bluuebunny/crossref_metadata_2025_split huggingface dataset:
The divergence of PD-1+CXCR5+CD4+ T cell differentiation and stage-specific regulation of GC-Tfh cells
Authors: Zhu Fangming , McMonigle Ryan J , Schroeder Andrew R , Xia Xianyou , Figge David , Greer Braxton D , González-Avalos Edahí , Sialer Diego O , Wang Yin-Hu , Chandler Kelly M , Getzler Adam J , Brown Emily R , Xiao Changchun , Kutsch Olaf , Pipkin Matthew W , Hu Hui 
Published: August 2023

Abstract
T follicular helper (Tfh) cells were discovered as CD4+ T cells in the B cell follicles that express CXCR5 and help germinal center (GC) B cell responses. However, it is not clear which PD-1+CXCR5+Bcl6+CD4+ T cells will differentiate into PD-1hiCXCR5hiBcl6hiGC-Tfh cells while the others have a different fate, nor is it clear how GC-Tfh cell differentiation is regulated. Here we report that the sustained Tigit expression in PD-1+CXCR5+CD4+ T cells marked the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit−PD-1+CXCR5+CD4+ T cells upregulated IL-7Ra to become CXCR5+CD4+ T memory precursor/memory cells—with or without a CCR7+ (or CCR7+CD62L+) central memory phenotype. Our study further shows that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. Mechanistically, we find that c-Maf exerted an important function in the pre- to GC-Tfh transition, and we have identified c-Maf downstream factor Plekho1 as a novel regulator that played a stage-specific role in GC-Tfh cell differentiation.
Covalent TCR-pMHC Interactions: A New Mechanism for T Cell Antigen Recognition and T cell Activation
Authors: Zareie Pirooz , Szeto Christopher , Wirasinha Rushika , Zhang Justin Boxuan , Nguyen Andrea , Riboldi-Tunnicliffe Alan , La Gruta Nicole , Gras Stephanie , Daley Stephen 
Published: August 2023

Abstract
Noncovalent bonds typically mediate interactions between a T cell receptor (TCR) and a peptide-major histocompatibility complex (pMHC) ligand. In this study, we describe a novel mechanism involving a covalent TCR-pMHC interaction through a cysteine-cysteine disulfide bond. By introducing cysteine resodues into the TCR CDR3 and into the peptide of a known TCR-pMHC combination, we show that this disulfide bond formation does not require structural rearrangement and can still occur even when the initial affinity of the TCR-pMHC interaction is low. This mechanism strongly activates TCR signaling and has potential applications in basic immunology to further our fundamental understanding of T cell activation/differentiation as well as applied clinically for improving the efficacy and sensitivity of adoptive T cell therapies. Our findings shed new light on T cell activation and provide additional avenues for the development of modern immunotherapy.
DNA demethylation fine-tunes IL-2 production during thymic development and promotes Regulatory T cell differentiation
Authors: Issuree Priya D , Teghanemt Athmane , Heath Jace , Thurman Andrew , Pezzulo Alejandro 
Published: August 2023

Abstract
Regulatory T (T reg) cells developing in the thymus are essential to maintain tolerance and prevent fatal autoimmunity in mice and humans. Expression of the T reg lineage-defining transcription factor FoxP3, is critically dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that ten-eleven translocation (Tet) enzymes, which are DNA demethylases, are required early during double positive (DP) thymic T cell differentiation and prior to the upregulation of FoxP3 in CD4 single-positive (SP) thymocytes, to promote Treg differentiation. We show that Tet enzymes selectively control the development of CD25− FoxP3lo CD4SPTreg cell precursors and are critical for optimal TCR-dependent IL-2 production, which drive chromatin remodeling at the FoxP3 locus as well as other Treg-effector gene loci in an autocrine/paracrine manner. Together, our results demonstrate a novel role for DNA demethylation in regulating the TCR response and promoting Treg cell differentiation. These findings highlight a novel epigenetic pathway to promote the generation of endogenous Treg cells for mitigation of autoimmune responses.
Sex disparities in pathological features and autoimmunity in high fat diet associated lupus mouse model
Authors: Zhang Xin , Meng Juan , Lobo Gitanjali , Patel Ronak , Ray Alicia Nicole , Quinet Robert , Davis William , Zakem Jerald , Hayat Samina , You Zongbing 
Published: August 2023

Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is more common in women than men. SLE has been reported with diverse clinical phenotypes of varying severity, which may be caused by sex hormones and environmental factors. Our recent studies showed that high-fat diet (HFD) exacerbated lupus development in MRL/lpr lupus-prone mice. Here we explored the gender difference in lupus progress and autoimmune response to HFD.
Twenty male and twenty female MRL/lpr mice were evenly grouped and fed with a regular diet (RD, 10% fat) or HFD (60% fat) for 14 weeks. Body weights were recorded weekly. SLE progression was monitored by skin lesions, urine protein, titers of anti-dsDNA antibody in serum. Kidney and skin from the dorsum of the neck were embedded for H&E, PAS, and Masson’s staining quantified as kidney index and skin score. Immune cells in the spleens were identified by immunofluorescence staining and flow cytometry.
HFD induced a greater weight gain in female mice than male mice (p&lt;0.01). Skin rash showed up as early as week 6 in female HFD group with a greater histopathological skin score (p&lt;0.01). Splenomegaly, proteinuria, and anti-dsDNA level were increased only in male HFD group. Kidney pathological changes were more severe in male HFD mice with significant increase of kidney index (p&lt;0.05). Significant increases of germinal center B cells, plasma cells, and T follicular helper cells were observed in HFD mice (p&lt;0.05).
SLE progression is sexually dimorphic in lupus-prone mice in response to HFD. Our results parallel many known clinical lupus phenotypes and sexual dimorphism in which male patients are more likely to have severe disease (such as nephritis) than female lupus patients who may have a broader range of lupus symptoms.
None
Regulation of CD4 T-cell immunity by eukaryotic Elongation Factor 2 Kinase
Authors: Peng Hao-Yun , Song Jianxun 
Published: August 2023

Abstract
CD4 T cells are a major source of inflammatory cytokines to manage the immune responses, and there is evidence showing that IL-17-secreting helper CD4 T cells (Th17 cells), play a critical role in autoimmune diseases. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is a protein kinase that negatively regulates the elongation step of protein synthesis. eEF2K regulates vascular inflammatory responses and hypertension development, yet a complete immunologic characterization of eEF2K, particularly in CD4 T cells and autoimmune diseases, remains obscure. Defining eEF2K-mediated CD4 T cell activities, including CD4 T cell inflammation and metabolism, will significantly enhance our knowledge toward the goal of improving health span. Here, we reported that eEF2K is essential for the survival and proliferative capacity of CD4 T cells. eEF2K deficient mice displayed a higher metabolic profile and increased production of inflammatory cytokines. By analyzing CD4 T cells from the wild type (WT) and eEF2K deficient mice, we revealed that eEF2K regulates mitochondrial stress capacity and the production of reactive oxygen species (ROS) through the master transcription factor, STAT3. Depletion of eEF2K agitated Th17-related autoimmune diseases, including arthritis and colitis. A STAT3 inhibitor, C188–9, attenuated Th17 cell-mediated autoimmune colitis by reducing inflammation in the murine colitis model that received eEF2K deficient CD4 T cells. Our findings provide insights into the regulation of CD4 T cells and autoimmunity by eEF2K, and further investigations would help design novel strategies by targeting eEF2K-based immunotherapy in autoimmune diseases.
Obesity Modulated Gut Microbiota Exacerbate Disease Severity in HLA-Class II Transgenic Mouse Model of Multiple Sclerosis
Authors: Shahi Shailesh K , Ghimire Sudeep , Lehman Peter , Rux Allison G , Mangalam Ashutosh K 
Published: August 2023

Abstract
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS where interaction among multiple environmental and genetic factors influence disease outcome. HLA class II alleles such as HLA-DR2 and –DR3 are considered strongest genetic factors linked with MS, whereas recently gut microbiota have emerged as an important environmental factor linked to MS. Additionally, obesity has been shown to promote MS disease severity. However, the mechanistic link between gut microbiota and obesity in pathobiology of MS is unknown. HLA-DR3 transgenic mice on a high-fat diet (HFD) to induce obesity, resulted in severe EAE compared to normal chow diet (NCD). Antibiotic-mediated gut microbiota depletion and fecal transplant studies established that the microbiota is necessary and sufficient for obesity to potentiate EAE severity. Obesity-associated microbiota alterations included increases in bacterial genes linked with hydrogen sulfide (H2S)-metabolism, with concordant increases in fecal H2S. Further, mice on HFD showed increased gut permeability and systemic inflammation compared with NCD group. Altogether, this study provides evidence for involvement of the gut microbiome and associated H2S-metabolism microbial genes in obesity induced modulation of EAE severity. Dissection of these pathways will help to identify novel therapeutic targets to reduce disease severity in obese patients.
The Author acknowledge funding from the National Multiple Sclerosis Society grant (RG 5138A1/1T), National Institutes of Health/NIAID (1R01AI137075), the University of Iowa Environmental Health Sciences Research Center, NIEHS/NIH (P30 ES005605), and a gift from P. Heppelmann and M. Wacek to AM.
Development of monoclonal antibodies and antigens as liquid biopsy reagents for IgA nephropathy
Authors: Ka Shuk-Man , Chen Yi-Liang , Chen Ann 
Published: August 2023

