bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCL22 impedes T cell activation capacities of dendritic cells by reducing membrane expression of MHC molecules and CD80
Authors: Kühnemuth Benjamin , Piseddu Ignazio , Knott Maximilian , Vetter Viola , Layritz Patrick , Endres Stefan , Anz David 
Published: January 2023

Abstract
The chemokine CCL22 is a well known modulator of immune responses. By binding to its receptor CCR4, which is highly expressed on several T cell subtypes as well as dendritic cells (DC), CCL22 mediates chemotaxis of responsive cells, thus influencing the distribution of these cells within tissues. For instance, CCL22 is known to be expressed in human and murine tumors contributing to the recruitment of regulatory T cells. Given that many chemokines show effects exceeding pure chemotaxis we hypothesized that CCL22 mediates modulation of immune responses by further activities.
In order to identify additional immune modulating properties of CCL22 on DCs and T cells we stimulated murine splenocytes isolated from healthy donor mice with recombinant CCL22 in vitro. We did not find any significant alteration in expression of cell surface activation markers like CTLA-4, PD-1 or CD62L on CD4+, CD8+ and FoxP3+ T cells. However, splenic CD11c+ DCs showed a significant reduction in MHC class I molecules on cell surface upon stimulation with CCL22. Notably, this reduction was most prominent in CD11c+ CD8α+ DCs which also showed decreased levels of MHC class II molecules as well as the costimulatory receptor CD80 after encountering CCL22.
In summary, our data indicate an alternative mode of action for CCL22 on Dendritic cells, especially on CD11c+ CD8α+ DCs. The CCL22-mediated modification of DC’s capabilities to present antigens and to activate T cells might represent a fine-tuning mechanism of adaptive immune responses.
Kinetics modeling of myeloid cells in rhesus macaques with pulse-chase BrdU labeling
Authors: He Ziyuan , Sugimoto Chie , Allers Carolina , Fujioka Hideki , Didier Elizabeth , Kuroda Marcelo J 
Published: January 2023

Abstract
Myeloid cells are continuously produced via bone marrow hematopoiesis and then cleared from the circulation to maintain homeostasis. To better understand the kinetics of such cell movement, we applied in vivo BrdU pulse-chase labeling and flow cytometry analysis to follow the kinetics of cell division during homeostasis of each subset of myeloid cells in peripheral blood in rhesus macaques. Results were applied to a mathematical model to estimate the half-life and daily production of each subset as follows; neutrophils (1.63±0.16 days, 1.42×109cells/L/day), basophils (1.78±0.30 days, 5.89×106 cells/L/day), classical monocytes (1.01±0.15 days, 3.09×108 cells/L/day), intermediate monocytes (1.23±0.14 days, 2.90×107 cells/L/day), non-classical monocytes (3.45±0.93 days, 1.58×107 cells/L/day), CD1c+ myeloid dendritic cells (DCs) (1.11±0.16 days, 1.65×107 cells/L/day), CD123+ plasmacytoid DCs (2.69±0.38 days, 9.67×105 cells/L/day). Unlike monocytes which were released into the blood circulation as soon as 1 day after dividing, neutrophils required ~4–5 days in bone marrow before being released. Interestingly, even within the granulocyte population, neutrophils and basophils exhibited distinct kinetics in peripheral blood and different bone marrow maturation times. We also applied our model to healthy rhesus macaques ranging from 3 to 19 years of age and observed that while the half-life of neutrophils did not change with increasing age, the older animals produced fewer neutrophils per day. In addition to neutrophils and monocytes, the non-classical (inflammatory) monocytes, pDCs and mDCs, as well as basophils, were relatively shorter-lived cells that may contribute to protection and homeostasis at steady state.
Sclerostin expression in distinct osteolineage cell types differentially regulates hematopoietic stem cell and B lymphocyte development
Authors: Manilay Jennifer , Murugesh Deepa , Yee Cristal , Economides Aris , Loots Gabriela 
Published: January 2023

