bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Fc-receptor engagement drives an anti-tumor vaccinal effect (VAC13P.1123)
Authors: DiLillo David , Ravetch Jeffrey 
Published: January 2023

Abstract
Passively-administered anti-tumor mAbs mediate killing of tumor targets via FcγR-mediated cytotoxicity, a rapid and short-term process. However, anti-tumor mAb treatment can also induce a vaccinal effect, in which mAb-mediated tumor death induces a long-term anti-tumor cellular immune response. To determine how such responses are generated, we utilized a murine model of a mAb-mediated anti-tumor vaccinal effect. Using mice with a conditional deletion of FcγRs on dendritic cells (DCs), we demonstrate that FcγR expression by antigen-presenting DCs is required to generate an anti-tumor T cell response upon ADCC-mediated tumor clearance by anti-tumor mAb. However, human FcγR expression differs from mice; humans express two activating FcRs, FcRIIA and FcRIIIA, on cytotoxicity-mediating NK cells and monocytes, while antigen-presenting DCs only express FcRIIA. Thus, we used FcγR-humanized mice, which express the full array of human FcγRs in place of mouse FcγRs, to demonstrate that anti-tumor huIgG1 must engage huFcγRIIIA on monocytes/NK cells to mediate ADCC, but also engage hFcRIIA on DCs to generate a potent vaccinal effect and anti-tumor cellular immune response. Thus, while next-generation anti-tumor antibodies with enhanced binding to only hFcγRIIIA for ADCC are now in clinical use, optimal anti-tumor antibodies must be optimized for both their short-acting cytotoxic effects as well as for engagement of hFcγRIIA on DCs to stimulate long-term anti-tumor cellular immunity.
Human cytomegalovirus reprograms human bone marrow progenitor cells into nitric oxide-producing, long-life, immune suppressive monocyte subset to achieve latency (VIR9P.1142)
Authors: Zen Ke , Pan Chaoyun , Zhu Dihan , Liu Fenyong , Zhang Chen-Yu 
Published: January 2023

Abstract
It is generally regarded that human cytomegalovirus (HCMV) achieves latency in human haematopoietic progenitor cells. However, the nature of host cell at HCMV latent infection and the mechanisms governing the differentiation of progenitor cells mediated by HCMV remain elusive. In the present study, we identify that nitric oxide (NO)-producing, long-life, and immune suppressive monocyte subset differentiated from human bone marrow CD34+ progenitor cells serve as the true host for HCMV latency. This monocyte subset can suppress T cell proliferation and activity via NO-based mechanism. Both gain-of-function and lose-of-function assays show that high level NO production in progenitor cells via inducible nitric oxide synthase during HCMV infection is a key to suppress HCMV immediate early (IE) protein expression and viral replication to induce HCMV latency. NO production, correlating with progenitor cell differentiation, is promoted by signal transducer and activator of transcription 3 (STAT3) which activity is increased by HCMV infection. As a control, HCMV strain with US28 deletion, which cannot activate STAT3, fails to produce NO and achieve latency in haematopoietic progenitor cells. Our results demonstrate for the first time that HCMV achieves latent infection through reprograming human haematopoietic progenitor cells into NO-producing, long-life, immune suppressive monocyte subset.
Temporal regulation of T cell priming during peripheral infection (VIR10P.1167)
Authors: Mueller Scott , Hor Jyh Liang , Heath William 
Published: January 2023

Abstract
The in vivo dynamics of CD4 and CD8 T cell priming in draining lymph nodes (dLN) following infection and the types of interactions that occur with different dendritic cell (DC) subsets remains unclear. Immune responses to pathogens that remain localized to peripheral tissues and do not directly infect the lymphoid organs critically rely upon migratory DC to traffic antigen to dLN. Following Herpes Simplex virus infection (HSV-1) migratory CD11b+ DC transport viral antigens from the skin to the dLN and then transfer antigen to LN-resident CD8a+ DC for CD8 T cell priming. Although migratory DC can present antigens to CD4 T cells ex vivo, which DC subset(s) activate CD4 T cells in vivo, when and where CD4 T cells provide ‘help’ for CD8 T cell priming and the dynamics of these interactions are not known. Using a HSV-1 flank infection model combined with intravital 2-photon imaging of the draining inguinal LN to concurrently visualize pathogen-specific CD4 and CD8 T cells we find temporally separated priming of CD4 versus CD8 T cells. Early priming of CD4 T cells involved clustering with migratory DC and more rapid responses by these T cells, followed by later interactions of CD8 T cells with LN-resident DC that resulting in priming. Together, these data suggest unexpected temporal differences in T cell activation by DC subsets following localized viral infection.
Mapping the interaction footprint of Viral Immunoevasins on a “platform” MHC-I molecule using solution NMR spectroscopy (APP2P.102)
Authors: Sgourakis Nikolaos 
Published: January 2023

