Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide

Stefanie Siegert, Hsin Ying Huang, Chen Ying Yang, Leonardo Scarpellino, Lucie Carrie, Sarah Essex, Peter J. Nelson, Matthias Heikenwalder, Hans Acha-Orbea, Christopher D. Buckley, Benjamin J. Marsland, Dietmar Zehn, Sanjiv A. Luther

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Adaptive immune responses are initiated when T cells encounter antigen on dendritic cells (DC) in T zones of secondary lymphoid organs. T zones contain a 3-dimensional scaffold of fibroblastic reticular cells (FRC) but currently it is unclear how FRC influence T cell activation. Here we report that FRC lines and ex vivo FRC inhibit T cell proliferation but not differentiation. FRC share this feature with fibroblasts from non-lymphoid tissues as well as mesenchymal stromal cells. We identified FRC as strong source of nitric oxide (NO) thereby directly dampening T cell expansion as well as reducing the T cell priming capacity of DC. The expression of inducible nitric oxide synthase (iNOS) was up-regulated in a subset of FRC by both DC-signals as well as interferon-γ produced by primed CD8+ T cells. Importantly, iNOS expression was induced during viral infection in vivo in both LN FRC and DC. As a consequence, the primary T cell response was found to be exaggerated in Inos -/- mice. Our findings highlight that in addition to their established positive roles in T cell responses FRC and DC cooperate in a negative feedback loop to attenuate T cell expansion during acute inflammation.

Original languageEnglish
Article numbere27618
Number of pages14
JournalPLoS ONE
Issue number11
Publication statusPublished - 14 Nov 2011
Externally publishedYes

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