Abstract
Investigation of the reciprocal effects of hematopoietic cell types and osteolineage cells on each other’s cell fates have clinical applications to improve bone fracture healing, prevent age-related bone loss and immune deficiencies. A significant knowledge gap exists as to the contribution of different osteolineage cells to the differentiation, proliferation, and long term survival of B cells in the BM. In global sclerostin knockout (SostKO) mice, we previously uncovered a cell-extrinsic requirement for sclerostin on B lymphocyte development. It is widely accepted that sclerostin is transcribed primarily in osteocytes (OCYs), but whether is it expressed and/or active in other bone progenitors has been controversial. In order to identify the Sost-expressing osteolineage cell type that is responsible for B cell support, we analyzed hematopoietic differentiation in mice lacking Sost in mesenchymal stem cells (MSCs) [Prx1-Cre], osteoblasts (OBs) [Col1a-Cre] and OCYs [Dmp1-Cre] through the use of conditional Sost-KO (cKO) mice. Loss of Sost expression in MSCs resulted in reduced BM cellularity, whereas this was unaffected by Sost-deficiency in OB and OCYs. Furthermore, MSC-specific depletion of Sost caused an accumulation of early B cell progenitors. In contrast, loss of Sost in OBs and OCYs resulted in a reduction of mature “recirculating” B cells in the BM. Remarkably, the percentage of long-term CD150+ CD48− HSCs was significantly reduced in MSC-cKO mice, but was not affected in OB- and OCY-cKOs. The data described herein suggest that Sost deficiency in MSCs, OBs, and OCYs differentially regulates hematopoietic stem cell retention, survival, maintenance and B cell differentiation in the bone microenvironment.
ERM family proteins regulate T cell signal initiation by limiting Lck activity and T cell receptor clustering.
Authors: Robertson Tanner Ford , Blumenthal Daniel , Chandra Vidhi , Burkhardt Janis K 
Published: January 2023

Abstract
Ezrin, radixin, and moesin (ERM) proteins create specialized membrane subdomains by linking phosphatidyl inositol lipids and protein binding partners in the plasma membrane to the underlying actin cortex. These proteins are widely expressed and have well-characterized roles in cell polarity, development, and cytokinesis. In recent years, it has become clear that these proteins are also intimately involved in signal transduction. In humans, mutations in ERM proteins cause severe immunodeficiency characterized by lymphopenia and poor T cell proliferation. To investigate the role of ERM proteins in T cell activation, we generated mice with T cells deficient in ezrin and moesin, the two ERM family members expressed by T cells. Preliminary analysis shows that ERM-deficient CD4+ T cells proliferate poorly in vitro. Interestingly, however, these T cells signal more robustly in response to TCR ligation and produce high amounts of IFNγ. At rest, ERM-deficient T cells exhibit enhanced phosphorylation of Lck and larger pre-clustering of the T cell receptor. These data are consistent with a model in which ERM proteins both maintain cortical actin fences to limit TCR clustering and recruit negative regulators of proximal signaling events to the plasma membrane, thereby governing early events in the TCR signaling cascade.
Human T-cell lymphoma and leukemia cell lines display Treg cell phenotypes and respond to external semaphorin 4A
Authors: Chapoval Svetlana P , Hritzo Molly , Qi Xiulan , Tamagnone Luca , Golding Amit , Keegan Achsah Dorsey 
Published: January 2023

Abstract
We have previously shown that neuroimmune semaphorin Sema4A regulates experimental allergic asthma severity and Treg cell number in vivo (Mucosal Immunol., 2012, 5:409). Later, a study from the Vignali laboratory (Nature, 2013, 501:252) demonstrated that Sema4 controls Treg cell function and survival acting through its Neuropilin 1 receptor. In our current study, we employed the human cell lines HuT78 and HuT102 to further investigate the contribution of Sema4A to Treg phenotypes. These cell lines were selected for phenotypic and functional assays as they variably express Treg cell markers including CD25 and Foxp3. Moreover, they both express high levels of Sema4A. Although we did not detect Neuropilin 1 on these cell lines, they both were found to express another Sema4A counter receptor, Plexin B1. Culture of these cell lines with soluble Sema4A led to downregulation of Plexin B1 and upregulation of Sema4A and CD25 expression with slightly increased yield of CD4+CD25+ and CD25+Foxp3+ cells. Our future research is aimed at defining the role of Sema4A-PlexinB1 signaling pathways in Treg cell stability and function. We will extend this study to Treg cells obtained from normal PBMC and from patients with autoimmune and cancerous conditions. This will help us to develop new Sema4A-based therapeutic measures to combat these diseases.
NEUTROPHILS PLASTICITY DURING Mycobacterium tuberculosis INFECTION IS RELATED TO THE DISEASE PROGRESSION
Authors: Silva Priscilla Mariane Cardoso , Zambuzi Fabiana Albani , Lima Leonardo , Brauer Vêronica , Soares Luana , Fontanari Carolina , Bollela Valdes , Frantz Fabiani 
Published: January 2023

