bluuebunny/crossref_metadata_2025_split huggingface dataset:
The tetraspanin CD151 is elevated on activated human CD4+ T cells with enhanced cytotoxic potential
Authors: Seu Lillian , Sabbaj Steffanie , Duverger Alexandra Emilie , Wagner Frederic Houston , Goepfert Paul Andres , Kutsch Olaf 
Published: January 2023

Abstract
Circulating cytotoxic CD4+ T cells are absent in healthy individuals, but have been reported in autoimmune and inflammatory states. Cytotoxic CD4+ T cells arise largely as a result of chronic viral infection, such as CMV. These cells are characterized by the loss of CD28/CD27, their memory differentiation status (TEM/EMRA), and a phenotype primed towards the targeting of viral antigens. While cytotoxic CD4+ T cells are speculated to complement cytotoxic CD8+ T cell activity, they may also contribute to MHC class II-directed immunopathogenic states (e.g., vascular complications resulting from endothelia damage). The molecular mechanism of how cytotoxic CD4+ T cells are propagated remains elusive. Recently, tetraspanins have been shown to influence the cytotoxic potential of immune cells- CD63 aids in mast cell degranulation whereas CD53 modulates NK cell cytotoxicity. Here, we report that the tetraspanin CD151 is elevated on circulating CD4+ T cells with enhanced cytotoxic potential. We observed that CD151+ frequencies were most elevated on CD28neg and TEM/TEMRA CD4+ T cells. Importantly, CD151+ frequencies were robustly enriched on CD4+ T cells containing preformed granzyme B (GzmB) (51 ± 18% vs. 14 ± 6%)- cell populations reported as elevated after primary CMV infection. Within CMV-seropositive donors, CD151+ frequencies were robustly enriched on IFN-γ+GzmB+ CD4+ T cells responding to overlapping peptides from CMV pp65 (60 ± 21% vs. 17 ± 8% baseline). In summary, the tetraspanin CD151 is a cell surface molecule that demarcates circulating CD4+ T cells with enhanced cytotoxic potential, particularly against CMV antigen. Tetraspanins may therefore be a class of molecules that tunes the effector cell response to persistent antigens.
ROCK is essential for directionally persistent migration of CD8+ effector T cells within inflamed lung
Authors: Mrass Paulus , Oruganti Sreenivasa R , Byrum Janie R , Moses Melanie E , Cannon Judy L 
Published: January 2023

Abstract
Recruitment of effector T lymphocytes into peripheral tissues, such as inflamed lung, contributes to an effective protection against infection and cancer. The rate of pathogen detection might be further influenced by the motility of recruited immune cells within three-dimensional tissues. Indeed, recent two-photon studies have shown that effector T cells navigate actively through inflamed lung tissue, but the molecular mechanisms that regulate this process are poorly characterized. Here, we used two-photon imaging of a murine lung treated with endotoxin to quantitatively analyze tissue navigation of lung-infiltrating CD8+ effector T cells. Tracking of individual T cells within inflamed lung tissue for several hours revealed that T cell movement transitions between periods of high directional persistence and confinement. Some T cells also moved in alignment with the vasculature. Treatment with pertussis toxin to inhibit chemokine receptor-dependent Gi-type G protein signaling led to a moderate reduction of the speed of lung-infiltrating T cells. Strikingly, pharmacological inhibition of the molecule ROCK, which promotes cytoskeleton-dependent squeezing through dense environments, led to a pronounced reduction of speed and almost completely abolished directional persistence of lung-infiltrating effector T cells. Together, these results show that migration of lung-infiltrating T cells is fine-tuned by environmental signals and dependent on the cell-intrinsic ROCK-signaling pathway.
Unique pattern of PMN-MDSC migration in cancer
Authors: Patel Sima , Condamine Thomas , Dominguez George , Partlova Simona , Languino Lucia R , Vonderheide Robert H , Gabrilovich Dmitry 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSC) are pathologically activated immature myeloid cells that contribute to an immunosuppressive tumor microenvironment. In order to exert their effects at either the primary tumor site or in metastases, PMN-like MDSC (PMN-MDSC) must first migrate to these sites. There is some evidence to suggest that chemokine gradients can mediate their recruitment. We have observed that human PMN-MDSC accumulation in colon and lung tumors strongly correlates with the expression of S100A9, CXCL1 and CXCL8 in those tumors. Moreover, we have found that, in comparison to PMN, patient PMN-MDSC have an increased chemotactic response to CXCL8 in spite of decreased cell surface CXCR2 expression. Similarly, in murine transgenic models of melanoma, pancreatic and prostate cancer, we have found that PMN-MDSC migrate more than PMN when stimulated with CXCL1, in spite of similar levels of cell surface CXCR2 expression. Interestingly, murine PMN-MDSC are more migratory even without stimulation, and have greater speed, mean squared displacement and random motility coefficient than PMN. It is possible that in addition to specific factors secreted in the primary and metastatic tumor sites, PMN-MDSC recruitment to these sites is regulated by an altered migratory behavior of the cells themselves.
Alpha-beta T cell positive selection is enhanced by CD3-delta via a quantitative developmental signaling mechanism
Authors: Wilton Katelynn Marie , Huseby April M , Ferrer Alejandro , Neier Steven C , Hoffmann Michele , Wettstein Peter , Carmona Eva M , Kappes Dietmar , Pages Diana Gil , Johnson Aaron J , Limper Andrew H , Schrum Adam G 
Published: January 2023

