bluuebunny/crossref_metadata_2025_split huggingface dataset:
VDJServer – a web-accessible analysis portal for immune repertoire sequencing analysis
Authors: Toby Inimary , Christley Scott , Scarborough Walter , Rounds William H , Fonner John , Mock Stephen , Monson Nancy , Scheuermann Richard H , Cowell Lindsay G 
Published: January 2023

Abstract
VDJServer is a comprehensive, web-accessible system for analysis of immune repertoire sequencing data. VDJServer provides a complete analysis workflow from pre-processing of sequence reads, to V(D)J assignment, to repertoire characterization and comparison. Recent enhancements in VDJServer include: --Automatic parallelization of analysis tools to handle very large data sets running on a high-performance supercomputer--Import and export subject and sample metadata. User-defined sample groups allows for sophisticated group analysis and comparison.--Extensive analysis functionality such as gene segment usage, CDR3 patterns, clonality, diversity measures, somatic mutation patterns, B cell lineage trees, and quantification of selection pressure. Analysis is performed for both samples and sample groups.--Interactive charting of analysis data provides exploratory visualization for ad-hoc comparison of samples and sample groups. Charts can be downloaded as image files for use in presentations and publications. All analysis data can be downloaded in standard TSV format for use with external tools.--Novel process workflow metadata that is automatically captured by VDJServer. Hiding the complexities of command line tools and their parameters, yet providing complete transparency of the analysis workflow for reproducibility.
VDJServer allows users to upload antigen receptor repertoire sequences and execute a customizable workflow for all steps in the analysis. Data and analysis results can be privately shared with other users for collaborative projects. VDJServer is funded by the NIAID and is freely available.
Tumor-experienced human NK cells express PD-L1 and display immunoregulatory functions
Authors: Fuertes Mercedes B , Iraolagoitia Ximena L Raffo , Ziblat Andrea , Nuñez Sol Y , Torres Nicolas I , Secchiari Florencia , Domaica Carolina I , Zwirner Norberto W , Sierra Jessica M 
Published: January 2023

Abstract
While NK cells play a key role in the elimination of infected cells and tumors, regulatory functions of NK cells are emerging in several models of viral infections and autoimmunity. In the tumor context, we have recently described an immunoregulatory population of PD-L1-expressing NK cells arising in tumor-bearing mice that inhibits CD8+ T cells priming. Since little is known about the expression of PD-L1 on human NK cells, the aim of this work was to study its expression on human NK cells after tumor recognition and the underlying mechanisms. After culture of human PBMCs from healthy donors with K562 tumor cells, PD-L1 expression was induced on NK cells. Transwell and receptor blockade experiments showed a dependence on cell-to-cell contact that involved NKG2D engagement. PD-L1 expression on isolated NK cells stimulated with K562 tumor cells could be further increased by soluble factors derived from tumor-stimulated PBMCs or by the addition of monocytes. Neutralization of different cytokines identified IL-18 as the main factor responsible for PD-L1 up-regulation, which can be produced by monocytes. These PD-L1hi NK cells were immunoregulatory, as they inhibited DC maturation in vitro. This population may be clinically relevant, as we detected PD-L1hi NK cells in the tumor microenvironment and in peripheral blood of human patients with kidney cancer, making PD-L1 expression on NK cells an attractive candidate as prognostic/diagnostic biomarker. Our results indicate that PD-L1 is expressed in tumor-experienced human NK cells which subsequently acquire immunoregulatory functions. Thus, rational manipulation of these regulatory cells could lead to improved anti-tumor immunity in vivo
Relevance of host and tumor PD-L1 expression in PD-L1 and PD-1 blockade
Authors: LIN HENG , Wei Shuang , Vatan Linda , Kryczek Ilona , Zou Weiping 
Published: January 2023

