activated t cells
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2022 ◽  
Vol 12 (3) ◽  
pp. 544-550
Author(s):  
Shuo Yang ◽  
Jincheng Sima ◽  
Wenbo Liao

Bone marrow mesenchymal stem cells (BMSCs) can release a large amount of exosomes (EXO) during bone remodeling by osteoclasts. EXO contains miRNA-211, which has a variety of biological effects. However, little is known about whether miR-211 from BMSC-EXO affects the surrounding cells. Therefore, we aim to study the role of miRNA-211 derived from BMSC-EXO in regulating osteoclasts differentiation. Macrophage colony stimulating factor (M-CSF) and nuclear factor kappa B receptor activator (RANKL) were used to stimulate bone marrow macrophages (BMM) to obtain osteoclasts, which were treated with BMSC-EXO or LPS followed by analysis of osteoclast-related genes expression by PCR, ROS release by flow cytometry, actin ring formation by immunofluorescence, and osteoclast differentiation by anti-tartrate acid phosphatase (TRAP) staining. Finally, an in vivo experiment was conducted to verify BMSC-EXO’s effect on osteoporosis. BMSC-EXO significantly inhibited RNAKL-induced osteoclast differentiation of BMMs. During osteoclasts formation, BMSC-EXO inhibited ROS production induced by RANKL and the subsequent activation of NF-κB signaling pathway induced by ROS. In addition, BMSC-EXO significantly down-regulated the osteoclast genes including nuclear factor, cytoplasmic 1 (NFATc1), C-fos, tartrate-resistant acid phosphatase (TRAP) and osteoclast-associated immunoglobulin-like receptor (OSCAR) in activated T cells. BMSC-EXO inhibited ROS release by promoting miR-211 expression, thereby inhibiting the NF-κB signaling and ultimately participating in osteoclasts differentiation. In LPS-induced mouse osteoporosis models, BMSC-EXO inhibited LPS-induced bone loss and exerted a protective effect. In conclusion, microRNA-211 derived from BMSC-EXO can regulate osteoclasts differentiation, suggesting that it might be used as a potential approach for treating osteoporosis.


Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 160
Author(s):  
Hirohito Ogawa ◽  
Daisuke Fujikura ◽  
Hikaru Namba ◽  
Nobuko Yamashita ◽  
Tomoyuki Honda ◽  
...  

Human herpesvirus 6B (HHV-6B) is a T-lymphotropic virus and the etiological agent of exanthem subitum. HHV-6B is present in a latent or persistent form after primary infection and is produced in the salivary glands or transmitted to this organ. Infected individuals continue to secrete the virus in their saliva, which is thus considered a source for virus transmission. HHV-6B primarily propagates in T cells because its entry receptor, CD134, is mainly expressed by activated T cells. The virus then spreads to the host’s organs, including the salivary glands, nervous system, and liver. However, CD134 expression is not detected in these organs. Therefore, HHV-6B may be entering cells via a currently unidentified cell surface molecule, but the mechanisms for this have not yet been investigated. In this study, we investigated a CD134-independent virus entry mechanism in the parotid-derived cell line HSY. First, we confirmed viral infection in CD134-membrane unanchored HSY cells. We then determined that nectin cell adhesion molecule 2 (nectin-2) mediated virus entry and that HHV-6B-insensitive T-cells transduced with nectin-2 were transformed into virus-permissive cells. We also found that virus entry was significantly reduced in nectin-2 knockout parotid-derived cells. Furthermore, we showed that HHV-6B glycoprotein B (gB) interacted with the nectin-2 V-set domain. The results suggest that nectin-2 acts as an HHV-6B entry-mediated protein.


2022 ◽  
Author(s):  
Marianna Halasi ◽  
Mor Grinstein ◽  
Avner Adini ◽  
Irit Adini

Epidemiological studies have linked pigment production to protection against certain human diseases. In contrast to African Americans, European descendants are more likely to suffer from angiogenesis-dependent diseases, and inflammatory diseases such as wet age-related macular degeneration (ARMD) and ulcerative colitis (UC), respectively. Here, we found that albino mice producing high levels of fibromodulin (FMOD) developed less severe acute colitis than mice lacking FMOD as assessed by the clinical symptoms and the histopathological changes. In a dextran sodium sulfate (DSS)-induced acute colitis mouse model, depletion of FMOD affected the expression and localization of tight junction proteins contributing to destruction of the epithelial barrier. Furthermore, this study demonstrates the development of a stronger inflammatory response after DSS treatment in the absence of FMOD. FMOD depletion led to an increase in activated T cells, plasmacytoid dendritic cells (pDCs), and type I IFN production. These findings strongly suggest that FMOD may serve as a potential biomarker in determining disease severity of UC in the population of light-skinned individuals with European descent.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Young-Il Kim ◽  
Kwang-Min Yu ◽  
June-Young Koh ◽  
Eun-Ha Kim ◽  
Se-Mi Kim ◽  
...  