Abstract
Mouse cytomegalovirus encodes immunoevasin proteins that interfere with MHC-I antigen presentation to CD8+ T cells and natural killer (NK) cells. Members of the m02-m16 family contribute to viral survival and infectivity. One member of this family (m04) binds MHC-I molecules in the endoplasmic reticulum and accompanies them to the cell surface, while the related m06 binds and directs MHC-I to endosomes. Despite many genetic and functional studies, the structural basis of the specificities and functions of these immunoevasins is poorly understood due largely to difficulty in co-crystallization with their MHC-I ligands. To bypass this bottleneck we have previously determined the structure of the m04 core domain, using a hybrid methodology that combines sparse datasets recorded from Nuclear Magnetic Resonance (NMR) spectroscopy with sophisticated Rosetta macromolecular modeling. The structure revealed a divergent Ig-like fold that is unique to this family of imunoevasins, with long loops that provide flexible scaffolds for MHC binding. Here, we employ solution NMR to map he interaction footprint of m06 on MHCI-I. We make use of a previously engineered α1α2 molecule based on H2-Ld that shows improved NMR spectral features and binding properties. This study provides insight into a key site on MHC-I “discovered” by the virus and helps us to understand the function of this important viral family with respect to T and NK cell MHC recognition.
Preliminary analysis of the contributions of major histocompatibility complex-H2 to autoantibody production in a murine model of systemic lupus erythematosus. (BA3P.116)
Authors: Ruck Melissa , Hermiston Michelle 
Published: January 2023

Abstract
The stochastic and heterogeneous nature of Systemic Lupus Erythematosus (SLE) supports a model whereby multiple genetic and/or environmental hits culminate in loss of tolerance and autoantibody production. Consistent with this model, the phenotype of CD45E613R mice that contain a single point mutation in the juxtamembrane wedge of CD45 depends on genetic context. Despite similar dysregulated phosphatase activity in all immune cells, CD45E613R mice on a C57Bl/6 (B6) background have no overt phenotype while BALB/c (BA) mice develop anti-double stranded (ds) DNA antibodies. An unbiased genome-wide screen for modifiers of autoantibody production between CD45E613R B6 and BA mice identified two candidate loci: Wedge Associated Modifier (Wam) 1 on Chromosome (Chr) 9 encompassing tlr9 and Wam2 on Chr 17 encompassing MHC H2. Previous work has shown that the hyporesponsive BA TLR9 allele permits anti-ds DNA antibodies while the B6 TLR9 allele is resistant. Here, we analyze the contribution of the MHC to this phenotype. CD45E613R BALB/c mice congenic for the B6 H2 locus develop anti-Sm antibodies while B6 mice congenic for the BALB/c H2 locus develop anti-Sm and anti-dsDNA antibodies. H2 congenic CD45E613R BALB/c mice have increased transitional B cells and a trend in increased B1 cells compared to congenic B6 mice. Thus, we hypothesize that MHC influences autoantibody specificity.
Type 1 interferon signaling alters tolerance by promoting self-reactive B cell survival in the germinal centers (BA3P.106)
Authors: Domeier Phillip , Soni Chetna , Elias Melinda , Shwetank .. , Schell Stephanie , Rahman Ziaur 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by high titers of somatically mutated autoantibodies (AutoAbs) that are produced by self-reactive B cells aberrantly selected within the germinal centers (GCs). Type 1 Interferon (IFNa) signaling is implicated in AutoAb mediated pathogenicity in SLE. However, a defined mechanism by which IFNa signaling may regulate the GC checkpoint is unknown. To understand how IFNa signaling regulates the spontaneously developed GC (Spt-GC) response and associated AutoAb production, we utilized B6.Sle1b mice that harbor the lupus-prone NZM2410 strain-derived SLAM locus. These mice exhibit elevated Spt-GC and follicular helper T cell (Tfh) responses that associate with impaired B cell selection in GCs. B6.Sle1b mice deficient in IFNα receptor1 (B6.Sle1b. IFNaR1-/-) had significantly fewer Spt-GC B cells and Tfh cells than B6.Sle1b mice, and exhibited defects in B cell proliferation in vitro. These defects correlated with decreased viability of the IFNaR1-/- B cells, indicating that GC B cell survival requires IFNaR1 signaling. Histological analysis suggests that follicular dendritic cells may produce IFNa in the GC to promote B cell survival. The reduced GC numbers in B6.Sle1b.IFNαR1-/- mice resulted in markedly decreased total IgG Ab titers, including self-reactive AutoAbs. Together, our findings indicate that IFNa signaling helps aberrantly selected GC B cells survive in the Spt-GCs leading to AutoAb production.
Dysregulation of type II interferon associated mediators precedes autoantibody accumulation and type I interferon elevation and predicts transition to systemic lupus erythematosus classification (BA3P.109)
Authors: Munroe Melissa , Fife Dustin , Zhao Yan , Lu Rufei , Robertson Julie , Guthridge Joel , Niewold Timothy , Tsokos George , Keith Michael , Harley John , James Judith 
Published: January 2023