Abstract
IgA nephropathy (IgAN) is the most common primary autoimmune glomerular disorder across the world. A renal biopsy examination is absolutely required for final diagnosis. In particular, IgAN has been categorized as an autoimmune disease that features IgA-ICs formed by galactose-deficient (Gd)-IgA1 (autoantigen) and corresponding IgG anti-Gd-IgA1 (autoantibody). Therefore, it is clinically warranted to develop a liquid kidney biopsy for non-invasive or only minimally invasive approaches for early diagnosis of IgAN and to ease monitoring the evolution of the disease. We have recently developed three monoclonal antibodies namely EASON1, EASON2, and EASON3, and each of them shows high discriminative rate in differentiating IgAN patients and healthy control subjects by doing ELISA-based analyses to determine serum Gd-IgA1 levels (Provisional patent - T2392-US, USA entitled “Production of IgG monoclonal antibody series anti-galactose deficient IgA1 and IgA1 bearing O-linked glycans; Provisional patent - 63/119,215, USA entitled “Development of a series of IgM monoclonal antibodies as non-invasive diagnostic reagents for IgA nephropathy; a regular patent application under review). Moreover, we have successfully developed 62 human hybridoma cell lines that produce Gd-IgA1, each of which will be useful in designing tests for the detection of serum IgG autoantibodies against Gd-IgA1 levels (Provisional patent - T2392-US, USA). In conclusion, both the 3 mouse monoclonal antibodies and 62 human Gd-IgA1-producing hybridoma cell lines may be further developed as promising diagnostic reagents for a liquid kidney biopsy for IgAN, allowing for early, rapid, and non-invasive tests for the renal disease.
Supported by grants from Ministry of Science and Technology, Taiwan (MOST 108-2321-B-016-002, 109-2314-B-016 -034 -MY3)
Distinct roles of kindlin-3 and talin-1 in neutrophil beta2 integrin clustering
Authors: Wu Yuanyuan , Wen Lai , Ley Klaus , Fan Zhichao 
Published: August 2023

Abstract
Neutrophils are the most abundant leukocytes in human blood. Neutrophil malfunction may cause various immunological diseases. Beta2 integrins are critical for neutrophil recruitment. Kindlin-3 and talin-1 are important regulators for beta2 integrin activation. We have confirmed this using conformation-specific antibodies KIM127 and mAb24 that recognize activation epitopes in beta2 integrin. Besides activation, clustering is also critical for beta2 integrin avidity and adhesion of neutrophils. Whether kindlin-3 and talin-1 are involved in beta2 integrin clustering remains unclear. Here we used super-resolution stochastic optical reconstruction microscopy (STORM) to study their roles in beta2 integrin clustering on human neutrophil-like HL60 cells. We find that lymphocyte function-associated antigen 1 (LFA-1) and macrophage-1 antigen (Mac-1) are significantly clustered in wild-type cells after IL-8 or fMLP stimulation. Using CRISPR-Cas9-mediated kindlin-3 and talin-1 knockout HL60 cells, we found that kindlin-3 but not talin-1 are responsible for beta2 integrin clustering. Our study provides new insights into the regulation of beta2 integrin clustering and leukocyte recruitment.
Supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454), and a startup fund from UConn Health.
In vivo cell tracking reveals the pattern of neutrophil tissue distribution at baseline and in response to glucocorticoid treatment
Authors: Bohner Ariel M , Gadkari Manasi , Makiya Michelle , Hong So Gun , Cao Qilin , Potter E Lake , Xing Fan , Calvo Katherine , Klion Amy , Howe Katherine N , Kaplan Mariana J , Roederer Mario , Sato Noriko , Dunbar Cynthia , Franco Luis M 
Published: August 2023

