusters, and the RORγt cluster increased in frequency. The Tcf-1 deficient Tregs in spite of being more Th17
like, suppressed T-cells, however they failed to suppress inflammation. This indicates a bifurcation of Treg
suppressive functions and begs the question, of whether it involves a co-operation between TCF-1 and Foxp3.
We have found that, TCF-1 and Foxp3 co-bind enhancer elements of genes involved in T cell activation and
Th17 differentiation. β-catenin induces newly accessible chromatin regions at these enhancers and
upregulates the expression of the associated genes. Moreover, the E-box binding protein HEB works together
with TCF-1 and potentially also Foxp3 to regulate these genes, since Treg specific ablation of both TCF-1 and
HEB (but not each one alone) rescues inflammatory and autoimmune pathologies associated with β-catenin
activation in Tregs. Consistently, HEB regulates RORγt, represses Foxp3 and peripheral Treg development. Our
findings are in line with the notion that FoxP3 directly activates or represses transcription, in a context- and
partner-dependent manner. They further implicate β-catenin, TCF-1, and HEB in partnering with Foxp3 to
independently regulate the diverse Treg suppressive activities. Based on these findings we hypothesize that,
Wnt/β-catenin signaling differentially regulates Treg suppressive functions and diversity, by controlling
access of Foxp3 and HEB to select chromatin sites bound by Tcf-1. To address this hypothesis in specific
Aim 1 we will determine the role of β-catenin and Tcf-1 in preparing the epigenetic landscape for Foxp3 binding
and in shaping Treg cell type diversity. In specific Aim 2 we will determine the role secreted Wnt ligands in
defining the functional properties of colon infiltrating Tregs. The proposed studies will elucidate fundamental co-
operations/antagonisms between TFs that regulate Treg properties in health, and how microenvironment
queues like Wnts exploit them in disease settings. The expected findings have the potential to inform novel
diagnostic and therapeutic tools for autoimmunity and cancer.
Status | Active |
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Effective start/end date | 7/1/14 → 6/30/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $16,768.00
- National Institute of Allergy and Infectious Diseases: $649,418.00
- National Institute of Allergy and Infectious Diseases: $514,490.00
- National Institute of Allergy and Infectious Diseases: $649,418.00
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