Abstract
CD3-delta has a critical role in alpha-beta T cell development; its absence greatly diminishes thymocyte positive selection. Despite this critical role, mice lacking CD3-delta have a low, but reproducible numbers of peripheral alpha-beta T cells, indicating that some T cell development occurs independently of CD3-delta. These T cells lacking CD3-delta developed via positive selection as evidenced by genetic Major Histocompatibility Complex-dependence, progression to single positive thymocytes in fetal thymic organ culture and the presence of functional immune responses in vivo. Given this data, CD3-delta must have either a qualitative or quantitative impact on positive selection. Specifically, a qualitative impact would mean that CD3-delta is required for a subset of T cell receptors (TCRs) to be selected, resulting in a starkly skewed TCR repertoire with corresponding absolute deficiencies in certain immune responses, or an altered immunodominance to specific infection. In contrast, a quantitative role in positive selection would show a conserved, diverse peripheral TCR repertoire with a decreased quantity of each TCR clone paired with present, though decreased, immune responses. The TCR repertoire complexity of T cells lacking CD3-delta was complex for both alpha and beta transcripts, likely indicating a quantitative role. Similarly, in vivo, mice lacking CD3-delta responded effectively to three independent immune challenges. These findings indicate that the CD3-delta protein quantitatively increases the efficiency of positive selection, likely through enhanced signal amplification, allowing the alpha-beta T cell pool to be more efficiently generated.
Multiparameter mass cytometry of T cell development and selection
Authors: Reich-Zeliger Shlomit , Setty Manu , Tadmor Michelle , Salame Tomer Meir , Pe’er Dana , Friedman Nir 
Published: January 2023

Abstract
T cell development and selection in the thymus play key roles in shaping the adaptive immune system and maintaining self-tolerance. Previous studies characterizing thymic development have largely relied on genetic perturbations and subsequent cell sorting that invariably perturb specific developmental compartments. Using mass-cytometry, allow us to capture the entire developmental progression of T cells, from the double-negative (DN) stages, through double-positive (DP) and the CD4 and CD8 branches, without perturbation. With 42 channels simultaneously measured, we collected a mass cytometry dataset profiling the mouse thymus with T-cell surface markers and transcription factors, chosen based on their broad functionality in T cell development. Using the newly developed “Wishbone” algorithm, we recovered the known stages in T cell development with high accuracy and developmental resolution. This allowed us to place DN, DP, CD4+ and CD8+ cells from a single thymus along a unified bifurcating trajectory. Our data allows for precise ordering of multiple events along the trajectory using un-sorted cells from mice that were not perturbed genetically. To characterize the selection process along the development trajectory we used Nur77-GFP mice in which GFP is induced by TCR signaling that occurs during positive and negative selection. By following GFP strength together with cell trajectory we were able to recognize and characterize the behavior of proteins that participate in selection and that are involved in the transition from the DP to SP stage. This approach enables us for the first time to place and follow coordinated changes in multiple markers that take part in T cell development and selection in the thymus using single snapshots
Development of regulatory T cells in the thymus - two paths to the same goal?
Authors: Farrar Michael A , Owen David L , Mahmud Shawn A. 
Published: January 2023

