Abstract
Memory T cells contribute to rapid viral clearance during re-infection, but the longevity and differentiation of SARS-CoV-2-specific memory T cells remain unclear. Here we conduct ex vivo ...assays to evaluate SARS-CoV-2-specific CD4
+
and CD8
+
T cell responses in COVID-19 convalescent patients up to 317 days post-symptom onset (DPSO), and find that memory T cell responses are maintained during the study period regardless of the severity of COVID-19. In particular, we observe sustained polyfunctionality and proliferation capacity of SARS-CoV-2-specific T cells. Among SARS-CoV-2-specific CD4
+
and CD8
+
T cells detected by activation-induced markers, the proportion of stem cell-like memory T (T
SCM
) cells is increased, peaking at approximately 120 DPSO. Development of T
SCM
cells is confirmed by SARS-CoV-2-specific MHC-I multimer staining. Considering the self-renewal capacity and multipotency of T
SCM
cells, our data suggest that SARS-CoV-2-specific T cells are long-lasting after recovery from COVID-19, thus support the feasibility of effective vaccination programs as a measure for COVID-19 control.
Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress ...syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1β-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1β-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.
Stress granules (SGs) are stalled translation initiation complexes comprising untranslated mRNAs and RNA-binding proteins (RBPs). RBP fox-1 homolog 2 (Rbfox2), a component of SGs, binds to ...retinoblastoma 1 (RB1) mRNA, which is closely related to cancer progression; however, the role of Rbfox2 in cancer progression remains largely unknown. In this study, we confirmed that Rbfox2, which is present in the nucleus as a splicing regulator, localizes to the cytoplasm of human colon cancer tissues and that induction of Rbfox2 dissociation from SGs by resveratrol treatment inhibits cancer progression. We also observed that Rbfox2 in SGs inhibited RB1 protein expression and promoted cell cycle progression. Additionally, resveratrol treatment inhibited SG-mediated Rbfox2 localization, further inhibiting RB1 protein expression, and inhibited specific Rbfox2 localization to the cytoplasm in melanoma B16-F10 cells, thereby effectively inhibiting metastasis and tumor growth ability. These results indicate that Rbfox2 dissociation from SGs attenuates cancer progression and offer insight into the mechanism associated with Rbfox2 dissociation, thereby marking Rbfox2 as a potential candidate target for cancer therapy.
Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8+ T cells by MHC ...class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer+ cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer+ cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8+ T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1+ cells than PD-1− cells among multimer+ cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8+ T cells elicited by infection or vaccination.
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•SARS-CoV-2-specific CD8+ T cells are effector memory cells in convalescents•CCR7+CD45RA+ cells are increased among SARS-CoV-2-specific cells in the late phase•SARS-CoV-2-specific CD8+ T cells have fewer IFN-γ+ cells than flu-specific cells•PD-1-expressing SARS-CoV-2-specific CD8+ T cells are not exhausted but functional
T cell responses have been demonstrated in COVID-19 patients, but ex vivo phenotypes and functions of SARS-CoV-2-specific T cells remain unclear. Rha et al. examined SARS-CoV-2-specific CD8+ T cells in acute and convalescent COVID-19 patients using MHC class I multimers, finding that PD-1-expressing SARS-CoV-2-specific CD8+ T cells are not exhausted but functional.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The liver is a critical immunological site for chronic alcohol consumption as it filters various antigens activating both innate and adaptive responses. The pathogenesis of alcoholic liver ...disease (ALD) in human is not clear in terms of the specific role of immune cell population. Mucosal associated invariant T (MAIT) cells are found to be abundant in the mucosal organs, especially within the liver organ in which the cells comprise up to 50 % of T cells. Here, we show that the percentage of circulating MAIT cells is severely reduced in ALD patients (p=0.0028), including patients with steatohepatitis (ASH, n=20), steatohepatitis with cirrhosis (ASHAC, n=15) and cirrhosis (AC, n=12), compared to age-matched healthy donors (HD, n=8). Moreover, compared to non-liver disease group, MAIT cells are depleted among liver infiltrating lymphocytes in ASH (p=0.0276) and ASHAC (p=0.0049) patients, whereas that of AC group is recovered. Although the percentage of MAIT cells is decreased, the cells display increased expression level of activation markers. Pro-inflammatory cytokines such as IL-17A and MIP-1 beta are up-regulated in ASH and ASHAC patients by PMA/Ionomycin stimulation. In addition, Perforin and Granzyme B, which are cytotoxic markers in granule, are significantly increased in both peripheral blood and liver of ASHAC group. Taken together, our results suggest that activated MAIT cell population in the liver may contribute to the pathogenesis of ALD.