Abstract
Therapeutic blockade of PD-1 or PD-L1 with monoclonal antibodies (mAb) leads to durable tumor regressions in patients across cancer types. Clinical responses to PD-L1 and PD-1 blockade may be associated with increased PD-L1 expression in the tumor tissues, tumor-infiltrating T cells, and tumor neoantigens. However, it is unclear which patient population(s) benefits from these treatments. Furthermore, why do some patients with PD-L1 negative tumor respond to PD-L1 and PD-1 blockade therapy? To dissect the molecular and cellular mechanisms that account for the clinical efficacy of PD-L1 and PD-1 blockade, we used Rag1tm1Mom(Rag1−/−), NOD.SCID gc-deficient (NSG), PD-L1 genetic deficient (PD-L1−/−), and PD-1 genetic deficient (PD-1−/−) mice, and studied PD-L1 blockade in MC38, ID8, B16-F10, and LLC models. We found a loss of therapeutic effect of anti-PD-L1 mAb treatment in Rag1−/−, NSG, PD-L1−/−, and PD-1−/−mice. We demonstrated the importance of PD-L1 expression on antigen presenting cells (APCs), particularly dendritic cells (DCs) in the tumor microenvironment and draining lymph nodes, in anti-PD-L1 treatment efficacy. Thus, the host immune system is indispensable for anti-PD-L1 therapy, and the host, rather than cancer cell-intrinsic PD-L1 may account for the therapeutic efficacy of PD-L1 signaling blockade.
Trichomonas associated protection against Salmonella infection
Authors: Lu Chunchi , Zhao Xiaodan , Lo Chia-Ta , Lyu Sin-Yi , Smith Kelly D 
Published: January 2023

Abstract
Colonization resistance (CR), defined as the ability of intestinal microbiota and host defenses to protect against pathogens, is the first line defense against intestinal infection. In our studies of innate immune recognition of intestinal Salmonella, we discovered Naip5−/− and Rag1−/− mice harbor microbiota that protect mice against Salmonella infection, which is associated with intestinal colonization by Tritrichomonas muris (Tm). Tm is a protozoon commonly found in laboratory, pet shop and wild mice, which has no definitive disease association. Recent studies have demonstrated Tm and other intestinal parasites are sensed by tastant receptors expressed by specialized intestinal tuft cells, which enhances intestinal barrier by tuft cell and goblet cell hyperlasia. Helminths and protozoa have been associated with changes in the intestinal microbiota, suggesting that intestinal protozoa may produce biologically significant alterations in the composition of gut bacteria. We demonstrate that Tm colonization of mice is associated with decreased inflammation in the intestine during Salmonella infection of streptomycin pretreated mice. Tm colonization is also associated with increased resistance to Salmonella infection and CR. Finally, we demonstrate that Tm colonized mice have an altered gut microbiome, suggesting that Tm cultivates a protective microbiome that helps prevent Salmonella colonization and infection. Our studies indicate that intestinal protozoa may influence the complex environment within the gut to help limit Salmonella invasion of the gut ecosystem and Salmonella induced intestinal inflammation, and provide insight into novel strategies that may help prevent Salmonella infection and transmission.
A Novel Population of TCRαβ-expressing CD11bhighCD14+F4/80+ Macrophages induced by a Pathogenic Murine Malaria enhances phagocytosis of parasites
Authors: Oakley Miranda S , Chorazeczewski Joanna , Majam Victoria , Chawla Bhavna , Aleshnick Maya , Takeda Kazuyo , Akue Adovi , KuKuruga Mark , Kumar Sanjai 
Published: January 2023

Abstract
Macrophages, a component of the innate immune system, are equipped with a wide array of invariant receptors that facilitate the host defense against invading pathogens via phagocytosis and the release of inflammatory cytokines, and help maintain tissue homeostasis by initiating the repair and remodeling processes. In malaria, macrophages perform both immune protective (parasite clearance) and pathogenic (severe malaria anemia and cerebral malaria) functions. Utilizing the virulent asexual stage Plasmodium berghei ANKA (Pb-A) parasite, which causes experimental cerebral malaria (ECM) in mice, we have identified a novel population of TCRαβ-expressing macrophages that expands during Pb-A infection and preferentially migrates to and sequesters in the brain during ECM. This novel population of macrophages is CD3−CD4−CD8− and has a Vβ TCR repertoire that is distinctly different from conventional T cells. We also find that optimal expression of combinatorial TCRαβ on CD11bhigh cells requires coexpression of CD14 and F4/80. In depth immunological studies demonstrate that macrophage TCRαβ induces proliferation, alters IL-4 and MIP1β production, and enhances phagocytosis of infected erythrocytes. Expansion and activation of TCRαβ+CD11bhighCD14+F4/80+ macrophages during malaria infection point towards a convergence of the innate and adaptive immune responses where both arms of the immune system cooperate to modulate the host response to invading pathogens. Our results suggest that targeting macrophage effector functions through vaccines and drugs should be explored as an approach to reduced malaria mortality and morbidity.
Effects of pH, Charybdotoxin, and PC12 cells on Jurkat T-cell proliferation
Authors: Snitsarev Vladislav , Petroff Elena 
Published: January 2023

