Differentially Expressed Potassium Channels Are Associated with Function of Human Effector Memory CD8+T cells

The voltage-gated potassium channel, Kv1.3, and the Ca2+-activated potassium channel, KCa3.1, regulate membrane potentials in T cells, thereby controlling T cell activation and cytokine production. However, little is known about the expression and function of potassium channels in human effector memory ( EM) CD8+ T cells that can be further divided into functionally distinct subsets based on the expression of the interleukin ( IL)-7 receptor alpha ( IL-7R alpha) chain. Herein, we investigated the functional expression and roles of Kv1.3 and KCa3.1 in EM CD8+ T cells that express high or low levels of the IL-7 receptor alpha chain ( IL-7R alpha(high) and IL-7R alpha(low), respectively). In contrast to the significant activity of Kv1.3 and KCa3.1 in IL-7Rahigh EM CD8+ T cells, IL-7Ralow EM CD8+ T cells showed lower expression of Kv1.3 and insignificant expression of KCa3.1. Kv1.3 was involved in the modulation of cell proliferation and IL-2 production, whereas KCa3.1 affected the motility of EM CD8+ T cells. The lower motility of IL-7Ralow EM CD8+ T cells was demonstrated using transendothelial migration and motility assays with intercellular adhesion molecule 1-and/or chemokine stromal cell-derived factor-1 alpha-coated surfaces. Consistent with the lower migration property, IL-7Ralow EM CD8+ T cells were found less frequently in human skin. Stimulating IL-7Ralow EM CD8+ T cells with IL-2 or IL-15 increased their motility and recovery of KCa3.1 activity. Our findings demonstrate that Kv1.3 and KCa3.1 are differentially involved in the functions of EM CD8+ T cells. The weak expression of potassium channels in IL-7Ralow EM CD8+ T cells can be revived by stimulation with IL-2 or IL-15, which restores the associated functions. This study suggests that IL-7Rahigh EM CD8+ T cells with functional potassium channels may serve as a reservoir for effector CD8+ T cells during peripheral inflammation.112Ysciescopu

Transient expression of ZBTB32 in anti-viral CD8+ T cells limits the magnitude of the effector response and the generation of memory

Virus infections induce CD8+ T cell responses comprised of a large population of terminal effector cells and a smaller subset of long-lived memory cells. The transcription factors regulating the relative expansion versus the long-term survival potential of anti-viral CD8+ T cells are not completely understood. We identified ZBTB32 as a transcription factor that is transiently expressed in effector CD8+ T cells. After acute virus infection, CD8+ T cells deficient in ZBTB32 showed enhanced virus-specific CD8+ T cell responses, and generated increased numbers of virus-specific memory cells; in contrast, persistent expression of ZBTB32 suppressed memory cell formation. The dysregulation of CD8+ T cell responses in the absence of ZBTB32 was catastrophic, as Zbtb32-/- mice succumbed to a systemic viral infection and showed evidence of severe lung pathology. We found that ZBTB32 and Blimp-1 were co-expressed following CD8+ T cell activation, bound to each other, and cooperatively regulated Blimp-1 target genes Eomes and Cd27. These findings demonstrate that ZBTB32 is a key transcription factor in CD8+ effector T cells that is required for the balanced regulation of effector versus memory responses to infection

Chromatin accessibility of circulating CD8(+) T cells predicts treatment response to PD-1 blockade in patients with gastric cancer

Although tumor genomic profiling has identified small subsets of gastric cancer (GC) patients with clinical benefit from anti-PD-1 treatment, not all responses can be explained by tumor sequencing alone. We investigate epigenetic elements responsible for the differential response to anti-PD-1 therapy by quantitatively assessing the genome-wide chromatin accessibility of circulating CD8(+) T cells in patients' peripheral blood. Using an assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify unique open regions of chromatin that significantly distinguish anti-PD-1 therapy responders from non-responders. GC patients with high chromatin openness of circulating CD8(+) T cells are significantly enriched in the responder group. Concordantly, patients with high chromatin openness at specific genomic positions of their circulating CD8(+) T cells demonstrate significantly better survival than those with closed chromatin. Here we reveal that epigenetic characteristics of baseline CD8(+) T cells can be used to identify metastatic GC patients who may benefit from anti-PD-1 therapy. Anti-PD-1 therapy could induce a durable response in patients with gastric cancer, however biomarkers to predict response to immunotherapy are generally lacking. Here the authors report that openness of chromatin in circulating CD8(+) T cells predicts treatment outcome in patients with metastatic gastric cancer treated with pembrolizumab

Dual oxidase 1 and NADPH oxidase 2 exert favorable effects in cervical cancer patients by activating immune response

Background Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) not only can promote cancer progression, but also they have recently emerged as mediators of the mucosal immune system. However, the roles and clinical relevance of the collective or individual NADPH oxidase (NOX) family genes in cervical cancer have not been studied. Methods We investigated the clinical significance of the NOX family genes using data from 307 patients with cervical cancer obtained from The Cancer Genome Atlas. Bioinformatics and experimental analyses were performed to examine NOX family genes in cervical cancer patients. Results Dual Oxidase1 (DUOX1) and Dual Oxidase 2 (DUOX2) mRNA levels were upregulated 57.9- and 67.5-fold, respectively, in cervical cancer patients. The protein expression of DUOX1, DUOX2, and NOX2 also identified in cervical squamous cell carcinoma tissues. Especially, DUOX1 and DUOX2 mRNA levels were significantly increased in patients infected with human papillomavirus (HPV) 16. Moreover, high DUOX1 mRNA levels were significantly associated with both favorable overall survival and disease-free survival in cervical cancer patients. High NOX2 mRNA levels was significantly associated with favorable overall survival. Gene set enrichment analyses revealed that high DUOX1 and NOX2 expression was significantly correlated with the enrichment of immune pathways related to interferon (IFN)-alpha, IFN-gamma, and natural killer (NK) cell signaling. Cell-type identification by estimating relative subsets of known RNA transcript analyses indicated that the fraction of innate immune cells, including NK cells, monocytes, dendritic cells, and mast cells, was elevated in patients with high DUOX1 expression. Conclusions DUOX1 and NOX2 expression are associated with mucosal immunity activated in cervical squamous cell carcinoma and predicts a favorable prognosis in cervical cancer patients.This work was supported by a grant from Korea Institute of Oriental Medicine (K18123), National Research Foundation of Korea funded by the Korean government (NRF-2017R1C1B1004924) and Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government (NRF-2019M3E5D1A02068557). The funding bodies had no involvement in the design of the study, collection, analysis, and interpretation of data and in writing the manuscript

Microstructure and Hardness of Cu-22Sn-xC Alloys Fabricated by Powder Metallurgy

Cu-Sn alloys have been known as bronze since ancient times and widely used as electrode materials, ornaments, tableware and musical instruments. Cu-22Sn alloy fabrication by hot forging process is a Korean traditional forged high-tin bronze. The tin content is 22 percent, which is more than twice that of bronze ware traditionally used in China and the West. Copper and tin have a carbon solubility of several ppm at room temperature, making Cu-Sn-C alloys difficult to manufacture by conventional casting methods. Research on the production of carbon-added copper alloys has used a manufacturing method that is different from the conventional casting method. In this study, Cu-22Sn-xC alloy was fabricated by mechanical alloying and spark plasma sintering. The carbon solubility was confirmed in Cu-Sn alloy through mechanical alloying. The lattice parameter increased from A0 to C2, and then decreased from C4. The microstructural characteristics of sintered alloys were determined using X-ray diffraction and microscopic analysis. As a result of comparing the hardness of Cu-22Sn alloys manufactured by conventional rolling, casting, and forging and Cu-22Sn-xC alloy by sintered powder metallugy, B0 sintered alloy was the highest at about 110.9 HRB

Austenitic Stability and Strain-Induced Martensitic Transformation Behavior of Nanocrystalline FeNiCrMoC HSLA Steels

The austenitic stability and strain-induced martensitic transformation behavior of a nanocrystalline FeNiCrMoC alloy were investigated. The alloy was fabricated by high-energy ball milling and spark plasma sintering. The phase fraction and grain size were measured using X-ray diffraction. The grain sizes of the milled powder and the sintered alloy were confirmed to be on the order of several nanometers. The variation in the austenite fraction according to compressive deformation was measured, and the austenite stability and strain-induced martensitic transformation behavior were calculated. The hardness was measured to evaluate the mechanical properties according to compression deformation, which confirmed that the hardness increased to 64.03 HRC when compressed up to 30%

Immunization with a recombinant antigen composed of conserved blocks from TSA56 provides broad genotype protection against scrub typhus

Scrub typhus is an acute febrile disease caused by Orientia tsutsugamushi infection. Despite the wide range of approaches explored during the last seventy years, an effective prophylactic vaccine is not yet available. Here, we developed a novel recombinant antigen derived from conserved regions of 56kDa type-specific antigen (TSA56), a major outer membrane protein responsible for genetic heterogeneity and antigenicity, and evaluated it as a protective vaccine antigen. Our findings demonstrate that immunization with conserved blocks of TSA56 (cTSA56) not only provides protective immunity against lethal challenges with the homologous genotype, but also confers significantly better protection against heterologous genotypes than TSA56. Adoptive transfer of CD4(+) or CD8(+) T cells from immunized mice provided significantly enhanced protection against lethal challenge, whereas immune B cells failed to do so, indicating that cellular immunity against the conserved epitopes plays a protective role. Moreover, immunization with a 10-mer peptide mixture, screened from CD8(+) T cell epitopes within the conserved region of TSA56, provided enhanced protection against lethal challenge with O. tsutsugamushi. Therefore, this novel recombinant antigen is a promising candidate for scrub typhus vaccine against a wide range of O. tsutsugamushi genotypes.OAIID:RECH_ACHV_DSTSH_NO:T201915551RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A079480CITE_RATE:6.032DEPT_NM:의과학과EMAIL:[email protected]_YN:YY

Effect of Sintering Holding Time and Cooling Rate on the Austenite Stability and Mechanical Properties of Nanocrystalline FeCrC Alloy

The effects of the sintering holding time and cooling rate on the microstructure and mechanical properties of nanocrystalline Fe-Cr-C alloy were investigated. Nanocrystalline Fe-1.5Cr-1C (wt.%) alloy was fabricated by mechanical alloying and spark plasma sintering. Different process conditions were applied to fabricate the sintered samples. The phase fraction and grain size were measured using X-ray powder diffraction and confirmed by electron backscatter diffraction. The stability and volume fraction of the austenite phase, which could affect the mechanical properties of the Fe-based alloy, were calculated using an empirical equation. The sample names consist of a number and a letter, which correspond to the holding time and cooling method, respectively. For the 0A, 0W, 10A, and 10W samples, the volume fraction was measured at 5.56, 44.95, 6.15, and 61.44 vol.%. To evaluate the mechanical properties, the hardness of 0A, 0W, 10A, and 10W samples were measured as 44.6, 63.1, 42.5, and 53.8 HRC. These results show that there is a difference in carbon diffusion and solubility depending on the sintering holding time and cooling rate

Urbanization of scrub typhus disease in South Korea.

BACKGROUND:Scrub typhus is an endemic disease in Asia. It has been a rural disease, but indigenous urban cases have been observed in Seoul, South Korea. Urban scrub typhus may have a significant impact because of the large population. METHODS:Indigenous urban scrub typhus was epidemiologically identified in Seoul, the largest metropolitan city in South Korea, using national notifiable disease data from 2010 to 2013. For detailed analysis of clinical features, patients from one hospital that reported the majority of cases were selected and compared to a historic control group. Chigger mites were prospectively collected in the city using a direct chigger mite-collecting trap, and identified using both phenotypic and 18S rDNA sequencing analyses. Their infection with Orientia tsutsugamushi was confirmed by sequencing the 56-kDa antigen gene. RESULTS:Eighty-eight cases of urban scrub typhus were determined in Seoul. The possible sites of infection were mountainous areas (56.8%), city parks (20.5%), the vicinity of one's own residence (17.0%), and riversides (5.7%). Eighty-seven chigger mites were collected in Gwanak mountain, one of the suspected infection sites in southern Seoul, and seventy-six (87.4%) of them were identified as Helenicula miyagawai and eight (9.2%) as Leptotrombidium scutellare. Pooled DNA extracted from H. miyagawai mites yielded O. tsutsugamushi Boryong strain. Twenty-six patients from one hospital showed low APACHE II score (3.4 ± 2.7), low complication rate (3.8%), and no hypokalemia. CONCLUSIONS:We identified the presence of indigenous urban scrub typhus in Seoul, and a subgroup of them had mild clinical features. The chigger mite H. miyagawai infected with O. tsutsugamushi within the city was found. In endemic area, urban scrub typhus needs to be considered as one of the differential febrile diseases and a target for prevention