Abstract
Neutrophils are the most abundant circulating immune cell in humans and primates, and they play a central role in inflammation and innate immunity. Glucocorticoids (GCs) are the cornerstone of anti-inflammatory and immunosuppressive therapies. While GCs are known to induce neutrophilia, little is known about the underlying kinetics or molecular mechanisms. To better define the kinetics of GC-induced neutrophilia, we studied healthy human volunteers and rhesus macaques, and found that the neutrophilia peaks within 4 hours of GC infusion and lasts beyond 72 hours. Flow cytometry, nuclear morphology, and single-cell RNA-seq confirmed that GC-mobilized neutrophils are mature and do not have the CXCR1lo/ICAM1hi reverse-transmigration phenotype. To study the pattern of neutrophil tissue distribution in vivo, we are performing live tracking of neutrophils by PET/CT and serial intravascular staining (SIVS), before and after GC in a rhesus model. Initial Zr-89 oxine PET/CT results indicate that re-injected radiolabeled neutrophils transit the lungs quickly and within 24 hours localize to the liver, bone marrow, and spleen, where the signal remains stable for at least 72 hours. GC treatment does not appear to lead to significant re-distribution of tissue neutrophils. Initial SIVS results indicate that most GC-mobilized neutrophils had been in circulation for less than a day and came from the intravascular compartment. In summary, our findings to date indicate that neutrophils have stable and prolonged tissue localization, and that GCs rapidly mobilize a small proportion of the total neutrophil pool, composed mainly of mature cells that were present in the intravascular compartment at the time of treatment.
supported by grants from NIH (Intramural Research Program – NIAMS/NIH)
Dendritic cells regulate innate cell trafficking and lymph node organization during inflammation
Authors: Huang Jessica , Wu Yixuan , Gerner Michael 
Published: August 2023

Abstract
Organization of immune cells within lymph nodes (LNs) is critical for effective host defense. During vaccination or infection, layers of innate cell activity in the outer periphery of the LN provide immediate protection, while antigen-presenting dendritic cells (DCs) migrate into the T cell zone (TZ), located deeper in the LN, to initiate later-stage adaptive responses. Using mouse models of vaccination and infection, we now find that DC activation and repositioning into the TZ is tightly associated with localized recruitment of multiple innate effector cells, including neutrophils, monocytes, and NK cells, which also rapidly infiltrate the TZ. As activated DCs migrated towards the TZ, they passed by the high endothelial venules (HEVs), where they expressed multiple inflammatory chemokines and high levels of the integrin ligand, ICAM-1, generating a chemokine- and adhesion molecule-rich matrix ripe for innate cell migration. Depletion of DCs, or conditional ablation of ICAM-1, significantly impaired innate cell trafficking into LNs, and cells which did enter remained largely trapped near the HEVs and were less able to infiltrate the TZ. While essential for innate defense, neutrophil influx also led to large-scale disruption of the TZ and impaired early T cell activation. However, over time this was controlled by DCs and DC-recruited monocytes, which efferocytosed the infiltrating neutrophils and cleared the TZ to allow productive adaptive responses to occur. Thus, in addition to their classical roles in antigen presentation, DCs orchestrate innate cell recruitment and activation across the entire LN, to promote both effective innate defense as well as rapid restoration of LN architecture for the generation of adaptive immunity.
Supported by grant from NIH (1F31AI161316-01).
Diabetic wound macrophage IL6 drives fibroblast dysfunction via the histone methyltransferase, SETDB2
Authors: Joshi Amrita D , Barrett Emily C , Mangum Kevin D , Mazumder Purba , Rocco Sabrina , Erturk Asuman , Kai Rohan , Moon Jadie Yoonjoo , Wolf Sonya , Gallagher Katherine 
Published: August 2023

