The lymph node stroma is composed of non-haematopoietic fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs). These lymphoid stroma cells have been previously reported to present self antigens to naive T cells and establish deletional tolerance. A recent study published in Nature Immunology reports that FRCs and LECs also control the proliferation of activated T cells in the lymph nodes.

lymphoid stroma cells ... control T cell proliferation through NO production

To investigate the role of FRCs and LECs during an ongoing T cell response in the lymph node, the authors established in vitro co-culture assays, in which T cells were stimulated in the presence of FRCs or LECs. Interestingly, both stromal cell populations were shown to inhibit T cell proliferation, and this was independent of the presence of other leukocytes.

So, what mechanisms are involved in the inhibition of T cell proliferation by lymphoid stroma cells? Activated T cells were shown to induce the expression of inducible nitric oxide synthase (iNOS) by lymphoid stroma cells. iNOS catalyses the production of nitric oxide (NO) — which can suppress T cell proliferation — and its expression was required for the suppressive function of FRCs and LECs.

Interestingly, exogenous interferon-γ (IFNγ) was found to induce the upregulation of iNOS expression in lymphoid stroma cells. Moreover, co-culture assays with activated T cells and lymphoid stroma cells that lacked expression of IFNγ or the IFNγ receptor showed that IFNγ secretion by the activated T cells was required for the suppressive function of lymphoid stroma cells.

However, IFNγ does not act alone to induce iNOS-mediated NO production by lymphoid stroma cells, as it increased mRNA but not protein levels of iNOS. In addition, tumour necrosis factor produced by activated T cells and T cell–stromal cell contact were found to be essential for NO production in the co-culture assays.

As T cell proliferation in response to antigen presentation by iNOS-deficient FRCs was comparable to that induced by dendritic cells, the authors sought to confirm their findings in vivo, using transgenic mice in which ovalbumin (OVA) expression is restricted to lymph node FRCs (iFABP-tOVA mice). Interestingly, adoptively transferred OVA-specific CD8+ T cells proliferated more in the lymph nodes of iNOS-deficient iFABP-tOVA mice than in the lymph nodes of iNOS-expressing iFABP-tOVA mice.

Thus, lymphoid stroma cells that are in close proximity with activated T cells control T cell proliferation through NO production. This crosstalk may be crucial for the protection of secondary lymphoid organs from unrestricted T cell activation.