Abstract
Tuberculosis is an infectious disease that affects one third of world population. The bacilli are spread by the illness bearer and can cause a serious pulmonary infection. Together with resident macrophages, neutrophils appear to be an important cell in the control of Mycobacterium tuberculosis infection. Recently, some studies are breaking paradigms about neutrophils, revealing that these cells can polarize to N1 and N2 profiles. These findings opened a different perspective in the study of Mtb infection and progress to active disease. Thus, the aim of this study is to determine how the polarization of neutrophils in N1/N2 profiles could influence the control of Mtb infection. For this purpose, neutrophils were isolated from peripheral blood of ten healthy volunteers. These cells were stimulated for one hour with GM-CSF and INF-γ for differentiation in the N1 profile or with IL-13 and TGF-β for N2. The polarized neutrophils were characterized by their morphology and production of reactive oxygen species. After the differentiation neutrophils were infected with Mtb and were evaluated the formation of NET and cytokine production. As results, the caracterization of polarized neutrophils revealed a different nuclear morphology and metabolic activity. When neutrophils are challenged with Mtb the N1 group shows an increase of IL-8, IL-1-β, INF-γ and the formation of NETs. By contrast N2 profile reveals a decline of these inflammatory cytokines and an increase of IL-4 and TGF-β. Further, in this condition is no longer possible to observe the formation of NETs. This result supports the idea of neutrophils plasticity and helps to understand better how the neutrophils may have different actions against Mtb.
A natural product inhibitor of the NLRP3 inflammasome derived from Glycyrrhiza uralensis for the treatment of inflammatory diseases
Authors: Yang Gabsik , Lee Hye Eun , Han Sin-Hee , An Tae-Jin , Jang Jae-Ki , Lee Joo Young 
Published: January 2023

Abstract
The NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a pattern recognition receptor complex recognizing invading pathogens and activating caspase-1 to induce maturation of interleukin (IL)-1β, thereby playing a critical role in the regulation of immune responses. Its aberrant activation is pathogenic to inherited issues for example, cryopyrin-associated occasional syndrome, multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. The root of Glycyrrhiza uralensis (GU) has been used as herbal medicine worldwide for over 4000 years. GU is a well-recognized, natural sweetener and used as a traditional medicine to treat several diseases and symptoms, including diabetes, lung diseases, and coughs. Although the effects of GU on immunity have been reported, its effects on inflammasomes, have not been fully studied yet. In this study, we elucidated the effect of GU on inflammasome activation using primary mouse macrophages. GU inhibited the production of caspase-1(p10) and mature IL-1β induced by NLRP3 inflammasome activation in primary mouse macrophages. Furthermore, GU markedly inhibited diet-induced adipose tissue inflammation and IL-1β and caspase-1 production in white adipose tissue. The results demonstrate that GU inhibits NLRP3 inflammasome activation in macrophages, suggesting that GU is a potential drug candidate for the treatment of NLRP3 inflammasome-associated inflammatory diseases.
Acknowledgement
This work was carried out with the support of “Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ01199002)” Rural Development Administration, Republic of Korea.
Four-dimensional correlation between frequency of degranulation and Natural Killer (NK) cell cytotoxicity
Authors: Gwalani Lavesh A , Orange Jordan S 
Published: January 2023

