T regulatory cells that express the transcription factor Foxp3 (Foxp3+ Treg) promote tissue homeostasis in several settings. We now report that symbiotic members of the human gut microbiota induce a distinct Treg population in the mouse colon, which constrains immuno-inflammatory responses. This induction, which we find to map to a broad, but specific, array of individual bacterial species, requires the transcription factor Rorγ, paradoxically in that Rorγ is thought to antagonize FoxP3 and promote T helper 17 (Th17) cell differentiation. Rorγ's transcriptional footprint differs in colonic Tregs and Th17 cells, controlling important effector molecules. Rorγ, and the Tregs that express it, contribute substantially to regulating colonic Th1/Th17 inflammation. Thus, the marked context-specificity of Rorγ results in very different outcomes even in closely related cell-types.

In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.

We identified three RORγt-specific inhibitors that suppress T helper 17 (Th17) cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drug with corresponding whole-genome transcriptome sequencing. RORγt acts both as a direct activator of Th17 cell signature genes and as a direct repressor of signature genes from other T-cell lineages, with the strongest transcriptional effects on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T-cell differentiation. The three inhibitors identified here modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.

IL-17–producing CD4+Th17 cells, CD8+Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8+ Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23–induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.

Generation of non-classical correlations (or entanglement)between atoms 1-7 , photons 8 or combinations thereof 9-11 is at the heart of quantum information science. Of particular interest are material systems serving as quantum memories that can be interconnected optically 3,6,7,9-11 . An ensemble of atoms can store a quantum state in the form of a magnon-which is a quantized collective spin excitation-that can be mapped onto a photon 12-18 with high efficiency 19 . Here, we report the phasecoherent transfer of a single magnon from one atomic ensemble to another via an optical resonator serving as a quantum bus that in the ideal case is only virtually populated. Partial transfer deterministically creates an entangled state with one excitation jointly stored in the two ensembles. The entanglement is verified by mapping the magnons onto photons, whose correlations can be directly measured. These results should enable deterministic multipartite entanglement between atomic ensembles.A quantum memory, that is, a device for storing and retrieving quantum states, is a key component of any quantum information processor. Optical memory access is highly desirable, as it is intrinsically fast and single photons are robust, easily controlled carriers of quantum states. Although a bit of quantum information (qubit) can be stored in a single two-level system, it can be expedient to instead use long-lived collective spin excitations of an atomic ensemble 12 . The ensemble can then be viewed as a 'macroatom' , whose excitations are quantized spin waves (magnons), such that transitions between its energy levels (magnon number states) correspond to highly directional (superradiant 20 ) photon emission or absorption 6,7,[12][13][14][15][16][17][18][19] .

We show that rubidium vapor can be produced within the core of a photonic band-gap fiber yielding an optical depth in excess of 2,000. Our technique for producing the vapor is based on coating the inner walls of the fiber core with organosilane and using light-induced atomic desorption to release Rb atoms into the core. As an initial demonstration of the potential of this system for supporting ultralow-level nonlinear optical interactions, we perform electromagnetically induced transparency with control-field powers in the nanowatt regime, which represents more than a 1,000-fold reduction from the power required for bulk, focused geometries.

We investigate resonant nonlinear optical interactions and demonstrate induced transparency in acetylene molecules in a hollow-core photonic-band-gap fiber at 1.5 mum. The induced spectral transmission window is used to demonstrate slow-light effects, and we show that the observed broadening of the spectral features is due to collisions of the molecules with the inner walls of the fiber core. Our results illustrate that such fibers can be used to facilitate strong coherent light-matter interactions even when the optical response of the individual molecules is weak.

We demonstrate a heralded quantum memory based on mapping of a photon polarization state onto a single collective-spin excitation (magnon) shared between two spatially overlapped atomic ensembles. The polarization fidelity is measured by quantum state tomography to be above 90(2)% for any input polarization, which far exceeds the classical limit of 2 3. The process also constitutes a quantum non-destructive probe that detects and regenerates a photon without touching itspotentially undetermined -polarization.The power of quantum communication can be boosted by quantum memories [1,2,3,4,5,6,7,8,9,10,11] that can receive, store, and release a quantum state typically carried by a photon. The advantages memories offer, however, are often thwarted by photon losses [1,12,13,14]. Such unpredictable failure may be largely remedied by a heralding feature that announces photon arrival and successful storage without destroying or revealing the stored quantum state. Heralded storage may thus advance long-distance quantum communication [1], linear-optics quantum computing [15], or schemes aimed at breaking quantum encryption [16].Quantum state storage has been investigated in various systems [2,3,4,5,6,7,8,9,10]. Atomic-ensemble quantum memories have been pursued both for continuous variables of electromagnetic fields [17,18], and for quantized photonic excitations [3,4,6,7,8,10,11]. In an elegant experiment, Julsgaard et. al.[18] mapped the quadrature variables of a weak coherent field onto an atomic ensemble through a field measurement and subsequent feedback onto the ensemble. Other advancements towards a continuous-variable memory include the recent demonstration of storage and retrieval of squeezed vacuum [19,20].Much progress has been made in the storage and retrieval of individual photons. Early work demonstrated capture and release of single photons of fixed polarization using electromagnetically induced transparency [6,7], as well as their adiabatic transfer between two ensembles via an optical resonator [21]. Matsukevich and Kuzmich showed that two atomic ensembles can serve as a twolevel system whose state can be prepared by a projective measurement [4]. Recently, Choi et. al. mapped photonic entanglement created by a polarizing beamsplitter onto two ensembles, and later retrieved the photon [11], realizing unheralded, but relatively high-efficiency, polarization storage. In work by Chen et. al., a successful Bell measurement between two photons resulted in probabilistic teleportation of a photon polarization state onto two atomic ensembles [22]. This can be viewed as a partially heralded quantum memory, where a two-photon coincidence between two beams with Poissonian statistics sometimes, but not always, heralds a successful Bell measurement and teleportation [22].In this Letter, we demonstrate a system where a single photon announces polarization storage in the form of a single collective-spin excitation (magnon) that is shared between two spatially overlapped atomic ensembles. The heralded storage occurs rarely...