AbstractWhile the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger individuals. To further understand differing COVID-19 manifestations in patients of different ages, three age groups of ferrets are infected with SARS-CoV-2. Although SARS-CoV-2 is isolated from all ferrets regardless of age, aged ferrets (≥3 years old) show higher viral loads, longer nasal virus shedding, and more severe lung inflammatory cell infiltration, and clinical symptoms compared to juvenile (≤6 months) and young adult (1–2 years) groups. Furthermore, direct contact ferrets co-housed with the virus-infected aged group shed more virus than direct-contact ferrets co-housed with virus-infected juvenile or young adult ferrets. Transcriptome analysis of aged ferret lungs reveals strong enrichment of gene sets related to type I interferon, activated T cells, and M1 macrophage responses, mimicking the gene expression profile of severe COVID-19 patients. Thus, SARS-CoV-2-infected aged ferrets highly recapitulate COVID-19 patients with severe symptoms and are useful for understanding age-associated infection, transmission, and pathogenesis of SARS-CoV-2.


Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 162
Author(s):  
Ruoxuan Sun ◽  
Alyssa Min Jung Kim ◽  
Allison A. Murray ◽  
Seung-Oe Lim

Leveraging the T cell immunity against tumors represents a revolutionary type of cancer therapy. 4-1BB is a well-characterized costimulatory immune receptor existing on activated T cells and mediating their proliferation and cytotoxicity under infectious diseases and cancers. Despite the accumulating interest in implementing 4-1BB as a therapeutic target for immune-related disorders, less is known about the pattern of its intracellular behaviors and regulations. It has been previously demonstrated that 4-1BB is heavily modified by N-glycosylation; however, the biological importance of this modification lacks detailed elucidation. Through biochemical, biophysical, and cell-biological approaches, we systematically evaluated the impact of N-glycosylation on the ligand interaction, stability, and localization of 4-1BB. We hereby highlighted that N-glycan functions by preventing the oligomerization of 4-1BB, thus permitting its membrane transportation and fast turn-over. Without N-glycosylation, 4-1BB could be aberrantly accumulated intracellularly and fail to be sufficiently inserted in the membrane. The N-glycosylation-guided intracellular processing of 4-1BB serves as the potential mechanism explicitly modulating the “on” and “off” of 4-1BB through the control of protein abundance. Our study will further solidify the understanding of the biological properties of 4-1BB and facilitate the clinical practice against this promising therapeutic target.


2022 ◽  
Vol 12 ◽  
Author(s):  
Sungyub Lee ◽  
Minsun Kim ◽  
Sooyeon Hong ◽  
Eom Ji Kim ◽  
Jae-Hyun Kim ◽  
...  

Postmenopausal osteoporosis is caused by an imbalance between osteoclasts and osteoblasts and causes severe bone loss. Osteoporotic medicines are classified into bone resorption inhibitors and bone formation promoters according to the mechanism of action. Long-term use of bisphosphonate and selective estrogen receptor modulators (SERMs) can cause severe side effects in postmenopausal osteoporosis patients. Therefore, it is important to find alternative natural products that reduce osteoclast activity and increase osteoblast formation. Sparganii Rhizoma (SR) is the dried tuberous rhizome of Sparganium stoloniferum Buchanan-Hamilton and is called “samreung” in Korea. However, to date, the effect of SR on osteoclast differentiation and the ovariectomized (OVX)-induced bone loss model has not been reported. In vitro, tartrate-resistant acid phosphatase (TRAP) staining, western blots, RT-PCR and other methods were used to examine the effect of SR on osteoclast differentiation and osteoblasts. In vivo, we confirmed the effect of SR in a model of OVX-induced postmenopausal osteoporosis. SR inhibited osteoclast differentiation and decreased the expression of TNF receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells 1 (NFATc1) and c-Fos pathway. In addition, SR stimulates osteoblast differentiation and increased protein expression of the bone morphogenetic protein 2 (BMP-2)/SMAD signaling pathway. Moreover, SR protected against bone loss in OVX-induced rats. Our results appear to advance our knowledge of SR and successfully demonstrate its potential role as a osteoclastogenesis-inhibiting and osteogenesis-promoting herbal medicine for the treatment of postmenopausal osteoporosis.


2022 ◽  
Author(s):  
Aleksandra Vuchkovska ◽  
David Glanville ◽  
Gina Scurti ◽  
Paula White ◽  
Michael I Nishimura ◽  
...  

