bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crucial roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in protection against West Nile virus within the CNS
Authors: Durrant Douglas M. , Cortes Alejandro , Alvarado Marina O 
Published: February 2023

Abstract
West Nile Virus (WNV) is a leading cause of mosquito-borne neuroinvasive disease in the US. Following infection, WNV can cause neuronal injury and disease. Previous studies have shown that the proper activation of virus-specific T cells results in protection from WNV infection and any associated disease. Dendritic cells (DCs) are often defined as pivotal inducers of immunity due to their role in activating immune defense mechanisms against invading pathogens. XCR1, a chemokine receptor expressed predominantly by a subset of DCs, has been shown to be essential in cross-presenting antigen and in activating anti-viral immunity. However, DCs are not readily present within the CNS and it remains unknown how DCs are recruited to the CNS during WNV encephalitis to fully activate antiviral immunity. XCL1, the ligand for XCR1, is expressed by activated T cells, DCs, macrophages, and NK cells. We hypothesize that following WNV infection, virus-specific T cells within the CNS produce XCL1 in order to recruit and stabilize their interaction with XCR1+ DCs thus ensuring their proper activation and subsequent protection against WNV encephalitis. Here we demonstrate that mice lacking XCR1+ DCs are more susceptible to WNV encephalitis, display increased neuronal cell death, as well as increased viral burden compared to control animals. In addition, in the absence of XCR1+ DCs, WNV-infected animals displayed decreased parenchymal localization of T cells within the brain compared to controls. These data indicate that XCL1-XCR1 interactions are crucial in the development of efficient anti-viral immunity. The knowledge gained from this work may then be applicable to other viral diseases of the CNS.
An interferon-stimulated transcriptionally independent isoform of ACE2 inhibits SARS-CoV-2 infection
Authors: Onabajo Olusegun O , Stanifer Megan , Banday A. Rouf , Vargas Joselin , Yan Wusheng , Obajemu Adeola , Ring Timothy , Kee Carmon , Doldan Patricio , Boulant Steeve , Prokunina-Olsson Ludmila 
Published: February 2023

Abstract
Regulation of ACE2, the SARS-CoV-2 receptor, could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a transcriptionally independent truncated isoform of ACE2, designated as deltaACE2 (dACE2). dACE2 starts from a new exon in intron 9 of ACE2, and is highly conserved in primates. dACE2, but not ACE2, is induced by interferons and viruses including SARS-CoV-2. In-vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Endogenous dACE2 protein appears to be unstable and poorly detectable. However, using our custom generated antibodies, we detected dACE2 in nasopharyngeal normal and tumor tissues by immunohistochemistry. In-vitro, overexpression of dACE2 inhibited SARS-CoV-2 infection, possibly by blocking internalization of the virus. Our results suggest that dACE2 might be an antiviral mechanism that evolved in primates to defend against certain viruses that utilize the ACE2 receptor for entry.
Distinct peripheral inflammatory profiles distinguish COVID-19 from influenza infection, with limited contributions from cytokine storm
Authors: Crawford Jeremy Chase , Mudd Philip A. , Turner Jackson S. , Souquette Aisha , Reynolds Daniel , Bender Diane , Bosanquet James , Anand Nitin J. , Striker David A. , Martin R. Scott , Boon Adrianus C.M. , House Stacey L. , Remy Kenneth E. , Hotchkiss Richard , Presti Rachel , O’Halloran Jane , Powderly William G. , Thomas Paul Glyndwr , Ellebedy Ali H. 
Published: February 2023

