bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD19 cytoplasmic tyrosine residues Y482 and Y513 are sufficient to promote normal B cell development and differentiation but induce a skewed humoral immune response.
Authors: VanValkenburg Arthur James , King R. Glenn , Justement Louis B 
Published: January 2023

Abstract
CD19 amplifies BCR signal transduction by recruiting SH2 domain-containing proteins to its nine cytoplasmic phosphorylated tyrosine residues. Previous studies have shown that Y482 and Y513, which recruit PI3K are required for normal B cell development/differentiation and a productive T-dependent humoral response. However, it has not been determined if CD19 Y482 and Y513 are sufficient to promote normal B cell differentiation or antibody response to immunization. Furthermore, the effects of upstream CD19 tyrosine-mediated Vav/PLCγ2 and Grb2/Sos signaling are not well characterized. Using mice expressing CD19 mutated to only express tyrosines Y482 and Y513, we demonstrate that CD19 mediated Lyn/PI3K signaling is sufficient for B1 B cell development, marginal zone B cell maturation, and germinal center B cell formation. However, these mice exhibit an increased antibody response against T-independent antigens and are impaired in their ability to generate class-switched germinal center B cells during a T-dependent immune response, as well as long-lived, class-switched antibody secreting cells. These findings suggest that cross-talk between signal effectors recruited to Y482 and Y513 and those recruited to other CD19 tyrosine residues is important for determining the qualitative nature of the humoral response.
mDia1 promotes T cell extravasation and enables induction of Experimental Autoimmune Encephalitis
Authors: Thompson Scott Beckett , Estin Miriam Laquer , Jacobelli Jordan 
Published: January 2023

Abstract
Self-reactive T cells play a central role in Multiple Sclerosis (MS) and invade the central nervous system (CNS) to drive neurological damage. To enter tissues, T cells extravasate through the vascular endothelial cell wall via a process known as transendothelial migration (TEM). While many of the adhesion molecules and chemokine signaling pathways required for TEM are well characterized, little is known about how downstream cytoskeletal effectors mediate the mechanical forces and shape changes needed for T cell TEM. Mouse Diaphanous Homolog 1 (mDia1) is a terminal cytoskeletal effector involved directly in actin network remodeling. It has been associated with the formation of membrane protrusions that likely function in migration and cell-cell interactions and is highly expressed by activated T cells. The goal of our study was to examine the role of mDia1 in T cell extravasation into the CNS and subsequent induction of neuroinflammation. mDia1 knock-out (KO) mice were partially protected from Experimental Autoimmune Encephalomyelitis (EAE), a mouse model of MS. mDia1 deficient ex-vivo activated auto-reactive T cells displayed similar activation kinetics compared to control T cells. However, when these activated mDia1 deficient T cells were transferred into wild-type mice, they were impaired in their ability to induce EAE. In vitro time-lapse microscopy data suggest that mDia1 deficient T cells have a reduced ability to complete TEM across brain endothelium. This defect may explain the reduced ability of mDia1 deficient T cells to induce EAE. Collectively our data suggest that mDia1 may be a promising therapeutic target for regulating T cell trafficking in MS.
Sirt1 modulates immunoglobulin class switch DNA recombination and somatic hypermutation by regulating B lymphocyte Aicda expression through NF-kB deacetylation
Authors: Gan Huoqun , shen Tian , Sanchez Helia N. , Vasudev Anusha , Taylor Julia R. , Zan Hong , Casali Paolo 
Published: January 2023