Abstract
Mature thymic regulatory T cells (Tregs) are defined by dual expression of Foxp3 and CD25 on CD4SP thymocytes. However, the cellular pathways by which CD4 thymocytes differentiate into Tregs remain incompletely understood. Previous reports demonstrated that Treg development occurred via a two-step process. In step one, strong TCR signaling induces expression of CD25 leading to a CD25+ Foxp3− Treg progenitor (TRP). In step two, exposure of this TRP to IL2 results in conversion to a CD25+Foxp3+ Treg. Recently, work by Singer and colleagues have defined a CD25−Foxp3lo TRP that can also be converted by IL2 into CD25+Foxp3+ Tregs. A key question is why two distinct cellular pathways involving distinct TRP populations are needed to reach the same endpoint. Using a combination of maturation marker analysis and RAG2-GFP reporter mice we observed that CD25+Foxp3− TRP arise more rapidly than the CD25−Foxp3lo TRP following positive selection. Analysis of Nur77-GFP reporter mice revealed that these two progenitor populations also display distinct affinity spectrums for self-peptide. Further, TCR sequencing has provided evidence that these 2 progenitor populations contain largely distinct TCR repertoires, suggesting these different TRP populations may be required to provide tolerance to different antigens. Indeed, our preliminary data suggests that these TRPs home to different locations upon adoptive transfer. Our results suggests a model whereby cells are driven by high affinity or high avidity interactions with self-peptide through two discrete pathways to form a comprehensive Treg repertoire capable of protecting against autoimmunity and reactivity to commensal organisms.
Thymic epithelial cells control let-7 up-regulation in thymic B progenitors during the neonatal to adult transition
Authors: Xiao Shiyun , Zhang Wen , Manley Nancy 
Published: January 2023

Abstract
The postnatal thymus is an efficient microenvironment for T cell specification and differentiation. B cells are also present in the thymus, and have been recently implicated in the central tolerance. In Foxn1lacZmutant mice, which undergo premature thymic involution beginning 1 week after birth, T committed progenitors were progressively reduced, however, thymic B cells started to increase at 1 week and transiently formed a peak at 3–4 weeks. These increased B cells were developed from neonatal derived BM progenitors possessing a high B potential, were originally generated in the thymus. Most of them showed CD19loB220loCD24hiCD43+/−IgM−progenitor phenotype with increased expression of Ly51 but decrease of CD25 accumulating at pre-B-II stage. These B progenitors showed a delayed down-regulation of Lin28b, an impaired up-regulation of Let-7 with an increased expression of Arid3a. However the treatment of these progenitor B cells with Vitamin D3 might up-regulate Let-7 and down-regulate Arid3 in vivo coculture. These changes were associated with a transient increase in IL7, decreased CCL25, DL4 and Cyp27b1, IL15 in thymic epithelial cells (TECs), which also reflected the changes of progenitor switch from fetal to adult type during neonatal. Our data show that signaling provided by TECs control the development of thymic B cells by regulating Let-7 and Arid3a expressions in the thymic progenitor B cells during the neonatal to adult transition.
The role of Pdia3-dependent 1α,25-dihydroxy vitamin D3 signaling on IgE-mediated mast cell activation
Authors: Baker Bianca , Barnstein Brian , Clark Nicholas , Boyan Barbara , Schwartz Zvi , Ryan John J 
Published: January 2023

