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The cGAS-cyclic GMP-AMP (cGAMP)-stimulator of IFN genes (STING) pathway induces a powerful type I IFN (IFN-I) response and is a prime candidate for augmenting immunity in cancer immunotherapy and vaccines. IFN-I also has immuneregulatory functions manifested in several autoimmune diseases and is a first-line therapy for relapsing-remitting multiple sclerosis. However, it is only moderately effective and can induce adverse effects and neutralizing Abs in recipients. Targeting cGAMP in autoimmunity is unexplored and represents a challenge because of the intracellular location of its receptor, STING. We used microparticle (MP)-encapsulated cGAMP to increase cellular delivery, achieve dose sparing, and reduce potential toxicity. In the C57BL/6 experimental allergic encephalomyelitis (EAE) model, cGAMP encapsulated in MPs (cGAMP MPs) administered therapeutically protected mice from EAE in a STING-dependent fashion, whereas soluble cGAMP was ineffective. Protection was also observed in a relapsing-remitting model. Importantly, cGAMP MPs protected against EAE at the peak of disease and were more effective than rIFN-b. Mechanistically, cGAMP MPs showed both IFN-I-dependent and -independent immunosuppressive effects. Furthermore, it induced the immunosuppressive cytokine IL-27 without requiring IFN-I. This augmented IL-10 expression through activated ERK and CREB. IL-27 and subsequent IL-10 were the most important cytokines to mitigate autoreactivity. Critically, cGAMP MPs promoted IFN-I as well as the immunoregulatory cytokines IL-27 and IL-10 in PBMCs from relapsing-remitting multiple sclerosis patients. Collectively, this study reveals a previously unappreciated immune-regulatory effect of cGAMP that can be harnessed to restrain T cell autoreactivity.

The time-series station, SEATS (18° N, 116° E) in the South China Sea was visited six times during October 2006–December 2008 to carry out seawater sampling and floating trap deployments for the determination of distributions and fluxes of POC, PIC, PN, 234Th, 210Pb, and 210Po in the upper 200 m of the water column. Radionuclide deficiencies resulted in removal fluxes from the euphotic layer of 1.1×103–1.8×103 dpm m−2d−1 and 7.1–40.2 dpm m−2d−1 for 234Th and 210Po, respectively. Due to atmospheric input, an excess of 210Pb relative to 226Ra is commonly observed in the upper water column. Sinking fluxes of total mass, POC, PIC, PN, 234Th, 210Pb, and 210Po measured at the euphotic depth were low in summer-fall and high in winter-spring, reflecting the seasonal variability of biological pumping. Excluding the suspiciously low primary productivity data point in July 2007, a relatively high e-ratio of 0.28–0.69 was estimated by the ratio of the POC flux at the euphotic depth and the integrated primary productivity. The ratios of 234Th, 210Pb, and 210Po to organic carbon, inorganic carbon, and nitrogen in the sinking particles were combined with the disequilibria of 234Th–238U, 210Pb–226Ra, and 210Po–210Pb to estimate export fluxes of POC, PIC, and PN from the euphotic layer. Compared with measured fluxes by the sediment trap and estimated fluxes by other approaches, it is concluded that the export production in the South China Sea, ranging from 1.8 to 21.3 mmol-C m−2d−1, can be reasonably estimated using 234Th, 210Pb, and 210Po as carbon proxies.

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor �� (TGF��) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGF�� enables TH17 cell differentiation remains elusive. Here we reveal that TGF�� enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor ��t (ROR��t). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGF�� signalling in a ROR��t-dependent manner. Ectopic SMAD4 expression suppresses ROR��t expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGF�� neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGF�� stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGF��-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of ROR��t to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGF�� controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases.