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

Veronika Lukacs-Kornek, Deepali Malhotra, Anne L. Fletcher, Sophie E. Acton, Kutlu G. Elpek, Prakriti Tayalia, Ai Ris Collier, Shannon J. Turley

Research output: Contribution to journalArticlepeer-review

198 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1096-1104
Number of pages9
JournalNature immunology
Volume12
Issue number11
DOIs
StatePublished - Nov 2011
Externally publishedYes

Bibliographical note

Funding 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).

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