Diabetes can be ameliorated by additive AIRE expression in peripheral DCs
Abstract
Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune ...tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms.
Phase relations in the pseudobinary system ZnO-Ga2O3 were investigated at 1723 K. The homologous phase Ga2O3(ZnO)m was formed in a region 9 ≦ n ≦ 38 for ZnO: Ga2O3 = n: 1, and Ga-doped ZnO (wurtzite ...structure) was in n ≧ 398. In between the two regions (i.e. 38 < n < 398) a composite of Ga-doped ZnO and the homologous phase Ga2O3(ZnO)mmax (mmax ≈ 38) was formed. Thermoelectric properties of the composite were examined along with Ga-doped ZnO and the homologous phase Ga2O3(ZnO)33. In the composite, the homologous phase appears to be very effective in lowering the thermal conductivity. As a result of a trade-off relationship between the power factor and the thermal resistivity, thermoelectric performance happened to be roughly the same for the composite and Ga-doped ZnO samples.
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•Phase relations in the pseudobinary system ZnO-Ga2O3 at 1723 K were presented.•A composite of Ga-doped ZnO and the homologous phase Ga2O3(ZnO)m was formed in a part of the phase diagram.•The homologous phase is effective in lowering the thermal conductivity in the composite.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
With recent advances in immune checkpoint inhibitors (ICIs), immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined ...empirically, taking individually conducted clinical trials into consideration, but without a standard method to evaluate them. Here we establish an advanced imaging system to visualize human PD-1 microclusters, in which a minimal T cell receptor (TCR) signaling unit co-localizes with the inhibitory co-receptor PD-1 in vitro. In these microclusters PD-1 dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2, upon stimulation with the ligand hPD-L1. In this system, blocking antibodies for hPD-1-hPD-L1 binding inhibits hPD-1 microcluster formation, and each therapeutic antibody (pembrolizumab, nivolumab, durvalumab and atezolizumab) is characterized by a proprietary optimal concentration and combinatorial efficiency enhancement. We propose that our imaging system could digitally evaluate PD-1-mediated T cell suppression to evaluate their clinical usefulness and to develop the most suitable combinations among ICIs or between ICIs and conventional cancer treatments.
In this paper, we report the synthesis, microstructure and some piezoelectric properties of (Bi0.5Na0.5)1−xBaxTi1−x(Fe0.5Nb0.5)xO3 (abbreviated as BNBTFN, x=0.000, 0.025, 0.050, 0.065, 0.075 and ...0.100). The BNBTFN powders were prepared by solid-state reaction method, and their green compacts were sintered at 1150°C for 2h. XRD study confirmed that there was no second phase for all the compositions. Morphotropic phase boundary (MPB) of rhombohedral and tetragonal phases existed at x∼0.050, which was close to that of the BNT-BT system. With increasing x, diffuse phase transition, decrease in transition temperature (Tm), and increase in dielectric maximum at the transition temperature (εrm) were observed. The A and B sites simultaneous substitutions, i.e. Ba2+ into (Bi0.5Na0.5)2+ and (Fe0.5Nb0.5)4+ into Ti4+, have some positive effects on piezoelectric properties for x⩽0.05 of (Bi0.5Na0.5)1−xBaxTi1−x(Fe0.5Nb0.5)xO3, despite the lowering of depolarization temperature.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Medullary thymic epithelial cells (mTECs), which express a wide range of tissue-restricted Ags (TRAs), contribute to the establishment of self-tolerance by eliminating autoreactive T cells and/or ...inducing regulatory T cells. Aire controls a diverse set of TRAs within Aire-expressing cells by employing various transcriptional pathways. As Aire has a profound effect on transcriptomes of mTECs, including TRAs not only at the single-cell but also the population level, we suspected that Aire (Aire
mTECs) might control the cellular composition of the thymic microenvironment. In this study, we confirmed that this is indeed the case by identifying a novel mTEC subset expressing Ly-6 family protein whose production was defective in Aire-deficient thymi. Reaggregated thymic organ culture experiments demonstrated that Aire did not induce the expression of Ly-6C/Ly-6G molecules from mTECs as Aire-dependent TRAs in a cell-intrinsic manner. Instead, Aire
mTECs functioned in
to maintain Ly-6C/Ly-6G
mTECs. Thus, Aire not only controls TRA expression transcriptionally within the cell but also controls the overall composition of mTECs in a cell-extrinsic manner, thereby regulating the transcriptome from mTECs on a global scale.