Abstract
Active 1,25(OH)2 Vitamin D3 (1,25D3) is most commonly known for its role in the regulation of bone metabolism. However, research has now indicated it is a potent immune regulator beyond its calcemic effects. Vitamin D deficiency has been implicated in the pathogenesis of allergic diseases including asthma and atopic dermatitis. 1,25D3 is known to signal through the canonical Vitamin D receptor (VDR) facilitating its anti-inflammatory properties and regulating over 100 genes. However, protein disulfide isomerase family A, member 3 (Pdia3), was recently shown to mediate rapid-membrane responses to 1,25D3. In this study, we show that upon IgE-mediated activation, VDR knockout mast cells display enhanced cytokine production. Additionally, 1,25D3 suppresses cytokine production independently of VDR supporting the possibility of an alternative receptor facilitating the suppressive properties of Vitamin D on mast cells. Pdia3 protein and mRNA levels were upregulated in response to 1,25D3 in both WT and VDR KO mast cells. Upon blocking Pdia3 signaling, VDR KO mast cells lost their suppressive response to Vitamin D. Prostaglandin E2, which is released during Pdia3-dependent 1,25D3 signaling, mimicked Vitamin D effects on WT and VDR KO mast cells. Suppressor of Cytokine Signaling 3 (SOCS3), which is known to be upregulated by PGE2, was induced by 1,25D3 in both WT and VDR KO mast cells. Interestingly, VDR KO mast cells showed an enhanced induction of SOCS3 in comparison to WT. Collectively, our data depict a novel signaling mechanism utilized by mast cells to respond to 1,25D3 that could be explored as a potential therapeutic target for the treatment of allergic and inflammatory diseases.
Suppression of established food allergy by a combination of anti-TSLP, anti-IL-33, and anti-IL-25 monoclonal antibodies.
Authors: Khodoun Marat , Krishnamurthy Durga , Strait Richard T , Tocker Joel , Potter Crystal , Finkelman Fred D 
Published: January 2023

Abstract
Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. In contrast, we recently reported (JACI, 131:442–50, 2013) that Ag-specific, IgE-mediated food allergy (FA) can be induced when a protein Ag is repeatedly ingested with a widely used nutrient, medium chain triglycerides (MCT), without any additional sensitization. Mice that have been repeatedly inoculated orally with MCT plus egg white (EW) develop a Th2 cytokine and an IgE response as well as shock (hypothermia) following oral EW + MCT challenge. Because MCT ingestion induces increased intestinal epithelial cell expression of the pro-Th2 cytokines TSLP, IL-25 and IL-33, we investigated the importance of these cytokines in establishing and maintaining FA. We found that treatment with neutralizing mAbs to any of the pro-Th2 cytokines could suppress MCT + EW-induced FA development, with aTSLP mAb causing near-total suppression and aIL-25 and aIL-33 each causing considerable suppression. In contrast, treatment with aTSLP mAb, by itself, had little effect on established FA to EW. Treatment of established FA with combinations of mAbs to any two pro-Th2 cytokines had a partial suppressive effect, with the combination of aTSLP + aIL-33 being most suppressive. Simultaneous treatment with mAbs to all three pro-Th2 cytokines caused complete loss of the hypothermia response to EW + MCT challenge and considerably reduced IL-4, IL-13, IgE, and mouse mast cell protease 1 responses. Thus, all three pro-Th2 cytokines are essential for FA induction, but these cytokines are somewhat redundant for FA maintenance in our model. These results provide a better understanding of the FA mechanisms and lead to the development of novel therapies.
High-molecular-weight kininogen and its cleavage product bradykinin are critical in the pathogenesis of autoantibody-induced arthritis
Authors: Xie Zhanli , Dai Jihong , Wu Yi 
Published: January 2023

Abstract
High-molecular-weight kininogen (HK) is a major component of plasma kallikrein-kinin system (KKS), the activation of which mediates HK cleavage to release bradykinin (BK). BK is a nonapeptide with potent proinflammatory and vasoactive activities. Although patients with rheumatoid arthritis (RA) exhibits the activation of the KKS and the cleavage of HK in plasma, the role of HK in arthritis pathogenesis has never been characterized. In this study we evaluated the phenotype of our newly-generated HK-deficient (Kng1−/−) mice in arthritis. To induce autoantibody-induced arthritis, two groups of Kng1+/+ and Kng1−/− mice were injected intraperitoneally with anti-type II collagen antibody cocktail (4 mg) on day 0 and lipopolysaccharide (LPS, 50 μg) on day 3. Although wild-type (WT) mice developed severe arthritis, the Kng1−/− mice exhibited significantly attenuated disease severity as evaluated by joint diameter change and clinical scores (p&lt;0.0001). Compared with WT mice, Kng1−/− mice displayed reduced synovial hyperplasia and cartilage erosions, and decreased protein and mRNA levels of IL-1b and IL-6 in joint tissue (p&lt;0.001). BK level and kallikrein activity in Kng1−/− plasma were significantly lower than that of WT mice. Incubation with collagen-anti-collagen antibody complex mediated BK production in human plasma. Consistent with the phenotype of Kng1−/− mice, the mice lacking BK receptors also displayed a reduced arthritis severity, as well as a decrease in IL-1b and IL-6 production in joint tissue. Our study provides the first genetic evidence indicating an important role of HK in the pathogenesis of arthritis, and the blockade of HK cleavage to prevent BK production might be a novel therapeutic strategy for RA treatment.
Characterization of CD4+ T cells expressing an elevated interferon-stimulated gene signature in SLE patients
Authors: Murray Sara , Speake Cate , Mason Michael J , Whalen Elizabeth , Buckner Jane H , Linsley Peter S 
Published: January 2023

