Abstract
Fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) are nonhematopoietic stromal cells of lymphoid organs. They influence the migration and homeostasis of naive T cells; however, their influence on activated T cells remains undescribed. Here we report that FRCs and LECs inhibited T cell proliferation through a tightly regulated mechanism dependent on nitric oxide synthase 2 (NOS2). Expression of NOS2 and production of nitric oxide paralleled the activation of T cells and required a tripartite synergism of interferon-γ, tumor necrosis factor and direct contact with activated T cells. Notably, in vivo expression of NOS2 by FRCs and LECs regulated the size of the activated T cell pool. Our study elucidates an as-yet-unrecognized role for the lymph node stromal niche in controlling T cell responses.
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Acknowledgements
We thank M. Curry for technical assistance at the Dana-Farber Cancer Institute Flow Cytometry Core Facility; A. Sharpe (Harvard Medical School) for PD-L1-deficient mice; L. Lefrancois (University of Connecticut) for iFABP-tOVA mice; L.-H. Ang, Y. Zheng and S.J. Hagen for technical assistance at the Imaging Microscopy Core of Beth Israel Deaconess Medical Center; and J. Astarita and A. Bellemare-Pelletier for critically reading the manuscript. Supported by the US National Institutes of Health (R01 DK074500 and P01 AI045757 to S.J.T.) and the Dana-Farber Cancer Institute (V.L.-K).
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V.L.-K. designed and did most of the experiments, analyzed and interpreted data and wrote the manuscript; D.M. did individual experiments and discussed and interpreted results; A.L.F. edited the manuscript; A.L.F., S.E.A., K.G.E., P.T. and A.C. discussed and interpreted results and provided technical help for the experiments; and S.J.T. directed the study, analyzed and interpreted results and wrote the manuscript.
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Lukacs-Kornek, V., Malhotra, D., Fletcher, A. et al. Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol 12, 1096–1104 (2011). https://doi.org/10.1038/ni.2112
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DOI: https://doi.org/10.1038/ni.2112