Interleukin 17 (IL-17)-producing TH17 cells are often present at the sites of tissue inflammation in autoimmune diseases, which has lead to the conclusion that TH17 are main drivers of autoimmune tissue injury. However, not all TH17 cells are pathogenic, in fact TH17 generated with TGF-β1 and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we show that TGF-β3, produced by developing TH17 cells, is dependent on IL-23, which together with IL-6 induces highly pathogenic TH17 cells. Moreover, TGF-β3-induced TH17 cells are functionally and molecularly distinct from TGF-β1-induced TH17 cells and possess a molecular signature that defines pathogenic effector TH17 cells in autoimmune disease.

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Uniform and extremely small-sized iron oxide nanoparticles (ESIONs) of < 4 nm were synthesized via the thermal decomposition of iron-oleate complex in the presence of oleyl alcohol. Oleyl alcohol lowered the reaction temperature by reducing iron-oleate complex, resulting in the production of small-sized nanoparticles. XRD pattern of 3 nm-sized nanoparticles revealed maghemite crystal structure. These nanoparticles exhibited very low magnetization derived from the spin-canting effect. The hydrophobic nanoparticles can be easily transformed to water-dispersible and biocompatible nanoparticles by capping with the poly(ethylene glycol)-derivatized phosphine oxide (PO-PEG) ligands. Toxic response was not observed with Fe concentration up to 100 μg/mL in MTT cell proliferation assay of POPEG-capped 3 nm-sized iron oxide nanoparticles. The 3 nm-sized nanoparticles exhibited a high r(1) relaxivity of 4.78 mM(-1) s(-1) and low r(2)/r(1) ratio of 6.12, demonstrating that ESIONs can be efficient T(1) contrast agents. The high r(1) relaxivities of ESIONs can be attributed to the large number of surface Fe(3+) ions with 5 unpaired valence electrons. In the in vivo T(1)-weighted magnetic resonance imaging (MRI), ESIONs showed longer circulation time than the clinically used gadolinium complex-based contrast agent, enabling high-resolution imaging. High-resolution blood pool MR imaging using ESIONs enabled clear observation of various blood vessels with sizes down to 0.2 mm. These results demonstrate the potential of ESIONs as T(1) MRI contrast agents in clinical settings.

Despite their importance, the molecular circuits that control the differentiation of naïve T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here, we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based tools for performing perturbations in primary T cells to systematically derive and experimentally validate a model of the dynamic regulatory network that controls Th17 differentiation. The network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, whose coupled action may be essential for maintaining the balance between Th17 and other CD4+ T cell subsets. Overall, our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles, and highlights novel drug targets for controlling Th17 differentiation.