Abstract
NK cells are cytotoxic lymphocytes required for early control of viral infections and tumor immunosurveillance. NK cytotoxicity occurs through directed secretion of lytic granules (LG) containing effector molecules such as perforin and granzymes. Cytoskeletal reorganization during the formation of an NK-cell immunological synapse (IS) enables delivery of LG to the IS. Fusion of LG with the NK cell membrane results in exocytosis of its contents into the IS leading to target cell death. While the requirements for LG transport and exocytosis are largely known, the minimum number of degranulation events sufficient for an NK cell to kill its target is unknown. In this study we performed four-dimensional quantification of degranulation events using a degranulation indicator (LAMP1-pHluorin) in concert with a target cell death sensor. Confocal microscopy of live single NK-target cell conjugates allowed visualization and measurement of the entire NK-cell kill. Degranulation events were quantified in LAMP1-pHluorin transduced human NK cell lines against their known targets. Killing exhibited two distinct patterns, fast and slow. In one NK cell line the minimal effective degranulation events for fast killing were almost half of that for slow killing and were similar to the minimal effective degranulation events in the other NK cell line. LD50 for vital dye extinction was calculated and was mediated by a surprisingly small number of degranulation events. Importantly, a strong temporal correlation existed between the appearance of degranulation events and target cell killing. With this study we have quantified NK cell degranulation at a single cell level and defined parameters of degranulation that correlate with NK-cell cytotoxicity.
Infant stool microbiota at the time of vaccination at 6 w of age is associated with vaccine responses measured at 2 y of age
Authors: Huda Md Nazmul , Ahmad Shaikh , Kalanetra Karen M. , Taft Diana H. , Lewis Zachery T. , Raqib Rubhana , Mills David A. , Stephensen Charles 
Published: January 2023

Abstract

Background
Gut microbiota in early infancy may shape a host’s vaccine response. We have previously reported that a high relative abundance (RA) of Bifidobacterium in early infancy is associated with vaccine responses measured near the time of stool collection (Huda MN et al., Pediatrics 2014 134:e362). In this study, we expanded the sample size and tested if the RA of Bifidobacterium measured at the time of vaccination (between birth and 15 w) is associated with T-cell and antibody (Ab) responses to those vaccines measured at 2 y of age.

Methods
This study included 306 healthy Bangladeshi infants (NCT01583972, NCT02027610). Stool microbiota was assayed at 6, 11 and 15 w and between 2 and 3 y of age. Vaccine-specific T-cell proliferation responses to BCG (Bacillus Calmette–Guérin), OPV (oral poliovirus), TT (tetanus toxoids), and HBV (hepatitis B virus) were measured at 15 w and 2 y of age. Plasma and stool Ab were measured at 2 y. Tuberculin skin test was performed at 15 w.

Results
Bifidobacterium RA at 6 w was positively associated with T-cell responses to BCG, OPV, HBV and TT measured at 15 w and 2 y, as predicted. Bifidobacterium was not associated with plasma Ab response. The abundance of Firmicutes and Proteobacteria were negatively associated with some vaccine responses. Microbiota at 2 y did not show consistent, significant associations with T-cell response or systemic Ab responses but Bifidobacterium was positively associated with polio-specific stool IgA levels.

Conclusion
Bifidobacterium RA at the time of vaccination is associated with systemic and mucosal vaccine-specific T-cell responses measured later in life, suggesting that interventions to enhance Bifidobacterium in early infancy may improve vaccine responses later in life.
Impairment of myeloid-derived suppressor cell expansion and enhancement of dendritic cell differentiation of MyD88-deficient bone marrow cells in graft-versus-host disease
Authors: Lee Young-Kwan , Ju Ji-Min , Kang Myung-Soo , Min Chang-Ki , Shon Woo-Jeong , Shin Dong-Mi , Choi Eun Young 
Published: January 2023

Abstract
Myeloid differentiation 88 (MyD88) is an adaptor molecule in toll-like receptor-associated signaling. To examine the effect of MyD88-deficiency in myeloid cell differentiation under inflammatory condition, we transplanted bone marrow (BM) cells isolated from MyD88-deficient C57BL/6 (B6) mice together with B6 T cells into MHC-matched allogeneic BALB.B strain mice. This transplantation induced more serious graft-versus-host disease in the BALB.B BM recipients, compared with the GVHD induced in the control BALB.B mice which received wild type B6 BM and T cells. The aggravation of GVHD was associated with impaired expansion of CD11b+Gr1+ myeloid derived suppressor cells (MDSCs) from the MyD88-deficient BM cells during the GVHD development. Instead of MDSC expansion, myeloid cells from MyD88-deficient BM cells showed enhanced apoptosis and dendritic cell (DC) differentiation, which resulted in enhancement of activation of allo-reactive B6 T cells. These results provide information helpful for the understanding of the role of MyD88 in myeloid cell differentiation and development of strategy to reduce the GVHD severity.
MAP1S-mediated TLR5 signaling induces autophagic cell death to inhibit breast cancer
Authors: Shi Ming 
Published: January 2023