Abstract
Maturation of the antibody response entails Ig class switch DNA recombination (CSR) and somatic hypermutation (SHM), which perfect the antigen-binding activity and diversify the effector functions of antibodies. By showing that HDAC inhibitors selective for class I/II HDACs dampened CSR and SHM by downregulating AID through upregulation of selected microRNAs that target Aicda, we have outlined an important role of these Zn-dependent HADCs in the modulation of the antibody response. Here we showed that Sirt1, one of the NAD+-dependent Class III HDACs or Sirtuins, also plays an important role in the regulation of B cell CSR and SHM. Sirt1 deletion in AID-expressing B cells of AicdacreSirt1fl/fl mice, whose B cells contain the normal complement of Aicda genes together with a Cre gene under control of an extra Aicda promoter, led to increased class-switched and somatically mutated antibodies in response to NP-CGG, as a result of upregulated AID expression, without alteration of Prdm1 expression or plasma cell differentiation. Sirt1-deficient B cells hyperacetylated p65, thereby activating the canonical NF-kB pathway, which mediates Aicda activation, without changes in DNA methylation or histone acetylation of the Aicda promoter. This was mimicked by increased concentrations of glucose, which reduced the NAD+ Sirt1 co-factor, leading to p65 hyperacetylation and Aicda upregulation in B cells. Conversely, treatment of B cells with NAD+ or SRT1720, a potent Sirt1 activator, dampened Aicda expression. Thus, our findings outline an important B cell-intrinsic role of Sirt1 in the modulation of the antibody response.
Unrelated respiratory infections promote the loss of pre-existing tissue resident influenza-specific memory CD8 T cells in the lung
Authors: Hayward Sarah L , Takamura Shiki , Kohlmeier Jacob E 
Published: January 2023

Abstract
Tissue resident memory CD8 T cells mediate protective immunity at common sites of infection such as the skin, gut, female reproductive tract, and lung. Lung-resident memory T cells (lung TRM) have been found to be important for protective heterosubtypic immunity to influenza, however the efficacy of cellular immunity to influenza viruses wanes over time. Our data suggests this decline in protective immunity is due to the gradual loss of flu-specific lung TRM, which, in contrast to circulating flu-specific memory T cells and TRM in other tissues, steadily decrease in number for several months following primary infection. Notably, the loss of flu-specific lung TRM occurs throughout the TRM pool regardless of expression of the tissue residency markers CD69 and CD103. Furthermore, parabiosis experiments using influenza memory mice show that flu-specific lung TRM are not exiting the tissue, and thus the gradual loss of these cells is likely due to increased cell death compared to the systemic memory T cell pool. As the lung is continually exposed to environmental and biological insults that can result in localized inflammation, we sought to determine whether lung inflammation could promote the loss of pre-existing flu-specific lung TRM. Infection of influenza-immune mice with Sendai virus resulted in a significant decrease of the number of pre-existing flu-specific lung CD8 TRM compared to PBS controls. Importantly, Sendai infection had no impact on the number of systemic flu-specific memory CD8 T cells in the spleen. Together, these data show that lung inflammation induced by unrelated respiratory infections can promote the loss of pre-existing lung TRM and may explain the gradual loss of cellular immunity in the lung.
West Nile virus antagonism of a RIG-I, type I interferon, and STAT5 signaling axis in human dendritic cells
Authors: Bowen James R , McDonald Circe E , Suthar Mehul S 
Published: January 2023

Abstract
West Nile virus (WNV) is a neurotropic flavivirus and the leading cause of mosquito-borne encephalitis in the United States. Murine models have found dendritic cells (DCs) are pivotal for viral control and programming of antiviral immunity in a RIG-I like receptor (RLR)- and type I interferon (IFN)-dependent manner. To better understand human WNV infection, we evaluated infection of monocyte derived DCs (moDCs). To define the antiviral landscape within moDCs, we combined mRNA sequencing with weighted gene co-expression analysis. Using molecular signatures for RLR and IFN signaling as filters, we found WNV partially induced expression of genes related to antiviral immunity. Specifically, WNV induced delayed IFN responses and failed to up-regulate inflammatory (IL-1β, IL-6, IL-12, TNF) or T cell co-stimulatory molecules (CD86, CD40, MHC II). Using cis-regulatory sequence analysis, STAT5 was identified as a regulatory node involved in RLR- and IFN-induced DC responses, but was minimally activated during WNV infection. Infected DCs failed to secrete multiple STAT5 signaling cytokines (GM-CSF, IL-4, IL-15) and STAT5 was not phosphorylated during WNV infection. Mechanistically, WNV blocked STAT5 phosphorylation downstream of RIG-I, IFN, and IL-4 signaling. Zika virus (ZIKV), a closely related flavivirus that also fails to activate human DCs, also blocked STAT5 phosphorylation. Our findings suggest STAT5 antagonism is a conserved mechanism used by pathogenic flaviviruses to subvert host immunity. In summary, we employed a systems biology approach to define the antiviral landscape within human DCs, identifying viral antagonism of a RIG-I, IFN, and STAT5 signaling axis that subverts DC immunogenicity during WNV and ZIKV infection.
Suppression of type-2 mediated allergic diseases by dectin-1
Authors: Gour Naina , Lajoie Stephane , Wills-Karp Marsha 
Published: January 2023