Abstract
Interactions between innate immune cells and structural cells are vital to proper tissue repair and regeneration after injury. Under pathologic conditions such as type 2 diabetes (T2D), Mϕs exist in a chronic inflammatory state that drives dysregulated wound repair, in part by altering the fibroblast response to injury. We have previously shown that wound Mϕs from a murine model that mimics T2D (diet-induced obese mice; DIO) physiology, display increased levels of inflammatory cytokines, including IL6. Here, we found that rIL6 drives CD202-, CD45-, CD31-, Epcam-, TER119-fibroblasts isolated from wounds to produce decreased levels of col1A and periostin, two mediators that are crucial for fibroblast function in wound repair. Although the underlying mechanisms remain unclear, we and others have shown that both immune and structural cell functions in tissues can be controlled by epigenetic modifications that alter gene expression. Using our human single cell sequencing data from T2D wounds we identified that the histone methyltransferase, SETDB2, was increased in T2D fibroblasts, compared to non-wounded controls. We then isolated fibroblasts from wounds and stimulated them with rIL6 and identified an increase in H3K9me3, the histone methylation mark specific for SETDB2, at the promoters of the col1A and periostin genes. Increase in this repressive mark serves to decrease gene expression. Our findings reveal a previously unreported role for SETDB2 in regulating fibroblast function in tissue repair. Moreover, our data suggest that the diabetic milieu promotes increased expression of SETDB2 which, in turn, may contribute to maintaining the impaired fibroblast function in diabetic wounds that hinders tissue repair.
Pulmonary Mycobacterium tuberculosis infection alters the hepatic immunometabolic landscape and compromises insulin responsiveness early after infection
Authors: Cooper Andrea May , Das Mrinal , Pearl John 
Published: August 2023

Abstract
Immunity against Mycobacterium tuberculosis (Mtb) is associated with both regional and systemic inflammation as well as with metabolic disruption in tuberculosis (TB) patients. The metabolic and immunological responses are intertwined but the specific impact of localized disease on systemic metabolism is not well defined. We investigated the impact of low dose aerosol infection of the lung with Mtb on the systemic metabolic regulatory organ – the liver. Using an unbiased approach we defined the mRNA and protein dysregulation occurring in the early stage of infection. We found that infection leads to immune pathway activation and reduced metabolic activity in liver. Comparison of the gene expression patterns between of the lung, liver and blood revealed organ specific metabolic gene dysregulation in the context of non-organ specific activation of interferon response pathways. We have also found that infection leads to suppression of carbohydrate and lipid metabolism, without alteration of fasting or random blood glucose levels. Infected mice show reduced sensitivity to exogenous insulin but the glucose tolerance remains intact indicating insulin resistance. Analysis of metabolomics data from public repository reveals a metabolic signature of insulin resistance correlates with TB progression. Taken together, our finding shows that aerosol Mtb infection influences hepatic metabolism very soon after infection and may contribute to early metabolic disease. Defining the early interplay between localised infection, inflammation and metabolic regulation is key to understanding the impact of latent and subclinical TB on the large proportion of the World’s population who do not exhibit TB symptoms but who are infected with Mtb.
Supported by Grants from Royal Society Wolfson Merit Award (AMC) Newton Fellowship (MKD), Wellcome Trust Institutional Support Fund Fellowship (MKD), MRC award MR/P011136/1 (AMC).
Investigating the Role of Bacterial Long-Chain Polyphosphates in Macrophages during Legionella pneumophila Infection
Authors: Farquharson Kara L , Platten Johannes , Brueck Kevin , Sharma Arjun , Bosmann Markus 
Published: August 2023

Abstract
Up to 10% of community-acquired pneumonia cases are identified as Legionnaires’ Disease, caused by the pathogen Legionella pneumophila. L. pneumophila naturally resides in freshwater systems and becomes pathogenic when man-made plumbing systems grow biofilm and amoeba if not maintained. Hosts are accidentally infected by L. pneumophilavia aerosol inhalation into the respiratory system. L. pneumophila primarily reside in human alveolar macrophages, entering and replicating via the Legionella-containing vacuole. This vacuole will also release and recruit hundreds of effector molecules to prevent itself from being phagocytosed and disguise itself as a host cellular component. Polyphosphates are highly conserved molecules found in essentially every cell performing essential functions. Long-chain polyphosphates, containing hundreds of phosphate units, are produced by bacteria to perform functions critical to their survival in hosts. We have previously found that long-chain polyphosphates produced by E. coli interfere with the host innate response against infection. Here, we show that the infection of L. pneumophila and synthetic long-chain bacterial polyphosphates interfere with the inflammatory response in macrophages. We utilized a mouse model for in vitro infection of L. pneumophila in bone-marrow-derived macrophages, showing a modulated inflammatory cytokine response and cell death. Additionally, the addition of S. cerevisiae derived exopolyphosphatase, which degrades long-chain polyphosphates, decreases inflammation in vitro.