Abstract
Autoantibodies and interferon (IFN) are associated with clinical illness in systemic lupus erythematosus (SLE), but how these factors influence autoimmune disease development is unknown. This study evaluates the timing and changes in SLE-linked autoantibody specificities, serum IFN-α activity, and IFN-associated soluble mediator levels in the years preceding SLE classification. Serial sera from 55 SLE cases spanning pre- and post-SLE classification (average time = 4.3 years) and matched healthy controls (HC) were obtained from the Department of Defense Serum Repository. Cases with positive serum IFN-α activity had more SLE-linked autoantibody specificities (p&lt;0.05). Growth curve modeling and path analysis corroborated that most autoantibody specificities precede IFN-α activity, and IFN-γ and IP-10 were elevated prior to or concurrent with autoantibody positivity (p&lt;0.01). The number of autoantibody specificities and IFN-associated soluble mediators, as well as female gender, predicted increases in IFN-α activity (p&lt;0.04; ANCOVA). IFN-γ and MCP-3 levels, as well as the presence of anti-chromatin and spliceosomal autoantibodies, best predicted transition to SLE with 93% accuracy &gt;4 years before SLE classification (Random Forest). These data indicate that pre-clinical immune system perturbations allow for the accumulation of autoantibodies and subsequent elevation in IFN-α activity immediately preceding clinical symptoms and SLE classification.
Fatal autoimmunity results from the conditional deletion of Snai2 and Snai3 (BA4P.121)
Authors: Pioli Peter , Chen Xinjian , Weis Janis , Weis John 
Published: January 2023

Abstract
Transcriptional regulation of gene expression is a key component of orchestrating proper immune cell development and function. One strategy for maintaining these transcriptional programs has been the evolution of transcription factor families with members possessing overlapping functions. Using the germ line deletion of Snai2 combined with the hematopoietic specific deletion of Snai3, we report that these factors function redundantly to preserve the development of B and T cells. Such animals display severe lymphopenia, alopecia and dermatitis as well as profound autoimmunity manifested by the production of high levels of autoantibodies as early as three weeks of age followed by death within 30 days of birth. Autoantibodies included both IgM and IgG isotypes and were reactive against cytoplasmic and membranous components. A regulatory T cell defect contributed to the autoimmune response in that adoptive transfer of wild type regulatory T cells alleviated symptoms of autoimmunity. The results demonstrated that appropriate expression of Snai2 and Snai3 in cells of hematopoietic derivation plays an important role in development and maintenance of immune tolerance.
Loss of peripheral protection in pancreatic islets by proteolysis-driven impairment of VTCN1 (B7-H4) presentation is associated with the development of autoimmune diabetes (BA4P.132)
Authors: Radichev Ilian , Maneva-Radicheva Lilia , Amatya Christina , Salehi Maryam , Ellefson Jacob , Savinov Alexei 
Published: January 2023

