Research ArticleImmunology

SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation

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Science Signaling  27 Aug 2019:
Vol. 12, Issue 596, eaaw3469
DOI: 10.1126/scisignal.aaw3469

SMACing down TH17 cells

Currently in clinical trials for cancer therapy, second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) target inhibitor of apoptosis proteins (IAPs) for degradation and sensitize tumors to tumor necrosis factor–α (TNF-α)–dependent cell death (see the Focus by Dougan and Dougan). In addition, SMs synergize with immune checkpoint inhibitors to promote durable tumor immunity in mice. Using a multiomics approach, Rizk et al. found that SMs altered CD4+ T helper (TH) cell differentiation. In vitro, SMs reduced TH17 cell differentiation in an NF-κB–inducing kinase (NIK)–dependent manner and increased the differentiation of TH9 and TH2 cells producing IL-9 and IL-13. SMs reduced the production of IL-17 and disease severity in a mouse model of multiple sclerosis. This study defines how these targeted agents alter T cell function and suggests that they may have therapeutic activity in TH17 cell–driven autoimmune diseases.

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