Regulation of T Lymphocytes by Fibroblastic Reticular Cells

Abstract

Lymph 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.