Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Paula M. Oliver

Abstract

T helper 17 (Th17) and Foxp3+ T regulatory (Treg) cells are antagonistic in their development, function, and abundance. Th17 cells protect against mucosal surface colonization by pathogenic organisms but are important drivers of autoimmune disease, while Treg cells play key anti-inflammatory roles in suppressing immune cell activation. Surprisingly, when mouse CD4 T cells lack Ndfip1, a co-activator of Nedd4-family E3 ubiquitin ligases, an increase in both Th17 and Treg cells is observed. This work investigates how Ndfip1 regulates these two cell types in order to promote immune homeostasis. We find that Ndfip1 opposes Th17 cell identity while enforcing Treg lineage stability in order to prevent spontaneous inflammatory disease. Ndfip1 drives the degradation of RORγT, which is essential for Th17 identity and cytokine production. Therefore, in Th17 cells, the absence of Ndfip1 results in reduced degradation and accumulation of RORγT. Upon in vivo transfer, Ndfip1-deficient Th17 cells are more powerful inducers of colitis through increased cytokine production and recruitment of inflammatory neutrophils, indicating that Ndfip1 dampens Th17 cell function to limit pathogenicity. In contrast, Ndfip1 promotes Treg cell function by enforcing lineage stability and preventing the expansion of IL-4-producing Treg cells. Thus the deletion of Ndfip1 in Treg cells leads to inflammation in the skin, lungs, and spleen driven by activated Treg cells that are highly proliferative, IL-4 producers. These Treg cells more likely to lose Foxp3 and become IL-4-producing TH2 cells. Proteomic and seahorse metabolic profiling indicated that these cells have altered metabolism marked by elevated glycolysis and mTORC1 signaling pathways. Therefore, Treg cells require Ndfip1 to suppress mTORC1 activity, limit glycolytic metabolism, and prevent IL-4 production to preserve lineage stability. Our data indicates that Ndfip1 similarly limits the expansion and proliferation of both Th17 and Treg cells but antagonizes the identity and function of proinflammatory Th17 cells while promoting Treg cell stability and function, with the overarching aim of preventing spontaneous inflammatory disease.

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