Abstract
Allergic diseases, which have escalated in prevalence in recent years, arise as a result of maladaptive immune responses to ubiquitous environmental proteins. Arthropods, such as mites, cockroaches, and crustaceans, are a major source of allergens, yet the majority of us live with or consume these invertebrates with no ill effects. Recent discoveries have raised the possibility that altered innate immune recognition of allergens, through pattern recognition receptors (PRR), may underlie disease susceptibility. Here, we identify the PRR, dectin-1 (CLEC7A), as a key receptor in mediating protection against dust mite-driven type 2 immune responses through the inhibition of epithelial cell IL-33 production, and the downstream recruitment of IL-13-producing innate lymphoid 2 cells (ILC2). Surprisingly, we observed that this effect was not mediated by the prototypical dectin-1 ligand, β-glucan, within allergen extracts. We discovered a novel protein ligand conserved across the arthropod phyla, sensing of which confers protection against aberrant type 2 responses that drive respiratory allergy and food anaphylaxis in mice. While this homeostatic pathway is functional in respiratory epithelial cells from healthy humans, dectin-1 is repressed in asthmatics and patients with chronic-rhinosinusitis. Importantly, we report a novel SNP in CLEC7A in the SAGE and GALAII GWAS studies, associated with lung function. Collectively, our findings reveal a previously unrecognized negative regulatory pathway in which ligation of dectin-1 results in reduction of type 2 immune responses, while disruption of this critical regulatory circuit is associated with susceptibility to a spectrum of allergic disorders.
Studies on the mechanisms of nickel induced immunosuppression
Authors: Pandolfi Franco , Altamura Simona , Nucera Eleonora , Frosali Simona , Rizzi Angela , Di Rienzo Alessia , Pascolini Lucilla , Buonomo Alessadro , Carusi Valentina , Chini Raffaella , Schiavino Domenico 
Published: January 2023

Abstract
Nickel (Ni) inhibits lymphoproliferative responses. Proliferation was performed on PBMC of 20 controls and 10 patients with Ni allergy. NiSO4 was used at a concentration of 0.1mM. PHA was added at a concentration of 5 μg/ml. Cells were incubated for 5 days and proliferation assessed by CFSE staining. At 0.1mM Ni strongly reduced (&gt;40%) PHA-induced proliferation. The inhibition decreases in a dose-dependent manner and response to PHA is restored at 20 mM Ni. Ni alone induces small (&lt;5%) proliferative response in both allergic and non allergic donors. Nickel inhibition requires the presence of Ni in the supernatant and is abrogated when Ni is incubated with the cells for up to 4 hours and the supernatant is washed.
Strong inhibition was also observed in preliminary experiments with tuberculin purified protein derivative (PPD) stimulated PBMC.
Staining for CD8 on CFSE cultures showed that PHA response was due to both CD8 and CD4 cells. Ni increased % of CD4 cells and decreased the % of CD8 cells.
PPD response was predominantly a CD4 response, with Nickel reducing the % of CD4 cells at higher concentations, while unaffecting the CD8.
Ni inhibits IL-6 production essential to normal PHA response. The addition of 10–100 IU of IL-6 and/or IL-2 to the cultures did not affect Ni inhibition of PHA proliferation. Addition of IL-6 increased CD25+ cells.
Our data suggest that Ni induced inhibition of PHA response is due to steric interference between PHA and its cellular ligand. Further studies will clarify the precise mechanism of Ni mediated inhibition of immune responses and its the role in the pathogenesis of Ni allergy.
Impaired BCR-induced NFAT1 nuclear translocation is implicated in low TACI expression in newborn B lymphocytes
Authors: Sakai Jiro , Coleman Adam S , Akkoyunlu Mustafa 
Published: January 2023

