Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes

Nat Immunol. 2011 Sep 18;12(11):1096-104. doi: 10.1038/ni.2112.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Growth Processes / genetics
  • Cell Movement / genetics
  • Cells, Cultured
  • Clonal Selection, Antigen-Mediated*
  • Endothelium, Lymphatic / immunology
  • Endothelium, Lymphatic / metabolism*
  • Endothelium, Lymphatic / pathology
  • Intercellular Junctions / immunology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Lymph Nodes / pathology
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / immunology
  • Nitric Oxide Synthase Type II / metabolism*
  • Stromal Cells / immunology
  • Stromal Cells / metabolism*
  • Stromal Cells / pathology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology
  • Transgenes / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse