bluuebunny/crossref_metadata_2025_split huggingface dataset:
Earliest Lymphoid Precursors in the Fetal Liver Contribute Constructing Mucosal Immunity in a HSC-Independent Manner
Authors: Kobayashi Michihiro , Cornelius Samuel , Cheng Haizi , Hughe David , Syed Alina , Lattore Augsto , Variente Noemi , Nishida Chika , Yoshimoto Momoko 
Published: November 2024

Abstract
We've been clarifing the role of hematopoietic stem cell (HSC) -indepenbdent progenitors for the consisting the post-natal immune-layers. Recent our repors, combining fate-mapping (FM) study and transplantation of E11.5 AGM cells, displayed nearly half of lympoid cells are maintained by HSC-independent progenitors even in old mice. Here, we characterized eariest lymoid progenitors in the E12.5 fetal liver (FL) by using IL-7RCre:flox-dTom mice and FM study. Unlike protein expression, dTom % in the E12 FL lin-Sca1-Kit+ (LSK) cells were more than 30% (34.8 ± 7.2%, n=7). Tom+ or Tom- LSK cells were further divided into HSC (CD48loEPCRhi) and MPP (CD+EPCRlo~dim) and sorted 4-populatios were transplanted into NSG mice. Recipients with Tom-HSCs showed multi-lineage reconstitution wile MPPs (Tom- or Tom+) repopulated B-1 and T-cells. Interestingly Tom+CD48loEPCRhi, phenotypically equivalent to HSCs, exibited unique properties that reconstituted only B-1 cells in PerC and IgA+ cells and type 2 innate lymphoid cells in the small intestine. These data suggest HSC-independent PerC B-1a cells and IgA+ cells share the common progenitor.
As for FM study, we labeled neonatal HSC with dTom by injecting p2 Tamoxifen into Fgd5-based FM model, resulted in very lower contribution to the IgA+ B-cells in the lamina proplia. Relative Tom percentage showed 0.382 ± 0.12, indicating IgA+ cells are maintained by largely HSC-indepent mannar than previously thought.
Siglec-H ablation in plasmacytoid dendritic cells alleviates acute liver injury by promoting IL-21+ CD4 T cells
Authors: Ahodantin James , Wu Jiapeng , Funaki Masaya , Flores Jair , Wang Xu , Zheng Pan , Liu Yang , Su Lishan 
Published: November 2024

Abstract
Siglec-H is an immune receptor specifically expressed in plasmacytoid dendritic cells (pDCs) that inhibits IFN-α production and regulates pDC maturation. Although, the role of pDCs in autoimmune disorders is well-known, the effect of Siglec-H expression in pDCs in acute liver injury (ALI) remains elusive. To investigate Siglec-H/pDCs axis in ALI, BDCA2 transgenic and Siglec-H knockout (SH KO) mice were administrated with concanavalin A (ConA) to induce a T cell-mediated ALI in combination of either pDCs depletion with anti-BDCA2 antibody or anti-IL-21R and Stat3 blockade. Here, we report that specific depletion of pDCs in BDCA2 transgenic mice exacerbated ALI. Surprisingly, SH KO mice were resistant to ALI (lower ALT, hyaluronic acid, IL-6 and TNF-α). Th1/IFN-γ response and Stat1 signaling were both inhibited in the liver of SH KO mice while intrahepatic IL-21 and Stat3 signaling pathways were elevated. Mechanistically, we identified that Siglec-H-null pDCs exhibited immunosuppressive phenotypes (CD40LowCCR9Low), resulting in a defective CD4 T cell activation and a promotion of IL-21-producing CD4 T cells in the liver. Finally, IL-21R and Stat3 inhibitions in Siglec-H deficient mice restored ConA-induced ALI. We conclude that, Siglec-H-null pDCs mediate hepatic tolerance via induction of IL-21+CD4 T cells in the liver during ALI. These findings indicate that targeting Siglec-H/pDCs axis may provide a novel approach to modulate CD4 T cell polarization and liver disease.
Liposomal clodronate attenuates inflammation in a mouse model of myocardial infarction
Authors: Boyanova Katherine , OBarr Stephen , Lambros Maria , Agyare Eugene 
Published: November 2024

Abstract
Heart failure (HF) is defined as the inability of the heart to pump eough blood to meet the demands of the body. HF affects over 64 million people worldwide and is the leading cause of death, yet current treatment options do not effectively decrease mortality. The relationship between HF onset and the immune system has been vastly explored, revealing that cardiac tissue undergoes harmful remodeling after a myocardial infarction (MI) that leaves a permanent scar on the heart. Prolonged inflammation and excessive macrophage infiltration lead to a larger infarct area and increased scar formation. Our lab has demonstrated that early inflammation inhibition reduces the damage caused by an (MI). Specifically, we used liposomal clodronate as a macrophage inhibitor to reduce the inflammatory response. In this study, MI was induced using a single high dose of isoproterenol and treated with liposomal clodronate 24hrs after MI. Inflammation levels were assessed through quantification of various pro- and anti-inflammatory cytokines by ELISA and macrophage depletion and polarization was tracked using flow cytometry. At 10 days, heart tissue was harvested for immunohistochemical (IHC) analysis. Our data indicated that liposomal clodronate has anti-inflammatory properties as supported by the decrease in pro-inflammatory cytokines and macrophages. Moreover, IHC analysis revealed less collagen fibers, suggesting a lower area of cardiac remodeling and retained overall structure.
Lrba-/- murine B cells show NF-κB overactivation and altered BCR signaling.
Authors: Pérez-Pérez Daniela , Flores-Hermenegildo José Mizael , Romero-Ramírez Hector , Kilimann Manfred , Santos-Argumedo Leopoldo , López-Herrera Gabriela 
Published: November 2024

Abstract
Lipopolysaccharide-Responsive Beige-like anchor (LRBA) is a scaffolding protein whose deficiency is associated with an inborn error of immunity error like common variable immunodeficiency. Patients with LRBA deficiency have a heterogeneous clinical presentation including hypogammaglobulinemia, reduction of B and T regulatory cells, recurrent infections, and autoimmune diseases. Functions of Lrba on T regulatory cells have been described, however, function on B cells remains unknown. This work aims to identify the function of Lrba in B-cell receptor (BCR) signaling.
Lrba-deficient mice (Lrba-/-) have a higher number of Transitional 1 B cells in the spleen. Flow cytometry assays showed reduced B cell proliferation and an increased cell death, in response to B-cell Receptor (BCR) crosslinking. Immunoblot and confocal microscopy revealed an increased activation of p50, p65, and IκBα (components of the canonical pathway of NF-κB) in Lrba-/- B cells under basal conditions with a subsequent reduced response after BCR crosslinking. Co-immunoprecipitation assays suggest an interaction between Lrba and components of BCR signaling such as PLC-γ2 and p65.
The activated phenotype of Lrba-/- B cells as well as the interaction with p65 and PLC-γ2 indicates that Lrba is involved in the regulation of NF-κB activation driven by BCR signaling, which finally impacts on survival of B cells.
Piezo1 impacts early CD4+ T cell activation that leads to increased expression of exhaustion markers and decreased effector persistence.
Authors: Santin Alicia , Myers Jay , Choi Sung Hee , Huang Alex 
Published: November 2024

Abstract
The emergence of novel biophysical approaches has revealed that mechanosensing at the immunological synapse is critical in regulating T cell activation and function. To investigate the role of the mechanosensitive cation channel, Piezo1, on T cell function, we generated T cell specific Piezo1 knockout mice (P1cKO). Previously we demonstrated that Piezo1 restrains inflammatory Th1 and Th17 polarization in vitro. However, Piezo1 deficiency in T cells ameliorated disease progression in primary autoimmune mouse models, while completely ablating disease phenotype in adoptive transfer autoimmune mouse models. Therefore, we hypothesized that Piezo1 deficiency in T cells increases T cell receptor (TCR) signaling and activation leading to increased T cell exhaustion and apoptosis. Preliminary studies of early TCR signaling suggest that P1cKO CD4+ T cells have increased phosphorylated ZAP-70 (pZAP-70) compared to wildtype, and Piezo1 activation by Yoda-1 conversely decreased pZAP-70. After 3 days of TCR stimulation P1cKO CD4+ T cells similarly expressed activation markers CD25, CD69, and CD95 compared to wildtype, but had an increased expression of exhaustion markers LAG-3, PD-1, and TIGIT. Cell tracking in vivo revealed that P1cKO effector CD4+ T cells expand rapidly after transfer but fail to persist long term. Taken together, our data suggests that Piezo1 plays an important role during early T cell activation that ultimately restrains hyper inflammatory CD4+ T cell responses.
Development of an anti-TRBC2 antibody for flow cytometry.
Authors: Rigaud Stephanie , Kannan Arthi , Cantor Joseph , Verma Shilpi 
Published: November 2024

Abstract
Each chain of the αβ T-cell receptor (TCR) contains a constant (C) region and an antigen-binding variable (V) region. There are two human isoforms of the TCR β chain, TRBC1 and TRBC2, differing slightly in the constant region, and individual αβ T-cells express one isoform or the other. The ratio of TRBC1+ to TRBC2+ αβ T-cells falls within a characteristic range of healthy donors; monoclonal T-cell malignancies skew this ratio dramatically. A monoclonal antibody specific for TRBC1 (clone JOVI.1) is unable to directly identify both TRBC1+ and TRBC2+ T cell malignancies as is done for B cell cancers using k and λ-specific antibodies. Here we characterize clone SAM.2.rMAb, to our knowledge the first monoclonal antibody that selectively binds TRBC2, and demonstrate its use by flow cytometry in combination with JOVI.1 to confirm the mutually exclusive expression of TRBC1 and TRBC2 in T cells, NKT cells, MAIT cells and Treg. This new clone allows direct identification of TRBC2+ cells, is compatible with BD buffers and can be used in phenotyping panels that include TCRαβ and CD3 antibodies. SAM.2.rMAb is thus a valuable flow cytometry reagent to potentially combine with JOVI.1 in building rapid and low-cost research use only immunophenotyping assays for basic and applied research on human T-cell malignancies.
For Research Use Only. Not for use in diagnostic or therapeutic procedures.
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Nerve- and Airway-Associated Interstitial Macrophages Regulate Anti-Tumor CD8 T Cell Immunity in Tumors in the Lung
Authors: Bartnicki Eric , Yeung Stephen , Damani-Yokota Payal , Khanna Kamal 
Published: November 2024

Abstract
The suboptimal response rates among cancer patients receiving T cell-based immunotherapy underscore the necessity of addressing additional facets of the immune system that may contribute to tumor promotion. Macrophages are a main immune cell subset in tumors and elucidating their immunomodulatory roles on T cell-mediated anti-tumor responses is paramount. We previously identified a novel macrophage subset known as Nerve- and Airway-associated interstitial Macrophages (NAMs), which exhibit a remarkable immunoregulatory phenotype. Thus, we investigated the hypothesis that NAMs promote tumor growth and metastasis. Using the B16F10 melanoma-based lung metastatic model, we observed that unlike alveolar macrophages (AMs), NAMs uniquely localize to tumors that form along large airways and vasculature. Moreover, tumors that were primarily infiltrated by NAMs exhibited less CD8 T cell presence when compared to tumors devoid of NAMs, suggesting that NAMs regulate anti-tumor T cell responses. Exclusive depletion of NAMs resulted in strikingly lower tumor burden in the lungs, which was associated with a significant increase in CD8 T cell recruitment to the TME; and increased presence of anti-tumor ‘CD8-DC-CD4 triad’ interactions within the TME with CD8 T cells exhibiting an exhausted progenitor-like anti-tumor phenotype. Our findings also furnish compelling evidence to redirect our endeavors towards prioritizing NAMs as a therapeutic target in lung tumors.
VH14-2 mediated nuclear speckles association contributes to radial positioning of the Igh locus and regulates VDJ recombination
Authors: Priyadarshi Saurabh , Drake Ellen , Bhat Khalid , Farooq Hammad , Kleiman Eden , Lei Xue , Liang Jie , Feeney Ann , Kenter Amy 
Published: November 2024

Abstract
The Igh locus undergoes large-scale contraction and repositions to the nuclear center prior to V(D)J recombination. However, little is known about the mechanisms that mediate these processes. We recently identified a chromatin loop anchor which corresponds to a highly transcribed VH gene promoter (VH14-2 Pr) (Nat Commun 14:1225, 2023). Here we report that VH14-2 deletion increased locus contraction which was expected to increase VDJ recombination. However, deletion of the VH14-2 gene severely reduced VDJ recombination. This implied that another mechanism may contribute to VDJ recombination. Strikingly, Igh loci accumulated toward nuclear periphery in Rag2-/-VH14-2-/- pro-B cells indicating the failure of radial repositioning. Thus, efficient VDJ recombination is linked to repositioning of the Igh locus and implies that the VH14-2 gene anchors the locus in the nuclear center. Highly transcribed genes often associate with nuclear speckles that tend to locate to the nuclear center. As VH14-2 is highly transcribed we asked whether it associates with nuclear speckles. We found that the Igh locus overlaps with nuclear speckles and this association was significantly reduced in Rag2-/-VH14-2-/- pro B cells as visualized using a combination of DNA and immuno-fluorescence in situ hybridization (FISH). This study identified the VH14-2 gene as a tether that anchors the locus to nuclear speckles and in turn contributes to radial positioning and VDJ recombination.
Naturally occurring polymorphisms reveal the cis-regulatory sites and transcription factors controlling follicular and marginal zone B cells
Authors: Roman Carly , Hicks Sakeenah , Gupta Mansi , Scharer Christopher 
Published: November 2024

Abstract
The splenic B cell compartment consists of follicular (FoB) and marginal zone (MZB) B cells. In contrast to FoB, MZB exist in a poised state and rapidly respond to blood-borne pathogens in the absence of T cell help, predominately generating a rapid wave of short-lived plasma cells. These differences in responses are driven by differential genetic and epigenetic priming of each subset. MZB epigenetic programming are enriched for bHLH, POU, Rel and RUNT motifs, whereas FoB are enriched for IRF and KLF motifs. MZB also exhibit increased expression of genes associated with Notch signaling, Myc, and mTORC1 pathways. However, it is unclear how sequence specific transcription factors directly and indirectly regulate distinct states in MZB and FoB that underpin B cell activation, differentiation, and acquisition of effector functions. To address this, we generated an F1 hybrid model which utilizes naturally occurring polymorphism present in the wild-derived mouse line Spret/EiJ compared to the reference strain C57BL/6. The monoallelic polymorphisms present in this F1 generation allows us to use the allelic imbalance to dissect how alterations in genetic features impact TF binding, epigenetic architecture, and ultimately resulting gene expression programs. MZB and FoB were sorted from naive (Spret x B6) F1’s and subject to RNA and ATAC-seq. This study aims to define the cis-regulatory mechanisms responsible for the epigenetic and transcriptional differences of FoB and MZB cells.
Opposing roles of SWI/SNF chromatin remodeling complex BAF and PBAF in Effector Differentiation during Chronic Viral Infection
Authors: Kharel Arjun , Brown Ryan , Gai Kexin , Cui Weiguo 
Published: November 2024

Abstract
During chronic viral infection, CD4+ T cells help in the form of IL-21 is critical for the development of highly cytolytic effector CD8+ T cells. However, the exact signaling pathways from IL-21 that regulate CD8+ T cell function remain unclear. The current dogma states that IL-21 predominantly signals through STAT3, to generate effector CD8+ T cells during chronic viral infection.
Here, we reveal a novel mechanism of IL-21 signaling via STAT4 for effector CD8+ T cell development following chronic LCMV infection. Furthermore, STAT4-mediated effector differentiation is epigenetically regulated by BAF, a SWI/SNF chromatin remodeling complex. In the absence of either STAT4 or BAF, virus specific CD8+ T cells fail to differentiate into highly cytolytic effector CD8+ T cells capable of controlling viral infection.
The effector differentiation phenotype is balanced by PBAF, another component of the SWI/SNF complex, which promotes CD8+ T cell exhaustion during chronic LCMV infection. Conditional knockout of PBAF from CD8+ T cells impairs the development of T cell exhaustion, resulting in immunopathology and mortality of chronic LCMV-infected mice. Interestingly, this phenotype is dependent on the STAT4 and BAF-mediated transcriptional and chromatin changes. Overall, our findings underscore the delicate balance between effector and exhaustion pathways, governed by BAF and PBAF complex, to dictate the outcomes of immunopathology during chronic viral infections.
Deciphering the links between microbiome and immune profiles by multi-omics analysis during aortic plaque progression and helminth-induced regression
Authors: Lin Jian-Da , Chen Yen-Ting , Chao Pei-An , Lin I-Jung , Chou Tzu-Yin , Ye Yu-Zhen , Lien Chia-Jung , Yang Chen-Hsuan 
Published: November 2024

Abstract
Atherosclerosis is influenced by immune cells that mediate inflammation. The gut microbiota contributes to atherosclerosis by fostering inflammation when its composition is imbalanced (dysbiosis). However, the specific gut microbiota and the immune profiles that drive this process are elusive. Our multi-omics analysis addresses this gap by using spectral flow cytometry (36 markers), CITE-seq, and 16S rRNA sequencing on dysbiosis-conditioned mice to collect comprehensive data on immune profiles and microbiota composition. We induce atherosclerosis in Nod2-/- mice, which are predisposed to inflammatory bowel disease, to evaluate factors including plaque size, immune profiles, and microbiota diversity, comparing to atherosclerotic wild-type mice. Our findings highlight the Nod2 gene in helminth-induced atherosclerosis regression and illustrate unique immune cell dynamics, such as memory T cells, Ly6C+/- monocytes, and type 2 immune responses, in both wild-type and Nod2−/− mice. We observe marked shifts in microbiota diversity during the progression of atherosclerosis and the regression induced by helminths. By constructing multi-omics networks with machine learning models, we strive to link specific bacterial orders with immune cell types during atherosclerosis progression and regression. This integrative study aims to illuminate the complex interactions within the gut-heart axis and to explore novel therapeutic potentials of helminths in the treatment of atherosclerosis.
Enhanced host protection and survival to Listeria monocytogenes infection after small molecule innate training
Authors: Kim Marie , Knight Hannah Riley , Esser-Kahn Aaron 
Published: November 2024

