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

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.