Abstract
Antigen‑specific activation of T cells is an essential process in the control of effector immune responses. Defects in T cell activation, particularly in the co‑stimulation step, have been associated with many autoimmune conditions including type 1 diabetes (T1D). Recently, we demonstrated that V-set domain-containing T cell activation inhibitor-1 (VTCN1) protein is reduced on antigen-presenting cells from diabetes-susceptible NOD mice and human T1D patients. Here, we show existence of a similar defect in the pancreatic islets, as both α and β cells gradually lose their VTCN1 protein during T1D development despite the up‑regulation of the VTCN1 gene. Diminishment of functional islet cells’ VTCN1 is caused by the metalloproteinase NRD1 and leads to a significant induction of proliferation and cytokine production by diabetogenic T cells. Inhibition of NRD1 activity, on the other hand, stabilizes VTCN1 and dulls the anti-islet T cell responses. Therefore, we suggest a general endogenous mechanism of defective VTCN1 function, which affects both lymphoid and peripheral target tissues during T1D progression and results in aggressive anti-islet T cell responses. This mechanism is tied to up-regulation of NRD1 expression and likely acts in two synergistic proteolytic modes: cell-intrinsic intracellular and cell-extrinsic systemic. Our results highlight an importance of VTCN1 stabilization on cell surfaces for the restoration of altered balance of immune control during T1D.
Increase of endosomal Sec61 enhances antigen cross-presentation and induces immune glomerular injury: a novel ‘self-organized criticality theory’ explaining the cause of systemic lupus erythematosus (BA4P.129)
Authors: Tsumiyama Ken , Shiozawa Shunichi 
Published: January 2023

Abstract
Objective: We found that systemic lupus erythematosus (SLE) was induced by repeatedly immunizing the mice with antigen, and have proposed a novel ‘self-organized criticality theory’ explaining the cause of SLE. CTL generated via antigen cross-presentation induces lupus tissue injuries. Here we examine the molecular mechanism of antigen cross-presentation in relation to lupus nephritis. Methods: Bone marrow-derived DC (BMDC) and splenic DC (spDC) were cultured with OVA and an inhibitor of Sec61 Exotoxin A (Exo A) to examine the localization of early endosome antigen 1 (EEA1), calnexin, Sec61 and OVA. Sec61 was immunoprecipitated from DC, followed by detection of OVA. OVA in cytoplasm was also detected. Mice were repeatedly immunized with OVA and Exo A. Sec61 in endosome of spDC was detected using immunoprecipitation of EEA1. Results: In DCs, OVA was co-localized with an endosomal marker EEA1, and subsequently separated from EEA1. OVA was not co-localized with ER marker calnexin. Instead, OVA was co-localized and co-precipitated with Sec61. OVA was detected in cytoplasm of BMDC, however, Exo A abolished the detection of OVA. In spDC of mice developed glomerular injury, not only Sec61 in endosome but also OVA in cytoplasm were increased. Further, co-immunization with OVA and Exo A abrogated the development of glomerular injury. Conclusion: Increase of Sec61 in endosome promotes antigen cross-presentation and is essential for the development of glomerular injury likely of SLE.
Ketone body beta-hydroxy butyrate deactivates NLRP3 inflammasome in myeloid cells (CAM1P.153)
Authors: Goldberg Emily , Youm Yun-Hee , Nguyen Kim , Alnemri Emad , Dixit Vishwa 
Published: January 2023

Abstract
The NLRP3 inflammasome is a major regulator of sterile inflammation. It is now known that many age-related diseases are NLRP3-dependent, including metabolic disease, cognitive decline, bone loss, and thymic demise. Therefore, decreasing inflammasome activation during aging may prevent many chronic diseases known to limit healthspan. Calorie restriction and prolonged fasting reduce inflammation. During fasting, the body uses fat for energy, leading to an increase in ketone body production as a byproduct of fatty acid oxidation. We tested the hypothesis that switching the substrates from glucose to ketones could inhibit inflammasome activation in myeloid lineage cells, macrophages and neutrophils. Here we present novel data that ketone body beta-hydroxy butyrate (BHB) inhibits NLRP3-dependent IL-1β secretion. Notably, related short chain fatty acid, butyrate does not impact the inflammasome and oxidation of ketones for energetic utilization was not required for inflammasome deactivation in myeloid cells. Instead, ketones directly inhibit inflammasome complex assembly by blocking ASC oligomerization and prionization. BHB also inhibits NLRP3 dependent inflammasome activation in vivo and in neutrophils of aged mice. Therefore, ketones may represent an anti-inflammatory intervention to prevent chronic inflammation during aging that is normally associated with functional decline and death in the elderly.
A small animal model of immune reconstitution inflammatory syndrome following antiretroviral therapy (CAM1P.159)
Authors: Huante Matthew , Nusbaum Rebecca , Vijayakumar Sudhamathi , Sutjita Putri , Cirillo Jeffrey , Ferguson Monique , Gelman Benjamin , Valbuena Gustavo , Endsley Janice 
Published: January 2023

