The cytokine tumour-necrosis factor (TNF) has a key role in promoting the activation of innate cells and the release of pro-inflammatory cytokines that influence the transition from innate to adaptive immune responses. Now, a study published in Cell shows that TWEAK (TNF-related weak inducer of apoptosis) balances TNF activity by repressing the production of pro-inflammatory cytokines and attenuating the transition from innate to adaptive immunity.

To analyse the role of TWEAK in immune responses, Maecker et al. generated TWEAK-deficient mice. These mice were healthy and developed normally, but they had more natural killer (NK) cells compared with age-matched wild-type littermate control mice. This was a result of impaired elimination of NK cells by activation-induced cell death, rather than impaired generation of NK cells in the bone marrow.

Using a lipopolysaccharide (LPS) systemic-challenge model, the authors showed that TWEAK-deficient mice were more susceptible to LPS-induced death than were wild-type control mice. Furthermore, Tweak−/− NK cells and macrophages produced greater quantities of the pro-inflammatory cytokines interferon-γ (IFNγ) and interleukin-12 (IL-12) but reduced levels of the anti-inflammatory cytokine IL-10, indicating that TWEAK functions to dampen the innate inflammatory responses.

So, how does TWEAK attenuate the production of pro-inflammatory cytokines? First, the authors assessed the effect of TWEAK on the transcription factor STAT1 (signal tranducer and activator of transcription-1), which is important for the production of IFNγ and IL-12 by NK cells and macrophages. Tweak−/− mice had increased basal levels of STAT1 phosphorylation and increased LPS-induced STAT1 phosphorylation compared with control mice, as well as reduced induction of SOCS1 (suppressor of cytokine signalling 1). So, attenuation of STAT1 activation through SOCS1 induction is one mechanism by which TWEAK represses the production of IFNγ and IL-12.

Next, the authors looked at the effect of TWEAK on the nuclear factor-κB (NF-κB) pathway, as TNF induces the expression of IFNγ and IL-12 through activation of this pathway. TNF induces transient phosphorylation of the p65 subunit of NF-κB, leading to its association with the p50 subunit and translocation to the nucleus, where the heterodimer transactivates target genes by association with the p300 transcriptional co-activator. By contrast, TWEAK was found to induce prolonged phosphorylation of p65, leading to association not with p300, but with histone deacetylase 1 (HDAC1), which represses target gene transcription. So, HDAC1-mediated transcriptional repression is a second mechanism by which TWEAK modulates pro-inflammatory cytokine production.

To further assess the role of TWEAK in modulating the transition from innate to adaptive immunity, the authors used the C57BL/6 model of rejection of B16 melanoma cells, which is mediated by NK cells and T cells. In contrast to wild-type littermate controls, Tweak−/− mice rejected moderately aggressive B16–F10 melanoma cells and had greater numbers of splenic NK cells and CD8+ T cells. When Tweak−/− mice were injected with more aggressive B16–BL6 melanoma cells, the tumours were infiltrated with 2–8 times more NK cells and T cells than wild-type mice, and together with macrophages, these cells produced more IFNγ and IL-12 upon re-challenge ex vivo. Generation of bone-marrow-chimeric mice showed that TWEAK did not act directly on T cells, but rather, it acted indirectly by modulating the T-cell-priming environment.

Together, these results show that TWEAK and TNF act in a 'Yin and Yang' manner in modulating the transition from innate to adaptive immunity.