Abstract
We developed a prospective observational cohort of COVID-19 and influenza patients to assess the quality and magnitude of their immune responses at the cellular and protein levels. Although COVID-19 patients exhibited equivalent lymphocyte counts compared to influenza patients, they had fewer monocytes and lower surface HLA-class II expression on select monocyte populations compared to influenza patients and healthy controls. Decreased HLA-DR on intermediate monocytes was a significant predictor of COVID-19 disease severity. Protein cytokine levels were measured in two distinct COVID-19 cohorts, composed of 73 and 89 patients, revealing multiple inflammatory phenotypes. Only four percent of patients (7 of 162) exhibited a distinct Cytokine Storm Syndrome (CSS) phenotype. Furthermore, COVID-19 patients generally exhibited lower cytokine levels than influenza patients. Upregulation of a few innate inflammatory mediators, including IL-6, GCSF, IL-1RA, and MCP1, predicted death from acute respiratory failure among COVID-19 patients but were not statistically higher than those of influenza patients. Single-cell transcriptional profiling of 2 healthy controls as well as 3 COVID-19 and 3 influenza subjects with respiratory failure was concordant with the profound suppression in type I and type II interferon signaling in COVID-19 patients across multiple cell types. In contrast, COVID-19 cells were enriched for alterations in metabolic, stress, and apoptotic pathways. When considered across the spectrum of peripheral innate and adaptive immune profiles, the immune pathologies underlying severe influenza and COVID-19 are substantially distinct, with COVID-19 patients generally less inflamed than those with influenza.
Interferon signature in cutaneous lesion of COVID toes
Authors: Komura Kazuhiro , Ichimura Yuki , Okiyama Naoko , Watanabe Kazuyoshi , Muramoto Hiroaki , Matsushita Takashi 
Published: February 2023

Abstract
Increasing reports have showed several kinds of dermatological manifestation in Coronavirus disease 2019 (COVID-19). Some of them may occur as a direct implication of coronavirus infection. Within those, acral skin changes, recently called COVID toes, have a potential to provide a diagnostic value. We herein described a 49-year old Japanese man with COVID toes. The skin lesions appeared simultaneously with fever. The rash was similar for cold-induced erythema multiforme of the patients with familial Chilblain; hereditary type I interferonopathy. Histopathological staining indicated up-regulated expression of MxA, effected by local enhancement of type I interferon. These speculated that the specificity of COVID toes may depend on interferon up-regulated by specific mechanisms.
ARID3a Defines a Novel Subset of Naïve B Cells in SLE Patients
Authors: Garton Joshua W , Shankar Malini , Guthridge Joel , James Judith A , Webb Carol 
Published: February 2023

Abstract
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease characterized by overproduction of autoantibodies by B cells and the loss of tolerance to nucleic acids. Our previous studies show that AT-rich interacting domain 3a (ARID3a), a DNA-binding protein, is more abundant in SLE B cells than in healthy control B cells. Increased numbers of ARID3a+ B cells in SLE correlated with increased disease activity in patients. ARID3a expression in SLE patient blood occurred in naïve B cell subsets which do not express ARID3a in healthy controls. Studies by the Sanz laboratory revealed that activated naïve B cells and may be precursors for the double negative (DN) B cells linked to pathogenic responses in SLE. We hypothesize that ARID3a expression in naïve B cells also defines precursors of pathogenic B cells. In individual patients, ARID3a is bimodally expressed, such that only a fraction of the naïve B cells express ARID3a at any given time. We took advantage of this bimodal expression using single cell technology to perform RNA-seq analyses of ARID3a+ and ARID3a− SLE B cells to identify differentially expressed genes associated with ARID3a. PCA analyses of scRNA seq data show that ARID3a+ naïve B cells cluster together and away from ARID3a− cells. This allows for analyses within and among individual samples by binning cells based on ARID3a expression. Preliminary data indicate that ARID3a expression is correlated with innate immune response genes, transcription factors, and epigenetic regulators. These studies will be informative regarding how ARID3a expression contributes to disease pathogenesis in patients with SLE and will provide novel information defining a new subset of naive B cells that may be directly linked to breaches in tolerance.
CD8 T follicular cell function in autoimmune disease
Authors: Mullins Genevieve N , Valentine Kristen M , Davalos Oscar , Hoyer Katrina K. 
Published: February 2023

