Who Watches the Watchmen: Molecular Coordinators of Homeostasis in Regulatory Cell-Types

The human body is exposed to a wide variety of stressors, both intrinsic and extrinsic, that can disrupt homeostasis. Unique subsets of cells have evolved to manage and mitigate these stresses. Here, I detail my findings regarding the molecular pathways that modulate the functions of two ‘regulatory’ cell-types: specialized phagocytes and peripheral T regulatory cells.

The first half of this dissertation looks at specialized phagocytes, which respond to the intrinsic stresses of cell death by clearing apoptotic corpses from tissues in a phosphatidylserine (PtdSer) dependent manner. Here, I demonstrate that PtdSer receptors have distinct functions, dependent on the tissue context. Specifically, I show that overexpression of one PtdSer receptor BAI1, in mice lacking a different PtdSer receptor, MerTK, rescues phagocytic defects in Sertoli cells but not in the retinal pigmented epithelium (RPE). I further demonstrate that MerTK is uniquely critical for RPE function as it regulates phagocytosis-independent processes including the visual cycle and transcription of genes related to metabolism and retinal disease.

In the second half of this dissertation, I present my findings on peripheral T regulatory cells, which suppress inflammatory responses to innocuous foreign antigens. Our data reveal that the phosphatase PP2A dephosphorylates the critical Treg transcription factor FoxO1. However, pharmacological inhibition of PP2A does not impair Treg function ex vivo, indicating that these ex vivo assays do not recapitulate in vivo assays of Treg function.