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.
Bibliographical noteFunding Information:
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).