Abstract
Autoimmune disease comprises more than 80 well characterized disorders that affect 24 million Americans and many of these disorders are characterized by the presence of high-affinity auto-antibodies. The production of these high-affinity antibodies requires activation, affinity maturation, and differentiation of B cells into class-switched plasma cells. This process occurs within the germinal center and requires the help of specialized T follicular helper (Tfh) cells. Traditionally, Tfh are CD4 T cells that become activated and differentiate, acquiring the surface proteins required to migrate into the germinal center and interact directly with B cells to induce germinal center responses. Recently, a population of CD8 T follicular (Tfc) cells that are phenotypically similar to CD4 Tfh have been described in chronic viral infection, cancer, and autoimmune disease. These cells have been shown to function similarly to CD4 Tfh cells as well as cytotoxic CD8 T cells under various conditions. Further, the mechanism and localization of CD8 Tfc cell function in autoimmune disease has not yet been investigated. Using immunofluorescence CD8 Tfc cells were found to localize and produce cytokines in the B cell follicle and germinal center in autoimmune disease. Indirect co-culture of CD8 Tfc cells with B cells show that while CD8 produced IL-21 does not influence B cell function, CD8 produced IL-4 does. This data indicates that CD8 Tfc and CD4 Tfh cells may rely on slightly different mechanisms to influence B cell function within and without the germinal center.
Leukemic Cytokines co-opt Regulatory T cell and Th17 immunity to promote chronic myeloid leukemia
Authors: Camacho Virginia , Matkins Victoria , Patel Sweta , Kuznetsova Valeriya , Anderson Ashlyn E , Harrington Laurie E , Welner Robert S 
Published: February 2023

Abstract
Non-immune roles of Regulatory T cells (Tregs) have been described across various tissues. However, the mechanisms by which T cells regulate the bone marrow in myeloproliferative neoplasms lack resolution. A hallmark of leukemic progression is the increase in pro-inflammatory cytokines, cellular inflammation, and an expansion of CD4 T cells. In this study, we demonstrate that this inflammatory milieu promotes pathogenic skewing of both regulatory and effector T cells. We characterized the altered CD4+ T cell compartment in chronic myeloid leukemia (CML) and we found that Tregs are unstable and dysregulated across leukemic tissues. Specifically, the CML environment effectively co-opts Treg function and stability. This contributes to a phenotype of immune activation as well as an increase of pathogenic inflammatory T cells. Notably, our findings reveal that Treg/Th17 ratios are disrupted in leukemia and that loss of Tregs and activation of Th17 cells influence disease progression. Additionally, we found that Treg-secreted IL-10 directly influences myeloid and neutrophil differentiation of leukemic progenitors has beneficial anti-inflammatory effects. We demonstrate that restoring Treg function and expanding their IL-10 production can be used therapeutically to limit leukemic progression. Our results support the hypothesis that Tregs are compromised during leukemic progression as a consequence of pro-inflammatory cytokines from the myeloid associated disease. These findings highlight how the Treg/Th17 balance regulates disease progression. Furthermore, these studies provide an avenue by which Treg secreted IL-10 can be used for therapeutic intervention in the context of hematopoietic malignancies.
Intestinal interleukin (IL)-22Ra1 signaling mediates the onset of systemic metabolic disorders
Authors: Gaudino Stephen , Huang Huakang , Jean-Pierre Makheni , Lin Xun , Kumar Pawan 
Published: February 2023

Abstract
Interleukin (IL)-22 has been shown to protect against detrimental high fat diet (HFD)-induced phenotypes. However, it is unknown where IL-22Ra1 signaling specifically occurs to regulate HFD-induced metabolic disorders. To examine this, we utilized intestinal epithelium-specific Il22Ra1fl/fl;Villin-cre+ (IL22Ra1ΔIEC), white adipose tissue (WAT)-specific Il22Ra1fl/fl;Adipoq-cre+ (IL22Ra1ΔWAT), and liver-specific Il22Ra1fl/fl;Albumin-cre+ (IL22Ra1ΔLiver) knockout mice as well as their respective littermate cre-(IL22Ra1fl/fl), mice. When placed on long term HFD, IL22Ra1ΔIECand IL22Ra1ΔLiver mice but not IL22Ra1ΔWAT mice displayed impaired systemic glucose metabolism. We specifically observed that impaired glucose metabolism of IL22Ra1ΔIEC mice was microbiota dependent. IL22Ra1ΔIEC mice also possessed altered lipid metabolism since their intestinal tissues expressed increased levels of peroxisomal β-oxidation genes. Furthermore, extra-intestinal tissues from IL22Ra1ΔIEC mice displayed altered metabolism. Liver tissue of IL22Ra1ΔIEC mice displayed decreased expression of G6PC, a key glycolytic enzyme, and WAT displayed increased expression of peroxisomal Acox1 and decreased levels of certain fatty acids. These liver- and WAT-specific changes were dependent on IL-22 since Il22−/− mice displayed opposite trends in gene expression. We decided to examine where intestinal IL-22Ra1 signaling may specifically occur to mediate these effects. Interestingly, we observed a unique role of Paneth cell-specific IL-22Ra1 signaling in mediating systemic glucose metabolism. Overall, our data highlight a specific importance of intestinal IL-22Ra1 signaling in regulating HFD-induced metabolic disorders.
Neurokinin A blocks the ABCA1 channel to promote IL-10-dependent mast cell regulation
Authors: Williams Li’an , Hawse William F , Cattley Richard , Carey Cara D , Zhang Jiying , Falo Louis D , Larregina Adriana T , Sumpter Tina L 
Published: February 2023

