Regulation of T Lymphocytes by Fibroblastic Reticular Cells
Brown, Flavian Duvallé
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CitationBrown, Flavian Duvallé. 2018. Regulation of T Lymphocytes by Fibroblastic Reticular Cells. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42015706
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