Abstract
Neuroimmunological diseases involve T-cell attacking neurons. We showed previously that acid-sensing ion channels (ASICs) and voltage-gated channels (Kv) from different cells can interact leading to inhibition of Kv. We hypothesized that this interaction may exist between Kv of Jurkat T-cells (JTL) and ASICs of PC12 cells (neuronal model), and that this interaction is pH- and Charybdotoxin (ChTX)-dependent.
JTL were seeded on top of confluent PC12, or without PC12. The effects of 200 nm ChTX and pH 7.2 on JTL doubling time (DT) were tested.
Without PC12, DT was 12.2±0.5h at pH 7.4, 25.6±1.1h with ChTX, and 17.0±1.0h at pH 7.2; in ChTX at pH 7.2, DT was 40.8±5.0h.
With PC12, JTL DT was 34.1±2.9h at pH 7.4, 30.1±2.3h with ChTX, and 20.7±1.8h at pH 7.2; in ChTX at pH 7.2, DT was 32.2±1.8h.
Paired comparisons without PC12 show that DT was significantly longer at pH 7.2 vs pH 7.4 and in ChTX at pH 7.4; pH 7.2 and ChTX synergistically increased DT vs pH 7.2 and vs ChTX at pH 7.4.
With PC12, all corresponding DTs were significantly longer. Paired comparisons showed that at pH 7.2 DT was significantly shorter than at pH 7.4, opposite to without PC12. This can be potentially explained by lower pH relieving inhibition of Kv on JTL by the ASICs on PC12. At pH 7.4, ChTX did not have any effect possibility due to JTL’s Kv already blocked by PC12’s ASICs, and at pH 7.2 ChTX inhibited the free Kv.
Thus, both acidic pH and ChTX independently slow down JTL proliferation, and in the presence of PC12, effects of low pH and ChTX are consistent with ASIC-Kv interaction.
We speculate that ASICs expressed in APCs and Kv in lymphocytes may be a new unrecognized interaction in the immunological synapse, and disruption of neuronal ASIC-lymphocytic Kv interaction may play a role in autoimmune disease.
Blunting age-associated chronic inflammation preserves hematopoiesis and immunity and reduces leukemogenesis
Authors: Henry Curtis J , Casas-Selves Matias , Kim Jihye , Zaberezhnyy Vadym , Aghili Leila , Daniel Ashley E. , Jimenez Linda , Azam Tania , McNamee Eoin N. , Clambey Eric T. , Klawitter Jelena , Serkova Natalie J. , Tan Aik-Choon , Dinarello Charles A. , DeGregori James 
Published: January 2023