Abstract
Cutaneous mast cells (MCs) reside in close proximity to peripheral sensory nerve fibers and are susceptible to regulation by neuropeptides. The tachykinin family member, Neurokinin A (NKA) binds with highest affinity to the Neurokinin 2 Receptor, expressed on MCs. MCs are poised to respond to NKA, but its role in the MC biology is, to our knowledge, under-explored. The objective of this study was to evaluate the effects of NKA on bone marrow (BM) MCs and peritoneal (P)MCs in vitro and in the murine model of passive cutaneous anaphylaxis (PCA) in vivo. Neurokinin A inhibited FceRI-initiated phosphorylation and nuclear localization of STAT5, and release of TNF and IL-13 in an IL-10-dependent manner. NKA affected the MC secretome, abrogating ABCA1-dependent release of the cysteine protease, calpain. Extracellular calpain, in turn, degraded IL-10. In vivo, NKA administration reduced PCA, inhibiting edema, and induction of inflammatory cytokines and in a manner that relied on MC derived-IL-10. Likewise, direct inhibition of the ABCA1 phenocopied the effects of NKA, reducing IgE-initiated MC responses in vitro and in vivo. In conclusion, NKA minimizes IgE-initiated inflammation though an IL-10-dependent mechanism and inhibits ABCA1-dependent release of the IL-10 degrading enzyme, calpain. This study illuminates a novel tier of neuropeptide mediated MC regulation through the ABCA1. Strategies interfering with the ABCA1 may be promising therapeutics for targeting MCs in cutaneous inflammatory diseases.
Glutamine metabolism drives NKT cell homeostasis and function
Authors: Kumar Ajay , Yarosz Emily L , Hong Hanna , Lyssiotis Costas , Chang Cheong-Hee 
Published: February 2023

Abstract
Cellular metabolism is essential in dictating T cell development and function, but its role in natural killer T (NKT) cells has not been well studied. Activated CD4 T cells undergo a metabolic switch from oxidative to glycolytic metabolism to fuel their proliferation and effector function. We have previously shown that NKT cells operate distinctly different metabolic programming from CD4 T cells. We found that, unlike CD4 T cells, NKT cells rely more on glutamine for their homeostasis. In fact, we observed that resting NKT cells have higher levels of glutamine-derived metabolites than conventional CD4 T cells. However, the precise mechanisms by which NKT cells use glutamine for their proliferation and cytokine production remain unknown. Glutamine is metabolized into glutamate and then into alpha-ketoglutarate (α-KG) and glutathione (GSH). Using the pathway specific inhibitors revealed that NKT cells rely on both pathways for cell homeostasis, but cytokine production is associated with α-KG production. These glutamine oxidation processes control optimal mTORC1 activity and mitochondrial functions. Importantly, we observed a novel role of 5′ AMP-activated protein kinase (AMPK) in regulating glutamine metabolism in NKT cells. Taken together, glutamine metabolism is essential for NKT cell homeostasis and cytokine production.
A B cell actomyosin arc network couples integrin co-stimulation to mechanical force-dependent immune synapse formation
Authors: Wang Jia C , Yim Yang-in , Wu Xufeng , Hammer John A 
Published: February 2023

