Mathis, DianeFerrando Gomez, Hector2026-07-0720262026-06-032026Ferrando Gomez, Hector. 2026. Regulatory T Cells at the CNS Borders: Responsiveness to GLP-1 Receptor Agonism and Characterization of the Human Dural Compartment. Masters Thesis, Harvard Medical School.32672969https://dash.harvard.edu/handle/1/42744121The meninges, once regarded as mere structural membranes, are now recognized as a dynamic immunological hub that maintains central nervous system (CNS) homeostasis through continuous dialogue with the peripheral immune system. Recent work has identified a population of regulatory T cells (Tregs) within the murine dura mater that actively suppresses local effector responses and preserves hippocampal function at steady state; however, the upstream signals that govern this population, its conservation in humans, and its behavior in neurodegenerative diseases (NDDs) remain poorly understood. First, we investigate whether glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide modulates the dural immunologic compartment in mice. Using both lean and diet-induced obesity models, we demonstrate that semaglutide selectively increases dural Treg frequency without altering other immunocyte populations in the meninges, brain, or spleen. This effect is amplified in obese mice, where it is accompanied by a reduction in dural macrophages (MPs) that inversely correlate with Treg expansion, and by a normalization of high-fat diet (HFD)-induced disease associated microglia (DAM). Second, we ask whether the meningeal Treg compartment defined in mice is conserved in humans. Using high-parameter flow cytometry and paired single-cell RNA sequencing of dura and matched peripheral blood obtained during routine neurosurgical procedures, we show that human dural Tregs phenocopy their murine counterparts and are transcriptionally distinct from circulating Tregs, exhibiting a tissue-residency program and an effector suppressive signature. Complementary analyses of whole-dura cadaveric tissue further reveal spatial heterogeneity and a marked reduction in dural Treg frequencies in patients with NDDs. Together, these findings establish that the dural regulatory compartment is responsive to systemic metabolic signals and is conserved across species, positioning it as a potential therapeutic target in neurological disease. application/pdfenImmunologyThesis or Dissertation2026-07-070009-0000-3298-9114