Abstract
In HIV-infected patients with latent or subclinical tuberculosis (TB), the development of immune reconstitution inflammatory syndrome (IRIS) following restoration of T cell populations by anti-retroviral therapy (ART) can produce a life threatening inflammatory reaction. The objective of this study was to use our humanized mouse model of Mycobacterium tuberculosis (Mtb) and HIV co-infection to develop a small animal model of IRIS. Humanized BLT mice (HuMice) were infected i.n. with Mtb H37Rv, and following development of TB disease were given TB chemotherapy (rifampicin and isoniazid) by oral gavage. Bacteria were not detected in the lung following TB chemotherapy, but low numbers of Mtb were detected two months after stopping drug treatment, which mimics subclinical TB. When Mtb-infected and TB drug-treated HuMice were infected i.v. with HIV-1 Ada, the animals developed HIV-1 co-infection as determined by the presence of the HIV p24 capsid protein in peripheral blood by ELISA. ART was performed to reduce viral load in blood plasma and restore T lymphocyte function in animals with subclinical TB. In ongoing studies, the development of inflammatory responses, Th1 cell activation and lung pathology are being determined to understand how immune recovery, due to ART, drives inflammation in the setting of subclinical TB. This model will facilitate investigations to understand the mechanistic basis for IRIS and identify targets for host-directed therapies.
The role of HMGB1's critical cysteines are explored in human monocytes (CAM1P.151)
Authors: Bauer Eileen , Deng Peng , Gollapudi Venkata Sashi , Shapiro Richard , Li Tunliang , Billiar Timothy 
Published: January 2023

Abstract
High Mobility Group Box 1 protein, HMGB1 is a prototypical DAMPs. While HMGB1 is present in the nucleus of every cell under homeostatic conditions, cellular stress leads to its release into the extracellular milieu, where it activates a variety of pattern recognition receptors. HMGB1 has multiple functions. Under certain conditions HMGB1 acts as a cytokine, causing the release of pro-inflammatory cytokines including TNFα. In addition, HMGB1 may act as a chemokine. We now know that HMGB1 contains three critical redox-sensitive cysteines (C23, C45, C106). Modifying the redox state of these cysteines determines the action of HMGB1. Here we created 3 HMGB1 mutants replacing the cysteines with serines and systematically evaluated their role in human monocytes based on cytokine expression. Human monocytes are classically used to evaluate HMGB1’s ability to produce TNFα thus creating a comparison to other published work on HGMB1. While it is known that a disulfide bond between C23 and C45 is necessary for the cytokine like effect of HMGB1 our data show that the presence of all three cysteines is necessary for this action. Also, mutation of C23 or C106 to serine led to suppression of basal TNF release, changes in autophagy induction and signaling events. This suggests that terminal oxidation of either of these cysteines acts to suppress inflammation. Understanding the role of these cysteines hopefully will allow us to create better therapeutics targeting diseases driven by HMGB1.
IQGAP1 critically promotes CXCR4 chemokine receptor expression and signaling by regulating CXCR4 intracellular trafficking through EEA-1 endosomes (CCR3P.212)
Authors: Hedin Karen , Bamidele Adebowale , Kremer Kimberly , Hirsova Petra , Gores Gregory , Billadeau Daniel 
Published: January 2023

Abstract
IQGAP1 is a ubiquitous, cytoskeletal-interacting scaffold protein frequently overexpressed in cancer. CXCR4 is a chemokine receptor that signals upon binding stromal cell-derived factor 1 (SDF-1, CXCL12). CXCR4 regulates lymphocyte migration and development and cancer cell proliferation and metastasis. Here, we show that IQGAP1 potently enhances CXCR4’s expression, trafficking, and function in the Jurkat T cell line and epithelial cancer cells. The SDF-1-induced cell migration and activation of ERK MAPK were impaired in IQGAP1-deficient cells, even after forced CXCR4 overexpression. Exploring the mechanism, we found that SDF-1 treatment induced CXCR4 endocytosis and caused IQGAP1 to bind a-tubulin and localize to EEA-1 endosomes containing endocytosed CXCR4. In IQGAP1-deficient cells, CXCR4-containing EEA-1 endosomes accumulated at the distal ends of microtubules instead of moving towards the centrosome. This inhibited CXCR4’s signaling and cell-surface expression by preventing CXCR4 from trafficking into the Rab11 endosomes previously shown to be a critical site of CXCR4 signaling and recycling to the cell-surface. In contrast, IQGAP1 depletion had no effect on TCR trafficking, which does not require EEA-1 endosomes. Together, these results characterize a novel function of IQGAP1 as a regulator of EEA-1 endosomes, and in addition identify IQGAP1 as a critical enhancer of CXCR4 cell-surface expression and signaling in lymphocytes and epithelial cancer cells.