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of immunoglobulin-type lectins that mediate protein-carbohydrate interactions via sialic acids attached to glycoproteins or glycolipids. Most of the CD33-related Siglecs (CD33rSiglecs), a major subfamily of rapidly evolving Siglecs, contain a cytoplasmic signaling domain consisting of the immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) and mediate suppressive signals for lymphoid and myeloid cells. While most CD33rSiglecs are expressed by innate immune cells, such as monocytes and neutrophils, to date, the expression of Siglecs in human T cells has not been well appreciated. In this study, we found that Siglec-5, a member of the CD33rSiglecs, is expressed by most activated T cells upon antigen receptor stimulation. Functionally, Siglec-5 suppresses T cell activation. In support of these findings, we found that Siglec-5 overexpression abrogates antigen receptor induced activation of Nuclear factor of activated T cells (NFAT) and Activator protein 1 (AP-1). Furthermore, we show that GBS β-protein, a known bacterial ligand of Siglec-5, reduces the production of cytokines and cytolytic molecules by activated primary T cells in a Siglec-5 dependent manner. Our data also show that some cancer cell lines express a putative Siglec-5 ligand(s), and that the presence of soluble Siglec-5 enhances tumor-cell specific T cell activation, suggesting that some tumor cells inhibit T cell activation via Siglec-5. Together, our data demonstrate that Siglec-5 is a previously unrecognized inhibitory T cell immune checkpoint molecule and suggests that blockade of Siglec-5 could serve as a new strategy to enhance anti-tumor T cell functions.


2022 ◽  
Vol 12 ◽  
Author(s):  
Hai Zhou ◽  
Hongcheng Lu ◽  
Li Sun ◽  
Zijie Wang ◽  
Ming Zheng ◽  
...  

T cell-mediated rejection (TCMR) is an important rejection type in kidney transplantation, characterized by T cells and macrophages infiltration. The application of bioinformatic analysis in genomic research has been widely used. In the present study, Microarray data was analyzed to identify the potential diagnostic markers of TCMR in kidney transplantation. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) was performed to determine the distribution of immune cell infiltration in the pathology. Totally 129 upregulated differently expressed genes (DEGs) and 378 downregulated DEGs were identified. The GO and KEGG results demonstrated that DEGs were mainly associated with pathways and diseases involved in immune response. The intersection of the two algorithms (PPI network and LASSO) contains three overlapping genes (CXCR6, CXCL13 and FCGR1A). After verification in GSE69677, only CXCR6 and CXCL13 were selected. Immune cells Infiltration analysis demonstrated that CXCR6 and CXCL13 were positively correlated with gamma delta T cells (p < 0.001), CD4+ memory activated T cells (p < 0.001), CD8+ T cells (p < 0.001) and M1 macrophages (p = 0.006), and negatively correlated with M2 macrophages (p < 0.001) and regulatory T cells (p < 0.001). Immunohistochemical staining and image analysis confirmed the overexpression of CXCR6 and CXCL13 in human allograft TCMR samples. CXCR6 and CXCL13 could be diagnostic biomarkers of TCMR and potential targets for immunotherapy in patients with TCMR.


2022 ◽  
Vol 12 ◽  
Author(s):  
Francisca Ugarte ◽  
Daniela Santapau ◽  
Vivian Gallardo ◽  
Carolina Garfias ◽  
Anahí Yizmeyián ◽  
...  

BackgroundTubular damage has a role in Diabetic Kidney Disease (DKD). We evaluated the early tubulointerstitial damage biomarkers in type-1 Diabetes Mellitus (T1DM) pediatric participants and studied the correlation with classical DKD parameters.MethodsThirty-four T1DM and fifteen healthy participants were enrolled. Clinical and biochemical parameters [Glomerular filtration Rate (GFR), microalbuminuria (MAU), albumin/creatinine ratio (ACR), and glycated hemoglobin A1c (HbA1c)] were evaluated. Neutrophil gelatinase-associated lipocalin (NGAL), Hypoxia-inducible Factor-1α (HIF-1α), and Nuclear Factor of Activated T-cells-5 (NFAT5) levels were studied in the supernatant (S) and the exosome-like extracellular vesicles (E) fraction from urine samples.ResultsIn the T1DM, 12% had MAU >20 mg/L, 6% ACR >30 mg/g, and 88% had eGFR >140 ml/min/1.72 m2. NGAL in the S (NGAL-S) or E (NGAL-E) fraction was not detectable in the control. The NGAL-E was more frequent (p = 0.040) and higher (p = 0.002) than NGAL-S in T1DM. The T1DM participants with positive NGAL had higher age (p = 0.03), T1DM evolution (p = 0.03), and serum creatinine (p = 0.003) than negative NGAL. The NGAL-E correlated positively with tanner stage (p = 0.0036), the median levels of HbA1c before enrollment (p = 0.045) and was independent of ACR, MAU, and HbA1c at the enrollment. NFAT5 and HIF-1α levels were not detectable in T1DM or control.ConclusionUrinary exosome-like extracellular vesicles could be a new source of early detection of tubular injury biomarkers of DKD in T1DM patients.


EBioMedicine ◽  
2022 ◽  
Vol 75 ◽  
pp. 103765
Author(s):  
Ayelén Aluminé Iglesias ◽  
Natalia Períolo ◽  
Carla María Bellomo ◽  
Lorena Cecilia Lewis ◽  
Camila Paula Olivera ◽  
...  

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