Abstract
Homeostatic training of innate immunity can improve protection against later infections. Our lab recently reported on small molecules that induce trained immunity in vitro. Here, we aim to show the protective potential of flunisolide (FN) using live infection model. We hypothesized FN training will alter hematopoiesis and innate functionality to improve outcome to L. monocytogenes. At homeostasis, FN training skewed towards GMP and MEP lineages and away from CLP lineage. To confirm FN-induced protection, mice were infected i.n. At d3 post-infection, FN mice showed lower pathogen burden in spleen, blood, and lung. Notably, systemic burden was lower in FN mice at d2 and d3. This may be due to improved immune functionality that led to faster clearance. To test this, phagocytosis and ROS levels at d3 were measured but no significant changes were seen. Further studies on lung immune functionality and earlier timepoints may show what hinders pathogen dissemination. BM at d7 after infection showed higher percentage of Lin+ in control and Lin- cells in FN mice. This suggests BM was recovering to homeostasis in FN mice, while inflammation control was active in control. Also, BM of FN mice had significantly higher percentage of CLP, suggesting earlier onset of adaptive immune response. Furthermore, FN mice showed improved survival up to d7. We showed FN can induce innate training, altering BM landscape at homeostasis and after infection, with improved response to L. monocytogenes.
T cell TRAF3 regulates IL-4R signaling through the phosphatase PTP1B
Authors: Hornick Emma , Arkee Tina , Bishop Gail 
Published: November 2024

Abstract
The adaptor protein TNFR associated factor 3 (TRAF3) is a multifaceted regulator of lymphocyte biology that plays key roles in modulation of the molecular signals required for T cell activation and function. TRAF3 regulates signals mediated by the T cell receptor (TCR), costimulatory molecules, and cytokine receptors, which in turn drive activation of the serine/threonine kinase Akt. The impact of TRAF3 upon TCR/CD28-mediated activation of Akt, and thus on the diverse cellular processes regulated by Akt, including CD4 T cell fate decisions, remains poorly understood. We show here that TRAF3 deficiency led to impaired Akt activation, and thus to impaired in vitro skewing of CD4 T cells into the TH1 and TH2 fates. We investigated the role of TRAF3 in regulation of signaling pathways that drive TH1 and TH2 differentiation, and found that TRAF3 enhanced activation of Signal transducer and activator of transcription 6 (STAT6), thus promoting skewing toward the TH2 fate. TRAF3 promoted STAT6 activation by regulating recruitment of the inhibitory molecule Protein tyrosine phosphatase 1B (PTP1B) to the IL-4R signaling complex, in a manner that required integration of TCR/CD28- and IL-4R-mediated signals. This work reveals a new mechanism for TRAF3-mediated regulation of STAT6 activation in CD4 T cells, and adds to our understanding of the diverse roles played by TRAF3 as an important regulator of T cell biology.
Enhancement of autophagy in macrophages via the p120-catenin-mediated mTOR signaling pathway
Authors: Kanmani Suganya , Song Xue-Min , Kanmani Paulraj , Wu Xiao-Jing , Minshall Richard , Hu Guochang 
Published: November 2024

Abstract
Autophagy serves as a critical regulator of immune responses in sepsis. Macrophages are vital constituents of both innate and adaptive immunity. In this study, we delved into the intricate role of p120-catenin (p120) in orchestrating autophagy in macrophages, particularly in their response to endotoxin stimulation. Depletion of p120 effectively suppressed lipopolysaccharide (LPS)-induced autophagy in both J774A.1 macrophages and murine bone BMDMs. LPS not only elevated the interaction between p120 and LC3I/II, but also facilitated the binding of p120 with mTOR. The absence of p120 led to the inhibition of LPS-induced dissociation between mTOR and ULK-1, consequently promoting the phosphorylation of ULK-1 upon LPS stimulation in macrophages. p120 depletion also heightened LPS-triggered macrophage apoptosis, as evidenced by increased levels of cleaved caspase 3. Notably, a decrease in apoptosis observed in macrophages overexpressing p120 upon LPS stimulation was reversed by inhibiting autophagy. Additionally, the ablation of p120 accentuated LPS-induced alveolar macrophage apoptosis in LPS-challenged mice. Collectively, our findings strongly suggest that p120 plays a pivotal role in fostering autophagy while concurrently hindering apoptosis in macrophages, achieved through modulation of the mTOR/ULK-1 signaling pathway in sepsis. This underscores the potential of targeting macrophage p120 as an innovative therapeutic avenue for treating inflammatory disorders.