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

John Rizk,Joseph Kaplinsky,Rasmus Agerholm,D. Kadekar,F. Ivars,William W. Agace,William W. Agace,W. Wong,Matthew J. Szucs,S. Myers,S. Carr,A. Waisman,Vasileios Bekiaris

Published 2019 in Science Signaling

ABSTRACT

By promoting noncanonical NF-κB signaling, SMAC mimetics can reprogram CD4+ T helper cell differentiation and curb autoimmunity. 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. Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanonical NF-κB signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated TH17 cell–driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-κB–inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed Il17a expression and IL-17A protein production, as well as the expression of a number of other immune genes. Induction of IL-22 production correlated with the NIK-dependent reduction in cMAF protein abundance and the enhanced activity of the aryl hydrocarbon receptor. Last, SMs also increased IL-9 and IL-13 production and, under competing conditions, favored the differentiation of naïve CD4+ T cells into TH2 cells rather than TH17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of TH17 cells and inhibit TH17 cell–driven autoimmunity.

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