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Abstract
Antigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently, we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes in vitro toward an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3. The TLR7/8 ligand R848 (Resiquimod) triggers the high release of cytokines from GM-CSF/IL-4-treated monocytes. These cytokines subsequently upregulate T cell suppressive factors, such as programmed death-ligand 1 (PD-L1) and indolamin-2,3-dioxygenase (IDO) through cytokine receptor-mediated STAT3 activation. Here, we reveal an essential role for the microRNA (miR, miRNA) hsa-miR-99b/let-7e/miR-125a cluster in stabilizing the suppressive phenotype of R848-stimulated APCs on different levels. On the one hand, the miR cluster boosts R848-stimulated cytokine production through regulation of MAPkinase inhibitor Tribbles pseudokinase 2, thereby enhancing cytokine-stimulated activation of STAT3. One the other hand, the STAT3 inhibitor suppressor of cytokine signaling-1 is targeted by the miR cluster, stabilizing the STAT3-induced expression of immunosuppressive factors PD-L1 and IDO. Finally, hsa-miR-99b/let-7e/miR-125a cluster regulates generation of the suppressive tryptophan (Trp) metabolite kynurenine by targeting the tryptophanyl-tRNA synthetase WARS, the direct competitor of IDO in terms of availability of Trp. In summary, our results reveal the hsa-miR-99b/let-7e/miR-125a cluster as an important player in the concerted combination of mechanisms that stabilizes STAT3 activity and thus regulate R848-stimulated suppressive APCs.
Highlights
Antigen-presenting cells (APCs) such as monocytes, macrophages, and dendritic cells (DCs) are highly plastic in nature and central players in the immune response
After having confirmed the upregulation of the hsa-miR-99b/ let-7e/miR-125a cluster by quantitative reverse transcriptase PCRs (Figure 1B), we checked the actual influence of the miRNAs on the suppressive APC phenotype
Monocytes isolated from blood of healthy donors were stimulated the day after isolation with GM-CSF, IL-4, and R848 (TLR7/8 ligand) to induce R848-stimulated suppressive APC
Summary
Antigen-presenting cells (APCs) such as monocytes, macrophages, and dendritic cells (DCs) are highly plastic in nature and central players in the immune response. APCs can facilitate immunity or favor tolerance via promoting anergy and deletion of T cells or regulatory T cells (Tregs) [1,2,3] Examples of APCs that prevent an immune response can be found in special niches of our body, such as the gastrointestinal tract and the liver, where they impede an overreaction against commensal bacteria, but at the same time possess the potential to switch to an immunogenic population after infection [4,5,6,7]. Suppressive APCs may downregulate already induced immune reactions. The range of tolerogenic/suppressive APCs is broad, some of the conducted immune inhibitory reactions appear to be universal and looked upon checkpoint mechanisms. Besides anti-inflammatory cytokine effects, inhibitory checkpoint mechanisms include programmed death-ligand 1 (PD-L1) binding to programmed cell death 1 (PD-1) on T cells [10,11,12] and modulation through indolamin-2,3-dioxygenase (IDO)catalyzed tryptophan metabolites [13,14,15]
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