Abstract
Neonates and infants have impaired immune responses to immunization compared to adults, resulting in high susceptibility to microbial infection. B cells have a central role in humoral immunity to immunization and infection, and signals via B cell receptor (BCR) are essential for the development and maintenance of B lymphocytes. T cell-independent type 2 (TI-II) antigens activate B lymphocytes through BCR and transmembrane activator and CAML interactor (TACI). Newborns, however, are unable to generate TI-II responses, partly because TACI expression is severely reduced in newborn B cells. Since BCR signaling regulates TACI expression, we hypothesized that suboptimal BCR activation may be responsible for the reduced TACI expression on newborn B cells. We found that engagement of murine newborn BCR with anti-mouse IgM f(ab′)2 results in ablated Nuclear Factor of Activated T-cells 1 (NFAT1) nuclear translocation as compared to adult BCR. Neither anti-IgM stimulation nor the calcium influx inducer, Ionomycin stimulation elicits a significantly different calcium influx profile between newborn and adult B cells, suggesting that the factors downstream of calcium influx are responsible for the suppression of NFAT1 activation. Diminished NFAT1 translocation is likely responsible for the reduced TACI expression in newborn B lymphocytes because blocking NFAT1 pathway with the selective NFAT inhibitor, FK506 prevents the upregulation of TACI in anti-IgM-stimulated adult B lymphocytes. We are currently investigating the activities of calcium-dependent NFAT1 activators calmodulin and calcineurin in newborn B lymphocytes to assess whether insufficiencies in these molecules are responsible for the ablated translocation of NFAT1.
K+ Channel Activation Promotes Tumor infiltrating Lymphocyte (TIL) Expansion and Enhances Expression of CCR7
Authors: Ritthipichai Krit , Machin Marcus , Simpson-Abelson Michelle , Mosychuk Christopher , Veerapathran Anand , Lotze Michael 
Published: January 2023

Abstract
Only two K+ channels are known to be expressed by T-cells. Activated effector T cells express high levels of Kv1.3; activated naïve and central memory T-cell subsets express high levels of KCa3.1. Overexpression of Kv1.3 in murine T-cells increases K+ efflux, improves effector function (IFNγ production) and promotes anti-tumor activity1. Inhibition of KCa3.1 suppresses murine T-cell proliferation and cytokine production. In human PBMCs and TIL, KCa3.1 expression was relatively low with upregulation observed within 24 h following stimulation with anti-CD3 and anti-CD28. The addition of the KCa3.1 agonist SKA-31 did not alter KCa3.1 expression but enhanced CCR7 expression significantly on TIL and human PBMCs. TILs propagated in the Rapid Expansion Protocol (REP) had a 1.42-fold greater expansion (p=0.002) in the presence of SKA-31 and significant increases in the CD8+CD28+ (p=0.04), CD8+CD27+(p=0.04), and CD8+CD27+CD28+subsets (p=0.002), consistent with a less differentiated phenotype. We thus demonstrate that SKA-31 treatment enhances CCR7 expression associated with memory cells, promotes TIL expansion, and attenuates T-cell differentiation. Targeting the KCa3.1 channel is a novel strategy to expand and sustain less differentiated TILs and may improve the clinical application of adoptive T-cell therapy.
1: Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Linehan WM, Roychoudhuri R, Restifo NP. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature. 2016;537):539–543.
Reprogramming of exhausted T cells following elimination of chronic antigen exposure
Authors: Abdel-Hakeem Mohamed , Khan Omar , Stelekati Erietta , Ali Mohammed-Alkhatim , Wherry E. John 
Published: January 2023

Abstract
T-cell exhaustion is a hallmark of immunological failure to control cancer and chronic infection. Blocking inhibitory receptors such as PD-1 can re-invigorate exhausted T cells (TEX), but clinically most patients fail to achieve durable tumor control. Thus, a deeper understanding of other mechanisms underlying reversal of T-cell exhaustion is needed. It is also unknown whether antigen elimination would allow recovery of TEX into durable functional cells. To address this, we investigated whether TEX become “reprogrammed” into more functional effector or memory T cells following non-immunological antigen elimination. Using the lymphocytic choriomeningitis virus (LCMV) model we adoptively transferred TEX from chronically-infected mice to immune mice, thus eliminating chronic exposure to viral antigens. We aim to determine the cellular profiles, molecular mechanisms, and population dynamics of recovering T cells (TREC). Our data indicate that some markers and capacities of memory T cells may be recovered upon cure of infection, though other aspects of TEX biology do not appear to be corrected simply by eliminating exposure to chronic infection. Ongoing studies are investigating whether these changes are linked to selective recovery of a specific subset of TEX, and whether improvements are accompanied by changes in the molecular pathways of these TREC. We expect these studies to enhance our understanding of the molecular signatures and mechanisms of recovery of TEX, and to identify candidate transcriptional circuits differentially regulated in TREC that could represent novel therapeutic targets for reversal of immune exhaustion.
Myeloid PPAR-γ suppresses acute host diseases and inhibits chronic fibrosis development following influenza infection
Authors: Sun Jie , Huang Su , Zhu Bibo , Jiang Li 
Published: January 2023

