Campbell, Daniel JMittelsteadt, Kristen Leigh2020-08-142020-08-142020-08-142020Mittelsteadt_washington_0250E_21799.pdfhttp://hdl.handle.net/1773/46129Thesis (Ph.D.)--University of Washington, 2020Foxp3+ regulatory T cells (TR) are a population of CD4+ T cells with a well-recognized ability to restrain inappropriate or overreactive immune responses against both self- and foreign-antigens. TR are vitally important in maintaining immune tolerance and act at different tissue sites to prevent the development of autoimmunity, lymphoproliferative disease, and pathological tissue damage. Our lab and others have demonstrated considerable phenotypic and functional heterogeneity among TR localized in lymphoid versus nonlymphoid tissues. Broadly, central TR (cTR) found in lymphoid tissues rely on paracrine IL-2 signals for their maintenance and prevent priming of autoreactive T cells, whereas effector TR (eTR) residing in nonlymphoid organs are dependent on T cell receptor (TCR)/costimulatory ICOS signals and modulate ongoing inflammatory responses. Adding another layer to this complexity, there is growing evidence that TR found across nonlymphoid tissues are distinct from one another and respond to unique cues within their respective microenvironments. Although they display hallmarks of eTR, tissue-specific TR exhibit unique transcriptional and epigenetic profiles, express distinct chemokine receptors and TCR repertoires, and exert functions that go beyond classical modulation of immune responses, including tissue repair and maintaining organismal metabolic homeostasis. The costimulatory molecule ICOS is highly expressed on eTR that migrate to nonlymphoid tissues and contributes to their maintenance and function in models of autoimmunity. In this dissertation, we report an unexpected cell-intrinsic role for ICOS expression and downstream PI3K signaling in limiting the maintenance, phenotype, and function of TR specifically in visceral adipose tissue (VAT). Icos–/– mice and mice expressing a knock-in form of ICOS with the inability to activate PI3K demonstrated increased VAT-TR abundance and expression of canonical VAT-TR markers. Loss of ICOS signaling facilitated enhanced accumulation of TR to VAT associated with increased CCR3 expression and resulted in reduced adipose inflammation and retained insulin sensitivity in the context of high-fat diet. In contrast, preliminary studies utilizing models of autoimmune central nervous system (CNS) inflammation indicated a requirement for ICOS signaling in disease resolution mediated by CNS-TR. Collectively, these findings suggest that eTR residing within different tissues and immune environments differentially rely on ICOS signaling, highlighting new and surprising mechanisms that regulate eTR development, accumulation, and function.application/pdfen-USnoneImmunologyMolecular and cellular biologyThesis