Abstract
The type I interferon (IFN) signaling pathway plays a key role in Systemic Lupus Erythematosus (SLE) pathology, and a majority of patients display elevated expression levels of interferon-stimulated genes (ISGs) in the peripheral blood. However, it is unclear which immune cells are responding to IFN to drive disease pathology. We compared the ISG signatures of cell types sorted from peripheral blood of IFNβ-treated relapsing-remitting multiple sclerosis (RRMS) patients with those of SLE patients. While systemic IFNβ treatment stimulated ISG expression in the monocytes and neutrophils of RRMS patients, the ISG signature in SLE patients was primarily detected in CD4+ T and B cells. This suggests these cells may be exposed to higher levels of IFN in microenvironments of inflammation within SLE patients, such as upon interaction with APC presenting SLE antigens. We hypothesize that a subset of primarily antigen-specific CD4+ T cells expand and express ISGs during SLE disease activity, and that these cells and their signature pathways can serve as disease biomarkers and therapeutic targets. To examine ISG expression by CD4+ T cells in SLE, we compared the expression of several ISG-correlated surface markers between high- and low-IFN score patients and healthy controls. Subsets of CD4+ T cells in high-IFN score patients expressed elevated levels of PD1, CD66a, and OX40, while the majority of cells expressed a similar level as cells in healthy controls. This suggests that only a small subset of CD4+ T cells is activated by localized IFN sources and is involved in SLE pathology. We have further characterized PD1+, OX40+ CD66a+, and SLE-specific memory CD4+ T cells by RNAseq and flow cytometry.
A novel mechanism for enhanced neutrophil recruitment, retention, and podocyte damage in immune complex-mediated glomerular disease.
Authors: Powell David W , McLeish Kenneth R , Tan Min , Sheehan Ryan M , Zheng Shirong , Caster Dawn J , Korte Erik A 
Published: January 2023

Abstract
Glomerulonephritis (GN) is characterized by immune complex deposition and ensuing inflammation within the glomerulus of the kidney. Frank J. Dixon, a pioneer in immunologic kidney disease research, reported in 1965 that injection of nephrotoxic antibodies in rats and rabbits resulted in proteinuria and glomerular accumulation of neutrophils, and that depletion of circulating neutrophils reduced this immune-mediated glomerular damage and proteinuria. In the decades since, studies have confirmed a role for glomerular neutrophil accumulation in human GN, but the mechanisms for neutrophil recruitment and neutrophil-directed injury have not been resolved. We previously reported genetic variants for a NF-κB inhibitor ABIN1 as risks for GN. Others also report that glomerular ABIN1 gene expression is altered in GN in mice and humans. Here we present that transgenic disruption of ABIN1 function results in exacerbated podocyte injury, glomerular expression of inflammatory mediators, and glomerular recruitment and retention of neutrophils in a mouse model of acute antibody-mediated GN. Moreover, a novel inhibitor of neutrophil granule release (SNAP23 peptide) also attenuates podocyte injury in this model. These in vivo findings are supported by in vitro experiments showing that secretome from homologous ABIN1 mutant podocytes activates neutrophil chemotaxis and granule release and neutrophil granule contents specifically disrupts cytoskeletal organization of ABIN1 mutant podocytes. These studies unfold a role for ABIN1 dysfunction in a novel neutrophil-mediated mechanism of podocyte injury in GN and presents inhibition of neutrophil granule release as a promising novel therapeutic direction for kidney inflammation.