Abstract
Influenza virus is the leading cause of respiratory infection. In addition to its induction of acute pulmonary diseases, severe influenza infection can lead to the development of chronic lung conditions including pulmonary fibrosis. Currently, the underlying mechanisms regulating the development of influenza sequelae in the respiratory tract are poorly defined. We found that PPAR-γ expression in macrophages is differentially regulated during low pathogenic (sublethal) or highly pathogenic (lethal) influenza infection. Myeloid deletion of PPAR-γ resulted in increased host mortality and morbidity following influenza infection. In the acute phase, myeloid PPAR-γ deficient mice exhibit enhanced macrophage cytokine production, diminished T cell immunity (day 10), delayed viral clearance and impaired lung repair responses following influenza infection. Strikingly, myeloid PPAR-γ deficiency also triggered the development chronic pulmonary fibrosis following influenza infection. We demonstrated that myeloid PPAR-γ deficiency caused scar formation, collagen deposition and fibrotic gene expression in the lungs at 60 days post infection. Mechanistically, myeloid PPAR-γ expression is required for the regeneration of tissue resident alveolar macrophages following influenza clearance, and the depletion of alveolar macrophages at the recovery stage resulted in impaired lung repair and chronic collagen deposition. Thus, our data has revealed that myeloid PPAR-γ expression is critical for the suppression of both acute and chronic pathogenesis of influenza, and suggested that the promotion of PPAR-γ activation may be employed to treat both acute influenza-associated diseases and to prevent chronic fibrosis development.
NKT cells control tumor associated macrophages and metastatic growth in neuroblastoma
Authors: Courtney Amy N , Tian Gengwen , Marinova Ekaterina , Wei Jie , Guo Linjie , Jin Jingling , Gao Xiuhua , Ghaghada Ketan B. , Heczey Andras , Metelitsa Leonid S 
Published: January 2023

Abstract
Va24-invariant NKT cells (NKTs) control tumor growth via poorly understood interactions with CD1d-positive tumor-associated macrophages (TAMs). TAMs comprise M1- and M2-like subsets, but only CD163high M2-like TAMs are associated with poor outcome in neuroblastoma (NB) patients. Here, we demonstrate that NKTs selectively target M2-like TAMs via contact-dependent and independent mechanisms. Upon direct contact with antigen-pulsed M1 or M2, NKTs selectively kill the latter. Additionally, we found that antigen-activated NKTs could reprogram M2 into functional M1-like macrophages via GM-CSF production. Furthermore, adoptive transfer of human NKTs resulted in M1-like polarization of TAMs in metastatic NB xenografts in humanized NSG mice. To further explore the role of NKT–TAM axis in tumor immune surveillance, we examined the effect of NKT deficiency on tumor progression and TAM accumulation in NB-Tag transgenic model of NB. Mice lacking either type I (Jα18−/−NB-Tag) or all (CD1d−/−NB-Tag) NKTs had shortened survival compared with NB-Tag mice (P &lt; 0.0002). At four month of age we observed an increase of CD11b+Ly6G-Ly6C-F4/80+ TAMs in primary tumors of NKT deficient groups compared with NB-Tag mice. Despite no difference in the size of primary adrenal tumors between groups, the increase of TAM frequency coincided with metastatic spread in NKT deficient groups as detected by CT imaging and confirmed by pathological analysis. By five months, nearly all mice in NKT deficient groups had distant metastases in liver and lungs but none of the NKT replete mice had detectable distant metastases. Thus, our results reveal a novel mechanism of immune regulation, in which NKTs selectively control M2-like TAMs and suppress tumor metastasis.