Vince JE et al
Vince JE et al., IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. IL-22 protect against fungal pathogens and drive many inflammatory diseases. The cellular Inhibitor of Apoptosis Proteins (cIAPs) are E3 ubiquitin ligases that regulate NF-B signaling and thereby influence cytokine production by T cells in a TRX 818 variety of settings(1). Yet, how cIAPs influence the differentiation and effector function of distinct TH cell subsets remains poorly understood. In this issue of em Science Signaling /em , Rizk et al. use small molecule inhibitors to demonstrate that the cIAPs control the balance between IL-22 and IL-17 production by TH17 cells through NIK dependent activation of NF-B2, and downstream expression of the aryl hydrocarbon receptor (2). These findings position the cIAPs as key inhibitors of TH17 effector function, and demonstrate that inhibition PTGFRN of cIAPs may also limit autoimmunity. Tumor necrosis factor (TNF) superfamily receptors play critical roles in nearly every immune cell type, influencing activation, differentiation, and survival, which underscores the importance TRX 818 of elucidating the events they control(1). The cIAPs are crucial components of the cytoplasmic signaling complex of multiple members of the TNF receptor superfamily in both mice and humans, which modulate the activation of canonical NF-B1 and non-canonical NF-B2(1, 3, 4). The E3 ubiquitin ligase members of the IAP family, which includes the cIAPs, are endogenously inhibited by the small protein second mitochondrial activator of caspases (SMAC). Small molecule SMAC mimetics (SMs) potently bind the cIAPs, inducing conformational changes, which promotes their rapid autoubiquitination and degradation(3C5). Although SMs were developed as apoptosis sensitizers for cancer treatment, they exert much of their biological activity through modulation of immune signaling (Figure 1)(1). Treatment of naive T cells with SMs promotes rapid activation of NF-B2 in a NIK dependent fashion. In contrast to the activity of SM in cancer cells, this does not stimulate T cell apoptosis, but rather cooperates with TCR signaling to enhance activation and proliferation(6). Thus, SM enhance co-stimulatory pathways, meaning that in the absence of TCR engagement, they have minimal impact on T cells. After engagement of the TCR, SM treated T cells increase production of IL-2, TRX 818 TNF and multiple cytokines associated with the TH2 lineage(6, 7). Rizk et al found an unexpected increase in the TH2 transcription factor GATA3 in TH17 cells activated in the presence of SMs, suggesting that the cIAPs may directly regulate TH2 cell differentiation(2). Indeed, under stimulation conditions that were permissive to multiple CD4+ T cell lineages (though notably not TH1), SMs skewed newly activated T cells toward the TH2 lineage at the expense of TH17 cells(2). Yet under TH17 polarizing conditions, expression of the transcription factor retinoic TRX 818 acid receptor-related orphan receptor gamma (RORt) was unaffected by SM treatment. Thus, SM effect TH17 function, rather than lineage stability itself(2). Whereas SM treatment suppressed IL-17 production by by RORT expressing cells through NF-B2, it augmented their production of IL-22 by a mechanism dependent on NIK and the aryl hydrocarbon receptor(2). This detailed analysis positions the cIAPs as molecular switches with fine control over TH effector function. Open in a separate window Fig. 1. SMAC mimetics Impact Lymphocyte Survival, Differentiation and skew cytokine production.SMAC mimetics (SM) have myriad cell type specific effects on lymphocytes. In newly activated CD4+ T cells, SMs augment the production of IL-2, enhance expression of CD25, and increase proliferation. Differentiation of CD4+ T cells is skewed by SM toward the TH2 lineage with increased production of IL-4, LIF, and IL-13. TH17 cells exposed to SM increased production of IL-22 and decrease production of IL-17. The impact of SM on TH1 cell differentiation is presently unknown, and information on Tregs is mixed, although excess IL-2 production generally supports Treg survival. SMs augment production of multiple cytokines form NKT cells and enhance proliferation, and increase the production of IL-2, IFNg, and CXCL10 from CD8 T cells which also show increased replication. SMs enhance B cell TRX 818 survival through activation of NF-kB2 downstream of BAFF while CD40 signaling through NF-kB1 is diminished, reducing.