Abstract
TLR5 signaling in breast cancer showed strong anti-tumor activity, which might represent a novel strategy in cancer immunotherapy. However, the underlying mechanism of TLR5 signaling-based tumor suppression is still not elucidated. Here, we found TLR5 agonist flagellin could induce excessive autophagy in breast cancer cells, and the expression level of autophagic adaptor MAP1S was elevated in response to flagellin treatment. Moreover, the elevated level of MAP1S robustly promoted tumor cell death in a TLR-dependent manner. Whereas MAP1S deletion led to decreased proinflamatory cytokines expression that induced by TLR5 signaling and blockage of autophagic process in breast cancer cells. In addition, MAP1S promoted the inhibition of inflammasome pathway and pyroptosis by TLR5 signaling. Therefore, we deducted that MAP1S played a key role in TLR5 signaling-based tumor suppression. Taken together, these results indicated a mechanism of antitumor activity that involved MAP1S-mediated TLR5 signaling in breast cancer.
Intravital 2 photon imaging approach to monitor monocyte rolling in experimental atherosclerosis
Authors: Saunders Brian T , Williams Jesse W. , Randolph Gwendalyn J , Zinselmeyer Bernd H 
Published: January 2023

Abstract
Atherosclerosis is the leading cause of heart disease, which is the largest contributor to deaths across the world. This disease involves the development of inflammation and plaque formation within the lumen of mid- and large-sized arteries following cholesterol-enriched diet. Our current study uses intravital two photon imaging to examine the initiating and propagating factors of this disease. Atherogenesis occurs at sites of endothelial damage most commonly near branching points and areas of high sheering stress in vasculature, including the aortic arch and carotid bifurcation. A minimally invasive technique was developed allowing us to monitor the movement of cells inside the vasculature. This technique involves isolating the right common carotid artery near the bifurcation and positioning it to monitor monocyte dynamics on the endothelium without disrupting the flow. Using a variety of fluorescent proteins on myeloid backgrounds crossed with LDLR−/− mice, we measure the monocyte dynamics on both normal diet and cholesterol diet at multiple different time points. We can trace the movement of monocytes in the blood and measure the interaction with resident cells in the luminal wall, finding that monocyte rolling is influenced by localization to plaque-areas and treatment with high cholesterol diet. Defining these differences in interactions and determining mechanisms of monocyte recruitment are key to understanding the initiation and growth of atherosclerotic plaque over time.
Immunophenotyping of chemokine receptor profile on osteoclast progenitors may help reveal mechanisms of their increased migration in collagen-induced arthritis
Authors: Flegar Darja , Sucur Alan , Markotic Antonio , Kovacic Natasa , Kelava Tomislav , Katavic Vedran , Ivcevic Sanja , Grcevic Danka 
Published: January 2023

Abstract
Osteoclasts, specialized bone resorbing cells of hematopoietic origin, become overactive in rheumatoid arthritis, leading to bone loss and joint destruction. Osteoclast progenitor cells (OCP) arise from myeloid precursors of monocyte/macrophage lineage and are found in the bone marrow and among circulatory monocytes. Under inflammatory conditions subpopulations of OCPs undergo through functional and phenotypic changes responsible for their increased migration to inflamed sites and osteoresorptive activity. In our study, we have been investigating frequencies of distinct OCP subsets and their expression of chemokine receptors in circulation and periarticular bone marrow (PBM) of C57BL/6 mice with collagen-induced arthritis (CIA). We found that both hematopoietic lymphoid-negative CD11b+CD115+ and CD11b−/loCD115+ subsets possess osteoclastogenic activity and are enlarged in blood and PBM of affected joints in CIA. OCP subsets substantially expressed CCR2 and CX3CR1, but had low expression of CCR5, CCR9 and CXCR4, with no difference between control and CIA group. Concurrently CCL2 serum levels were significantly increased in CIA, whereas CX3CL1 levels were comparable to control. In an in vitro migration assay, peripheral blood leukocytes from CIA mice after M-CSF and RANKL stimulation increasingly migrated toward CCL2 and CCL5 chemotactic gradients. Intravascular in vivo staining demonstrated increased recirculation of CD45+CD11b+ cells through areas of PBM affected by arthritis. These results suggest that highly induced OCP subpopulations in CIA migrate to inflamed joints due to chemotaxis and therefore blocking of chemokine signals may reduce osteoclast activity in arthritis.