bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective role of neutrophils in respiratory paramyxovirus infection (VIR5P.1157)
Authors: Cheemarla Nagarjuna , Banos-Lara Rocio , Guerrero-Plata Maria 
Published: January 2023

Abstract
Polymorphonuclear leukocytes (PMNs or neutrophils) are the most abundant leukocyte in humans and essential for innate immune responses against invading pathogens. The role of these cells in respiratory viral infections still remains largely unknown. Human metapneumovirus (hMPV) belongs to the Paramyxoviridae family and is a leading respiratory pathogen causing severe symptoms such as bronchiolitis and pneumonia in young children, the elderly and immunocompromised patients. In this study, we investigate the role of neutrophils in hMPV infection using an experimental mouse model. Our results demonstrate that neutrophils predominate in the lungs of infected mice (&gt;80%) during the acute phase of infection. In order to define the role of this robust response of neutrophils, we specifically depleted those cells using a monoclonal antibody. Our data indicate that neutrophil-depleted hMPV-infected mice exhibited significantly higher levels of inflammatory cytokines, pulmonary inflammation than competent mice. Moreover, depleted mice showed a more severe clinical disease (as indicated by an enhanced body weight loss and clinical illness) than competent animals. Interestingly, the recruitment of neutrophils to the site of infection was regulated by the expression of the hMPV G (attachment) protein. These novel findings indicate that neutrophils are critically important for the control of hMPV-induced disease and further our knowledge on the role of PMNs in respiratory viral infections.
TGF-β production associated with allergic asthma prevents influenza virus induced immunopathology (VIR5P.1160)
Authors: Furuya Yoichi , Sanfilippo Alan , Metzger Dennis 
Published: January 2023

Abstract
Asthma is believed to be a risk factor for influenza infection, however little remains known about how the asthmatic phenotype influences anti-viral immune responses. We therefore investigated the impact of asthma on susceptibility to influenza infection by using a mouse model of allergic airway inflammation. Unexpectedly, asthmatic mice were highly resistant to primary infection with the H1N1 2009 pandemic strain. Notably, the increased resistance was not attributed to enhanced viral clearance but instead was due to reduced lung inflammation. Asthmatic mice exhibited a significantly reduced cytokine storm as well as reduced total protein levels and cytotoxicity in the airways, indicators of decreased tissue injury. Further, we show that asthmatic mice have significantly increased levels of TGF-β1 and that the heightened resistance of asthmatic mice is abrogated in the absence of TGF-β receptor II. Thus, we conclude that the transient increase in TGF-β expression following an acute asthma episode is responsible for temporarily protection via suppression of influenza-induced immunopathology.
FcµR expression by B cells regulates maximal induction of plasma cell differentiation in vivo and in vitro (VIR5P.1136)
Authors: Nguyen Trang , Baumgarth Nicole 
Published: January 2023

Abstract
Secreted (s)IgM functions in immune defense and regulation. It supports B cell development, selection and the size and quality of the humoral response. We aimed to identify the mechanisms underlying the reduced IgG responses in sIgM-/- mice after influenza virus infection. To distinguish effects of sIgM on B cell development from those on immune regulation, we generated sIgM-/- x wild-type (wt) F1 mice. All B cells develop normally in these mice but 50% lack the ability to secrete IgM. Wt and sIgM-/- B cells from F1 mice were transferred into sublethally irradiated wt controls, which were infected with influenza A/Puerto Rico/8/34. sIgM-/- B cells mounted reduced antiviral serum IgG responses compared to controls, demonstrating a non-redundant function for sIgM in B cell response induction. Studies in mice lacking the FcµR only on B cells suggested that sIgM-mediated regulation is due at least in part to sIgM-FcµR direct interaction. These mice mounted IgG and Hemagglutination Inhibition titers that were reduced by about half, and their sera had strongly decreased passive protective capacity compared to wt mice. ELISPOT and FACS-analysis revealed reduced plasma cell differentiation in draining mediastinal LNs at day 8, and long-lived plasma cells in bone marrows at day 70 after infection, as well as following stimulation of B cells in vitro. The data identify sIgM-FcµR direct interaction as a non-redundant B cell differentiation signal after B cell activation.
Murine cytomegalovirus specific response of non-classical CD8+ T cells (VIR6P.1175)
Authors: Anderson Courtney , Reilly Emma , Brossay Laurent 
Published: January 2023

Abstract
MHC class Ib-restricted CD8+ T cells have been shown to participate in the immune response towards intracellular bacterial pathogens. In contrast, the role of non-classical CD8+ T cells during viral infections is largely unknown. We sought to further investigate their functions using murine cytomegalovirus (MCMV), a well-established model for human CMV infections. To circumvent the demonstrated role of classical CD8+ T cells, we utilized KbDb-/- mice, in addition to KbDbCD1-/- mice that also lack natural killer T (NKT) cells. Following MCMV infection, we find that a subset of non-classical CD8+ T cells undergoes expansion and acquires an effector phenotype. We also demonstrate that this response is not due to a bystander reaction. These innate-like T cells exhibit a memory-like phenotype, but do not express the transcription factor PLZF. Interestingly, despite the absence of both classical CD8+ T cells and NKT cells, these mice are relatively resistant to infection. However, there is a prolonged inflammatory phenotype not present in wild-type animals, which clear MCMV. Taken together, these data demonstrate that MHC class 1b-restricted CD8+ T cells contribute towards the immune responses to viral infection.
Assessing the capability of the mycobacterial ribosome to elicit a CD4+ T cell response (APP5P.115)
Authors: Kennedy Steven , Johnson Alison , Seidel Ronald , Chan John , Jacobs William , Porcelli Steven 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb) infects one third of the world’s population, and an effective vaccine is desperately needed to curb the spread of disease. We have identified that the CD4+ T cell response is critical in combating Mtb. Using an attenuated version of Mycobacterium smegmatis, IKEPLUS, our lab previously identified the mycobacterial ribosome as a potential target to enhance CD4+ T cell responses to Mtb in mice. To directly assess the CD4+ T cell response mounted against the individual mycobacterial ribosomal proteins, we used an E. coli expression system to express and purify all fifty-seven proteins that make up the Mtb ribosome. This Mtb ribosomal library was then used to identify which proteins of the mycobacterial ribosome elicited a CD4+ T cell response in IKEPLUS infected animals by IFN-γ ELISPOT. When CD4+T cells of infected animals were isolated and restimulated with the Mtb ribosomal protein library, twenty-five of the fifty-seven total proteins elicited significant CD4+ Tcell responses. These ELISPOT results indicate that the Mtb ribosome is a highly immunogenic structure with the ability to stimulate strong T cell responses in mice. Further studies will focus on the use of the mycobacterial ribosome and isolated ribosomal proteins as potential components of vaccination regimens for inducing protective immunity against Mycobacterium tuberculosis.
Thymic development of insulin reactive T cells (BA11P.128)
Authors: Lee Thomas , Tully Natalie , Bettini Maria , Bettini Matthew 
Published: January 2023