Abstract
IL-15 induces the proliferation of memory CD8+ T cells as well as NK cells. The expression of CD5 inversely correlates with the IL-15 responsiveness of human memory CD8+ T cells. However, ...whether CD5 directly regulates IL-15–induced proliferation of human memory CD8+ T cells is unknown. In the current study, we demonstrate that human memory CD8+ T cells in advanced stages of differentiation respond to IL-15 better than human memory CD8+ T cells in stages of less differentiation. We also found that the expression level of CD5 is the best correlate for IL-15 hyporesponsiveness among human memory CD8+ T cells. Importantly, we found that IL-15–induced proliferation of human memory CD8+ T cells is significantly enhanced by blocking CD5 with Abs or knocking down CD5 expression using small interfering RNA, indicating that CD5 directly suppresses the IL-15–induced proliferation of human memory CD8+ T cells. We also found that CD5 inhibits activation of the mTOR pathway, which is required for IL-15–induced proliferation of human memory CD8+ T cells. Taken together, the results indicate that CD5 is not just a correlative marker for IL-15 hyporesponsiveness, but it also directly suppresses IL-15–induced proliferation of human memory CD8+ T cells by inhibiting mTOR pathways.
Immune checkpoint inhibitors (ICIs), such as anti-PD-1 and anti-PD-L1 Abs, have shown efficacy for the treatment of various cancers. Although research has actively sought to develop new ICIs and ...immunomodulators, no efficient
assay system is available to evaluate their functional activities. In the present study, we established a two-round MLR with human PBMCs for evaluation of the T cell-activating capacity of anti-PD-1 and other immunomodulators. We initially performed conventional MLR for this purpose. However, anti-PD-1 blocking Abs could not increase the proliferation of allo-reactive T cells in conventional MLR because PD-L1
and PD-L2
cells disappeared gradually during MLR. Therefore, we re-applied the same stimulator PBMCs to the allo-stimulated responder cells as a second-round MLR on day 6 when anti-PD-1 or immunomodulators were also added. In this two-round MLR, the proliferation of allo-reactive T cells was enhanced by anti-PD-1 in a dose-dependent manner or by immunomodulators, such as lenalidomide and galunisertib, a TGF-β receptor-1 inhibitor. Proliferation was further increased by the combination of immunomodulators with anti-PD-1. Here, we established a modified two-round MLR method with human PBMCs for evaluation of the functional activities of anti-PD-1 and immunomodulators.
We present the discovery and mass measurement of the cold, low-mass planet MOA-2009-BLG-266Lb, performed with the gravitational microlensing method. This planet has a mass of mp = 10.4 ? 1.7 ...M{circled plus} and orbits a star of mass M = 0.56 ? 0.09 M at a semimajor axis of AU and an orbital period of yrs. The planet and host star mass measurements are enabled by the measurement of the microlensing parallax effect, which is seen primarily in the light curve distortion due to the orbital motion of the Earth. But the analysis also demonstrates the capability to measure the microlensing parallax with the Deep Impact (or EPOXI) spacecraft in a heliocentric orbit. The planet mass and orbital distance are similar to predictions for the critical core mass needed to accrete a substantial gaseous envelope, and thus may indicate that this planet is a 'failed' gas giant. This and future microlensing detections will test planet formation theory predictions regarding the prevalence and masses of such planets.
Collaborations in astronomy and astrophysics are faced with numerous cyber-infrastructure challenges, such as large data sets, the need to combine heterogeneous data sets, and the challenge to ...effectively collaborate on those large, heterogeneous data sets with significant processing requirements and complex science software tools. The cyberhubs system is an easy-to-deploy package for small- to medium-sized collaborations based on the Jupyter and Docker technology, which allows web-browser-enabled, remote, interactive analytic access to shared data. It offers an initial step to address these challenges. The features and deployment steps of the system are described, as well as the requirements collection through an account of the different approaches to data structuring, handling, and available analytic tools for the NuGrid and PPMstar collaborations. NuGrid is an international collaboration that creates stellar evolution and explosion physics and nucleosynthesis simulation data. The PPMstar collaboration performs large-scale 3D stellar hydrodynamics simulations of interior convection in the late phases of stellar evolution. Examples of science that is currently performed on cyberhubs, in the areas of 3D stellar hydrodynamic simulations, stellar evolution and nucleosynthesis, and Galactic chemical evolution, are presented.
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