Abstract
Aging is the single most important prognostic factor for the development of many cancers. While mutational accumulation may increase the risk of cancer in aged individuals, declining immunity due to chronic inflammation is also a likely contributing factor.
We have demonstrated that reducing aging-associated chronic inflammation abrogates fitness declines in B-progenitor cells, and significantly reduces leukemogenesis in aged mice (Henry et al., JCI, 2015). In addition to preserving the function of B-progenitor cells, subsequent studies have revealed that reducing chronic inflammation in aged mice augments immune responses. Specifically, reducing inflammation in aged mice (≥22 months) results in a two-fold reduction in the number of splenic M2 macrophage and T-regulatory cell populations, as well as, a three-fold reduction in the surface expression of the inhibitory protein PD-L1 on innate immune cells. Reducing chronic inflammation in aged mice also results in a three-fold increase in the percentage of interferon-gamma producing CD4+ and CD8+ T-cell lymphocytes when stimulated. These phenotypes were observed in aged, anti-inflammatory transgenic mice (alpha-1-anti-trypsin and interleukin-37) and in geriatric mice (≥27 months) treated with recombinant interleukin-37. Overall, these findings suggest that reducing chronic inflammation in aged populations can rejuvenate hematopoiesis and immunity, while also creating a less permissive environment for leukemogenesis.
Absence of estrogen receptor alpha in males does not impact disease severity during nephrotoxic serum-induced nephritis
Authors: Corradetti Chelsea , Cesaroni Matteo , Madaio Michael , Caricchio Roberto 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) exhibits a strong sex bias in which 90% of patients are female. Interestingly, male SLE patients experience greater progression and severity of disease. Glomerulonephritis (GN) remains one of the most serious manifestations of SLE and accounts for most morbidity and mortality among lupus patients. Due to the sex bias, our lab is interested in studying how estrogens may play a role in the pathogenesis of GN and in recent studies we revealed that estrogens exacerbate GN in females in an estrogen receptor alpha- (ERa)-dependent manner by altering activity of metabolic pathways. Although estrogen concentrations are lower, we were interested in investigating whether these sex hormones can also influence disease in males. We found that absence of ERa did not significantly affect the severity of NTS-induced nephritis (NTN) in male mice. Both immune cells and renal cells were involved in NTN progression, and chimera experiments revealed absence of ERa in either of these compartments does not alter the severity of disease. Although absence of ERa in males did not alter NTN disease phenotype, interestingly, analysis of the glomeruli of these mice revealed large differences in gene expression profiles between WT and ERaKO males even if the progression of NTN was similar. WT males exhibited increased expression of genes related to immune activation and cell adhesion, followed by downregulation of metabolic pathways, while ERaKO males undergo very few genetic changes during NTN. From these results, we conclude that ERa does not play a role in GN pathogenesis in males; however, the potential impacts of the gene expression changes induced by its absence warrants further investigation on other aspect of lupus disease.
Emergence of T Regulatory Cells Following Neural Precursor Cell Transplantation in Mouse Models of Multiple Sclerosis
Authors: McIntyre Laura Lynn , Plaisted Warren Christopher , Nguyen Quy , Kessenbrock Kai , Lane Thomas , Walsh Craig Michael 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is a chronic, autoimmune disease of the central nervous system for which there is no cure. Defects in neurological function are a result of demyelination and axonal loss caused by infiltrating immune cells. Transplantation of neural precursor cells (NPCs) is a promising therapeutic strategy to treat neurological diseases. However, studies evaluating NPC transplantation often employ a syngeneic donor or immune suppressed subjects. Therefore, it is important to consider how transplanted cells elicit an immune response. We report that human neural precursor cells (hNPCs) induce antigen specific Tregs which influence endogenous repair pathways to promote remyelination in murine models of MS. We observed remyelination and decreased neuroinflammation in mice receiving an intra-spinal transplant of syngeneic NPCs, which replaced damaged cells. Alternatively, mice receiving transplants of xenogeneic human NPCs displayed remyelination, a decrease in neuroinflammation, and an increase in CD4+CD25+FoxP3+ Tregs. Recovery was not a result of direct cell replacement as hNPCs underwent xenograft rejection. Importantly, ablation of Tregs abrogated histopathological improvement. Furthermore, hNPCs promoted generation of Tregs in vitro. These findings support an emerging role for Tregs in promoting tissue regeneration, distinct from immune modulation.
Altered flow triggers activated T cell accumulation and inflammation in early atherosclerosis
Authors: Xu Maria Mei , Menoret Antoine , Zhou Beiyan , Murphy Patrick A. , Vella Anthony T. 
Published: January 2023