Abstract
B cells that are activated by antigen-presenting cells form an immune synapse (IS), which supports B cell activation and a robust antibody response. The organization and dynamics of the actin cytoskeleton are essential for centralizing antigen and promoting the B cell receptor signaling that are central to IS formation. When antigen is limiting, B cells require integrin co-stimulation to form the IS. Given the indispensable function of actin in forming the IS, we tested the role of the actin cytoskeleton in integrin-dependent IS formation and B cell activation. Here we show, using live-cell super-resolution imaging of primary B cells, the formation of a dynamic actin arc network, which dominated the synaptic actin and appeared only when B cells bound both antigen and the integrin ligand, ICAM-1. Actin arcs were created by the formin mDia1 and were decorated with the motor protein myosin 2A, which organized actin arcs into a concentric, contractile network. Dynamic imaging of the actin in primary B cells on planar lipid bilayers showed that actin arcs moved centripetally together with antigen microclusters and that these microclusters were swept inward by individual actin arcs. Critically, integrin-dependent IS formation under limiting antigen conditions required myosin activity as blocking myosin with Blebbistatin prevented antigen centralization. Consistently, myosin inhibition also diminished B cell receptor signaling and disrupted the distribution of key signaling proteins at the IS. Together, these results argue that a contractile actomyosin arc network created downstream of integrin co-stimulation plays an important role in the mechanism by which integrin co-stimulation promotes B cell activation and IS formation.
Metabolic Control of T cell responses by HDAC3
Authors: Wilfahrt Drew Nicholas , Philips Rachael , Kizerwetter Monika , Lama Jyoti K , Rajcula Matthew , Kennedy Madeleine , Shapiro Virginia Smith 
Published: February 2023

Abstract
After activation, CD4+ T cells undergo metabolic modifications in order to orchestrate successful immune responses. In particular, naïve T cells shift to a more glycolysis-heavy metabolic program that produces the necessary metabolites for growth, division, and exertion of effector function. Histone Deacetylase 3 (HDAC3) has been shown to epigenetically regulate many T cell fate decisions and is also capable of post-translationally modifying non-histone proteins. Deletion of HDAC3 in mature CD4+ T cells using a distal Lck-Cre HDAC3 cKO mouse revealed a reduction in differentiated T-helper cell populations in vivo. In contrast, in vitro differentiation of HDAC3-deficient CD4+ T cells occurred normally, however, the numbers of T cells present within each culture was greatly diminished. CD3/CD28-stimulated HDAC3-deficient cells exhibited poor proliferation with decreased blastogenesis, decreased CD25 expression, and decreased IL-2 production. Signaling downstream of TCR is disrupted in the HDAC3-deficient T cells. HDAC3-deficient CD4+ T cells have an overabundance of Foxo1 protein, and diminished signaling downstream of mTOR, including reduced phosphorylation of Ribosomal Protein S6, and decreased expression of Egr2. Key transporters involved in cholesterol efflux, ABCA1 and ABCG1, were upregulated in HDAC3-deficient CD4+ T cells. Strikingly, the proliferation and blasting defects of HDAC3-deficient CD4+ T cells are restored with the addition of exogenous cholesterol, but the signaling defects remain. Thus, the failure of HDAC3-deficient CD4+ T cells to proliferate is due to alterations in cholesterol homeostasis.
Protein immunization induces T follicular helper memory cells and nonpolarized T helper (Tnp) memory cells
Authors: Sircy Linda M , Harrison-Chau Malia , Novis Camille , Baessler Andrew , Nguyen Jacklyn , Hale J. Scott 
Published: February 2023

Abstract
Acute viral infection generates lineage-committed T helper 1 (Th1) and T follicular helper (Tfh) memory cells that recall their lineage-specific functions following secondary challenge with virus. However, the lineage commitment of effector and memory T helper cells in vivo following protein vaccination is poorly understood. In this study, we analyzed effector and memory CD4+ T cell differentiation following adjuvanted glycoprotein immunization compared to acute lymphocytic choriomeningitis virus (LCMV) infection. Glycoprotein immunization-induced CXCR5-non-Tfh effector and memory CD4+ T cells that surprisingly had not undergone polarization toward any particular T helper cell lineage but had undergone memory differentiation. However, upon challenge with virus, these T helper lineage-nonpolarized memory CD4+ T cells were able to generate Th1 secondary effector cells, demonstrating their lineage plasticity. In addition, Tfh and memory Tfh cells were generated in response to protein immunization, and these cells differed from infection-induced Tfh cells by their lack of the transcription factor Tbet. Rechallenge experiments demonstrated that viral infection, but not protein immunization, during either the primary or secondary immune response, restricts the recall of Bcl6 expression and the generation of germinal center Tfh cells. Together, these data demonstrate that protein immunization generates a combination of nonpolarized memory cells that are highly plastic and memory Tfh cells that can undergo further Th1-like modulation during a secondary response to viral infection.