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dc.contributor.advisorBoussiotis, Vassiliki
dc.contributor.authorBrown, Flavian Duvallé
dc.date.accessioned2019-12-11T11:32:18Z
dash.embargo.terms2020-03-01
dc.date.created2018-03
dc.date.issued2018-01-12
dc.date.submitted2018
dc.identifier.citationBrown, Flavian Duvallé. 2018. Regulation of T Lymphocytes by Fibroblastic Reticular Cells. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42015706*
dc.description.abstractLymph node fibroblastic reticular cells (FRCs) organize and regulate several aspects of T cell biology. They support lymphocyte recruitment and compartmentalization in the lymph node and facilitate encounters between antigen-presenting dendritic cells and T cells. Upon sensing T cell activation, FRCs release nitric oxide, which restricts proliferation to regulate the size of the activated T cell pool. Mechanistically, additional insights described here demonstrate that FRC-derived nitric oxide specifically attenuates mitochondrial oxidative phosphorylation, which is essential for cell cycle progression in activated T cells. Therefore, to date, FRCs are primarily thought to negatively regulate the functions of newly activated T cells. In the thesis at hand, we now show that FRCs can also express immunostimulatory molecules in response to activated T cells including the gp130 family cytokine, interleukin-6 (IL-6). Specifically, FRC-derived IL-6 creates a supportive niche for activated T cells by enhancing their production of interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF). We used epigenetic profiling to deeply explore this seemingly immunostimulatory function of FRCs. Employing an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we unexpectedly found that activated T cells significantly remodel their chromatin landscape in response to FRCs and IL-6. These epigenetic changes altered unique patterns of enhancers and facilitated differential accessibility of specific transcription factor binding motifs — which coincided with profound increases in T cell metabolic flux, lipid biosynthesis, survival and differentiation. Importantly, we evaluated the impact of FRC-conditioning in vivo during influenza virus and lymphocytic choriomeningitis virus (LCMV) infections. Our data demonstrate that stromal programming of T cells results in enhanced lymphocyte longevity and differentiation into tissue-resident memory T cells. Mechanistically, we show that IL-6 is a major mediator of these changes. Although it remains to be determined if the suppressive and stimulatory programs run simultaneously, sequentially, or contextually in FRCs, this thesis illuminates a previously unknown function of lymphoid stroma in programming activated T cells for enhanced bioenergetics and longevity. We feel this new set of findings will be of considerable interest to the immunology, immunoregulation and stromal cell fields.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectFibroblastic Reticular Cell
dc.subjectLymph Node
dc.subjectT cell
dc.titleRegulation of T Lymphocytes by Fibroblastic Reticular Cells
dc.typeThesis or Dissertation
dash.depositing.authorBrown, Flavian Duvallé
dash.embargo.until2020-03-01
dc.date.available2019-12-11T11:32:18Z
thesis.degree.date2018
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberBrenner, Michael
dc.contributor.committeeMemberMempel, Thorsten
dc.contributor.committeeMemberBrowning, Jeffrey
dc.type.materialtext
thesis.degree.departmentMedical Sciences
thesis.degree.departmentMedical Sciences
dash.identifier.vireo
dc.identifier.orcid0000-0002-7008-2473
dash.author.emailflavian.brown@gmail.com


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