Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes; however, few have been identified that regulate immune cell differentiation and function. Here, we identified lnc-DC, which was exclusively expressed in human conventional dendritic cells (DCs). Knockdown of lnc-DC impaired DC differentiation from human monocytes in vitro and from mouse bone marrow cells in vivo and reduced capacity of DCs to stimulate T cell activation. lnc-DC mediated these effects by activating the transcription factor STAT3 (signal transducer and activator of transcription 3). lnc-DC bound directly to STAT3 in the cytoplasm, which promoted STAT3 phosphorylation on tyrosine-705 by preventing STAT3 binding to and dephosphorylation by SHP1. Our work identifies a lncRNA that regulates DC differentiation and also broadens the known mechanisms of lncRNA action.

The classical activation of macrophages, one of major innate effector cells, requires IFN-γ pretreatment (priming) and subsequent TLR stimuli (triggering). The priming effect of IFN-γ can promote macrophages to secrete higher level of proinflammatory cytokines but lower level of the anti-inflammatory cytokines, enhancing microbicidal and tumoricidal activity of macrophages. However, the underlying molecular mechanisms for IFN-γ–priming effect on macrophage activation remain to be fully understood. microRNAs (miRNAs) are now emerging as important regulators in immune response, including signaling transduction in immune cell function. In this study, we explored the effect of IFN-γ on miRNA expression profiling in macrophages and tried to identify the definite miRNA involved in the priming effect of IFN-γ. We discovered that miR-3473b, which was significantly downregulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. miR-3473b promoted Akt/glycogen synthase kinase 3 signaling and IL-10 production through directly targeting phosphatase and tensin homolog (PTEN) to suppress activation of macrophages and inflammatory response. Our data indicate that IFN-γ beefs up macrophage innate response and cytotoxicity by downregulating miR-3473b to release PTEN from suppression, and then the increase of PTEN contributes to the full activation of IFN-γ–primed macrophages. Our results provide mechanistic insight to priming effect of IFN-γ on macrophage classical activation by identifying an IFN-γ/miR-3473b/PTEN regulatory loop in the regulation of macrophage function.

Although myeloid-derived suppressor cells (MDSCs) have been demonstrated to contribute to tumor initiation, progression and metastasis, however, which MDSC subsets are preferentially expanded and activated, and what’s the key molecular mechanism responsible for specific MDSC subsets in promoting tumor progression need to be fully addressed. Here we identify that Ly6GmiLy6CloCD11b+CXCR2+ subpopulation (named CXCR2+ MDSCs) are predominately expanded and recruited in systemic and local tumor microenvironment during breast cancer progression and metastasis. The proportion of CXCR2+ MDSCs is inversely correlated with the infiltration of CD4+ or CD8+ T cells. Besides, CXCR2+ MDSCs promote breast cancer growth and metastasis to lung and/or lymph node in vivo. Furthermore, CXCR2+ MDSCs induce epithelial mesenchymal transition (EMT) of breast cancer cells via IL-6. Moreover, CXCR2+ MDSCs upregulate the expression of immunosuppressive molecules programmed cell death protein 1(PD1), PD1 ligand 1 (PDL1), lymphocyte activation gene 3 protein (LAG3), cytotoxic T lymphocyte antigen 4 (CTLA4), and T cell immunoglobulin domain and mucin domain protein 3 (TIM3) on CD4+ or CD8+ T cells, and induce exhaustion of the activated T cells partially via IFN-γ. These results demonstrate that CXCR2+ MDSCs accelerate breast cancer progression via directly inducing cancer cell EMT and indirectly promoting T cell exhaustion, suggesting that CXCR2+ MDSCs may be a potential therapeutic target of breast cancer.

Regulatory T (Treg) cells are important for the maintenance of immune homoeostasis and prevention of autoimmune diseases. Epigenetic modifications have been reported to modulate autoimmunity by altering Treg cell fate. Here we show that the H3K4 methyltransferase Ash1l facilitates TGF-β-induced Treg cell polarization in vitro and protects mice from T cell-mediated colitis in vivo. Ash1l upregulates Smad3 expression by directly targeting Smad3 promoter to increase local H3K4 trimethylation. Furthermore, we identify an lncRNA, namely lnc-Smad3, which interacts with the histone deacetylase HDAC1 and silences Smad3 transcription. After TGF-β stimulation, activated Smad3 suppresses lnc-Smad3 transcription, thereby recovering the Smad3 promoter accessibility to Ash1l. By revealing the opposite regulatory functions of Ash1l and lnc-Smad3 in Smad3 expression, our data provide insights for the epigenetic control of Treg cell fate to potentially aid in the development of therapeutic intervention for autoimmune diseases.

Type I interferon (IFN-I) production is efficiently induced to ensure a potent innate immune response to viral infection. How this response can be enhanced, however, remains to be explored. Here, we identify a new cytoplasmic long non-coding RNA (lncRNA), lncLrrc55-AS, that drives a positive feedback loop to promote interferon regulatory factor 3 (IRF3) signaling and IFN-I production. We show that lncLrrc55-AS is virus-induced in multiple cell types via the IFN-JAK-STAT pathway. LncLrrc55-AS-deficient mice display a weakened antiviral immune response and are more susceptible to viral challenge. Mechanistically, lncLrrc55-AS binds phosphatase methylesterase 1 (PME-1), and promotes the interaction between PME-1 and the phosphatase PP2A, an inhibitor of IRF3 signaling. LncLrrc55-AS supports PME-1-mediated demethylation and inactivation of PP2A, thereby enhancing IRF3 phosphorylation and signaling. Loss of PME-1 phenocopies lncLrrc55-AS deficiency, leading to diminished IRF3 phosphorylation and IFN-I production. We have identified an IFN-induced lncRNA as a positive regulator of IFN-I production, adding mechanistic insight into lncRNA-mediated regulation of signaling in innate immunity and inflammation.