Abstract
Atherosclerosis is linked to systemic inflammation. Yet, the inflamed plaques predicating cardiovascular morbidity and mortality preferentially develop in areas of low and disturbed flow (LDF). Partial carotid artery ligation (PCAL) of the left carotid exposes vascular endothelium to LDF without disturbing flow contralaterally and when combined with high fat diet, LDF regions develop plaques within 2 wks. We show that just 48 hr after PCAL, LDF triggers significant upregulation of IL-36, a new member of the proinflammatory IL-1 family, and Cathepsin S, its enzymatic activator. The IL-1 family and IFNγ are intimately tied to atherogenesis and our past work establishes IL-36 as a robust stimulator of IFNγ from effector T cells. Thus, we hypothesize that LDF triggers an IL-36-IFNγ loop, promoting early disease independent of plaque-specific antigen. To test this, we assessed the homing of adoptively transferred CD8 TCR transgenic T cells that were antigen-primed and CD137-costimulated within recipient mice. Comparison of physiologic LDF regions (aortic arch) with experimentally induced LDF (PCAL) reveals that effector CD8 T cells substantially and preferentially accumulate within LDF areas, even without TCR-specific stimuli in the vessel wall. Notably, cells isolated from these regions produce IFNγ in response to IL-36. Mass cytometry (CYTOF) and single cell RNA-seq analyses are underway to build mechanistic understandings of how LDF triggers immune cell recruitment and signaling cascades. Overall, our studies propose a novel role for IL-36 within the vascular system and provide insight into the early pathogenesis of atherosclerosis, especially in the context of autoimmunity and antigen-independent T cell activation.
Loss of the von-Hippel Lindau gene in osteocytes alters B lymphocyte development and immune response
Authors: Chicana Betsabel J. , Genetos Damian , Yellowley Clare , Murguesh Deepa , Loots Gabriela G. , Manilay Jennifer O. 
Published: January 2023

Abstract
The von-Hippel Lindau protein (VHL) regulates hypoxia-inducible factor (HIF) degradation. Conditional-deletion of VHL in osteoblasts and in hematopoietic progenitors have demonstrated a role for VHL in these cell types, but how changes in bone homeostasis affects immune development are not fully understood. Osteoblasts (OBs) support B cell development. OBs mature into osteocytes (OCYs) and to test if OCYs also support B cell development, we generated OCY-specific (Dmp-Cre) conditional VHL knockout (cKO) mice. cKO mice display dysregulated bone growth, high bone density, smaller bone marrow (BM) cavity volume, and overall decrease in BM cellularity compared to controls. In line with this, the frequencies and numbers of B cell precursors (B220+ IgM−), immature B (B220+ IgMint) and recirculating B (B220+ IgMhigh) cells in the bone marrow are significantly decreased. These data suggest that the change in bone homeostasis adversely affects B cell development in a cell-extrinsic manner. Although the absolute numbers of B cells in the spleens of cKOs were normal, we hypothesized that loss of VHL in OCYs could permanently and adversely affect B cell functional response. To test this, VHL cKO mice were immunized with a T-independent antigen (NP-Ficoll). IgM and IgG3 antigen-specific titers to NP-Ficoll in VHL cKOs were similar to WT mice. Testing of B cell responses to T-dependent antigens (NP-OVA) is ongoing. Taken together, our data suggest that OCY-specific VHL deletion might be helpful to increase bone density, but at the expense of B cell numbers. Further investigation is required to understand the molecular mechanisms by which VHL in OCYs contribute to its putative role as a B cell niche cell.
Long-lived plasma cells regulate patterns of hematopoiesis in aging.
Authors: Pioli Peter D. , Casero David , Montecino-Rodriguez Encarnacion , Morrison Sherie L. , Dorshkind Kenneth A. 
Published: January 2023

Abstract
In both humans and mice, aging results in significant alterations to the patterns of bone marrow hematopoiesis. This is highlighted by a precipitous reduction in B lymphopoiesis while myelopoiesis is enhanced. Treatment of young mice with factors such as GM-CSF or IL-1 can skew hematopoiesis towards myeloid development. This suggests that imbalances in the relative concentrations of various cytokines such as inflammatory mediators, whose production is thought to increase with age, could contribute to suppressed lymphoid and enhanced myeloid development in aging. In this case, the resulting stimulation of myelopoiesis would dominate the limited number of niches in the bone marrow environment at the expense of lymphopoiesis. However, whether the age-related decline in lymphopoiesis and increase in myelopoiesis are linked or represent distinct processes is not known. We observed that long-lived plasma cells from old mice acquire an inflammatory gene signature and accumulate in the bone marrow. Addition of long-lived plasma cells to long-term in vitro cultures demonstrated the ability of these cells to promote granulopoiesis from hematopoietic stem cells as well as myeloid progenitors. However, while depletion of long-lived plasma cells in old mice by injection of anti-CD138 antibodies resulted in a significant reduction in myeloid development, B lymphopoiesis remained suppressed. These data demonstrate a previously unappreciated ability of inflammatory plasma cells to stimulate myelopoiesis and provide evidence that, in the context of aging, enhanced myelopoiesis and depressed lymphopoiesis are distinct, independently regulated processes.