The nucleus in eukaryotic cells is a highly organized and dynamic structure containing numerous subnuclear bodies. The morphological appearance of nuclear bodies seems to be a reflection of ongoing ...functions, such as DNA replication, transcription, repair, RNA processing and RNA transport. The integrator complex mediates processing of small nuclear RNA (snRNA), so it might play a role in nuclear body formation. Here, we show that the integrator complex is essential for integrity of the Cajal body. Depletion of INTS4, an integrator complex subunit, abrogated 3'-end processing of snRNA. A defect in this activity caused a significant accumulation of the Cajal body marker protein coilin in nucleoli. Some fractions of coilin still formed nucleoplasmic foci; however, they were free of other Cajal body components, such as survival of motor neuron protein (SMN), Sm proteins and snRNAs. SMN and Sm proteins formed striking cytoplasmic granules. These findings demonstrate that the integrator complex is essential for snRNA maturation and Cajal body homeostasis.
Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) play essential roles in the positive and negative selection of developing thymocytes, respectively. Aire in ...mTECs plays an essential role in the latter process through expression of broad arrays of tissue-restricted Ags. To determine whether the location of Aire within the medulla is absolutely essential or whether Aire could also function within the cortex for establishment of self-tolerance, we used bacterial artificial chromosome technology to establish a semiknockin strain of NOD-background (β5t/Aire-transgenic) mice expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. Although Aire was expressed in cTECs as typical nuclear dot protein in β5t/Aire-Tg mice, cTECs expressing Aire ectopically did not confer transcriptional expression of either Aire-dependent or Aire-independent tissue-restricted Ag genes. We then crossed β5t/Aire-Tg mice with Aire-deficient NOD mice, generating a strain in which Aire expression was confined to cTECs. Despite the presence of Aire(+) cTECs, these mice succumbed to autoimmunity, as did Aire-deficient NOD mice. The thymic microenvironment harboring Aire(+) cTECs, within which many Aire-activated genes were present, also showed no obvious alteration of positive selection, suggesting that Aire's unique property of generating a self-tolerant T cell repertoire is functional only in mTECs.
Autoimmunity is prevented by the function of the autoimmune regulator AIRE (Aire in mice), which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic ...epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire.
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•Aire in the thymus and periphery prevents autoimmunity by self-antigen expression.•Mice overexpressing AIRE/Aire paradoxically developed muscle-specific autoimmunity due to the altered development of mTEC.•Level of Aire expression must be tightly controlled to maintain self-tolerance.•Altered AIRE expression might be a feasible mechanism of autoimmunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Actin and actin-related proteins (Arps), which are members of the actin family, are essential components of many of these remodeling complexes. Actin, Arp4, Arp5, and Arp8 are found to be ...evolutionarily conserved components of the INO80 chromatin remodeling complex, which is involved in transcriptional regulation, DNA replication, and DNA repair. A recent report showed that Arp8 forms a module in the INO80 complex and this module can directly capture a nucleosome. In the present study, we showed that recombinant human Arp8 binds to DNAs, and preferentially binds to single-stranded DNA. Analysis of the binding of adenine nucleotides to Arp8 mutants suggested that the ATP-binding pocket, located in the evolutionarily conserved actin fold, plays a regulatory role in the binding of Arp8 to DNA. To determine the cellular function of Arp8, we derived tetracycline-inducible Arp8 knockout cells from a cultured human cell line. Analysis of results obtained after treating these cells with aphidicolin and camptothecin revealed that Arp8 is involved in DNA repair. Together with the previous observation that Arp8, but not γ-H2AX, is indispensable for recruiting INO80 complex to DSB in human, results of our study suggest an individual role for Arp8 in DNA repair.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Porous Al2TiO5 ceramics with various starches as pore-forming agents have been prepared by the reactive sintering method using fine-grained starting materials. Commercially available corn, potato and ...rice starches were used as the pore forming agents. TG–DTA and XRD studies revealed that the rice starch most promoted the formation of Al2TiO5 among the three starches, presumably due to its strong heat flow during the combustion. Al2TiO5 samples sintered with each starch contained a bimodal pore-size distribution, viz., slit-like pores with the size of <~20 µm, and continuous open-pores with the size of several µm. The thermal expansion behavior of the sample with 30 wt.% rice starch was similar to those without starch.
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