Abstract
Type 1 Diabetes (T1D) is a T cell-mediated autoimmune disease that involves the destruction of insulin (Ins) producing β cells found within the pancreatic islets of Langerhans. While multiple studies have characterized the pathogenicity and diabetogenic potential of β-cell specific T cells, we have limited mechanistic insight into autoimmune T cell development and their escape from thymic selection. Utilizing the retrogenic mouse technology, we show that ectopic expression of InsB9-23 or insulin agonist mimetope (R22E) in the thymus influences the onset of diabetes. Our results demonstrate that increasing InsB9-23 expression in the thymus is insufficient to induce insulin reactive CD4+ T cell deletion, and upon escape from thymic selection, these insulin reactive T cells infiltrate the pancreas of NOD mice. Interestingly, these pancreatic-residing autoreactive CD4+ T cells are no longer able to induce spontaneous diabetes development. In contrast, when R22E mimetope is expressed, thymocyte development is halted at the double positive stage and insulin reactive T cells undergo negative selection. As a result, thymic expression of R22E completely prevents autoreactive thymocytes selection and diabetes development. Collectively, these results suggest that antigen dose or peptide:MHC complex stability of self-antigen presentation in the thymus can lead to multiple fates of insulin reactive CD4+T cell development and autoimmune outcome.
Self-lipid specific T cells, restricted by CD1b, contribute to the development of hyperlipidemia-associated skin inflammation (BA11P.133)
Authors: Bagchi Sreya , Zhang Hong , He Ying , Wang Chyung-Ru 
Published: January 2023

Abstract
Psoriasis, a chronic inflammatory skin disease, is associated with hyperlipidemia. While conventional T cells usually exacerbate psoriasis, the role of self-lipid reactive CD1-restricted T cells requires further study. CD1 molecules present lipid antigens to T cells and are divided in to two groups. Group 1 includes CD1a, CD1b, CD1c while CD1d belongs to group 2. Humans express both group 1 and group 2 CD1 molecules whereas mice only have CD1d. Thus, due to the lack of a suitable animal model, the role of autoreactive group 1 CD1-restricted T cells in hyperlipidemia-associated inflammatory diseases is unknown. To overcome this challenge, our lab generated mice that expressed human CD1b and a CD1b-autoreactive T cell receptor (hCD1Tg/HJ1Tg). hCD1Tg/HJ1Tg mice were crossed to the ApoE-/- background to examine the role of CD1b-restricted T cells in hyperlipidemia (hCD1Tg/HJ1Tg/ApoE-/-). Interestingly, hCD1Tg/HJ1Tg/ApoE-/- mice developed severe psoriasis-like skin inflammation characterized by T cell and neutrophil infiltration along with a Th17-biased cytokine milieu. They also showed significantly increased polar lipid accumulation in the skin as compared to hCD1Tg/HJ1Tg/ApoE+ mice. This suggested that the presence of excessive lipids in the skin resulted in activation of CD1b-autoreacitve T cells, leading to the onset of skin pathology. This work demonstrates that autoreactive group 1 CD1-reactive T cells might serve as a link between inflammatory processes and hyperlipidemia.
Aryl hydrocarbon receptor expressing Treg17 cells suppress type 1 diabetes in NOD mice (BA11P.140)
Authors: Singh Bhagirath , Nikoopour Enayat , Bellemore Stacey , Lee-Chan Edwin , Krougly Olga 
Published: January 2023

Abstract
The role of Th17 cells in type 1 diabetes (T1D) remains inconclusive. We found polarizing CD4+ T cells with TGF-beta+IL-6 or with IL-23+IL-6 cytokines induces different subsets of Th17 cells. Cells polarized with TGF-beta+IL-6 express high levels of transcription factor aryl hydrocarbon receptor (AhR) and IL-10 but minimal amounts of IL-22. Cells from T cell receptor transgenic BDC2.5 NOD mice polarized with IL-23+IL-6 produced large amounts of IL-22, expressed little AhR expression but induce T1D in young NOD mice. Cells derived with TGF-beta+IL-6 and termed as Treg17 cells were nonpathogenic and did not induce T1D. All adoptive transfer studies were done in young NOD mice and not NOD.SCID mice to prevent the conversion of Th17 cells into Th1 cells. We have also found IL-22-producing Th17 cells in the pancreas of diabetic NOD mice. The expression of IL-22 receptor in the pancreas of NOD mice increased with disease progression. Neutralization of IL-22 by antibody in vivo during adoptive transfer of pathogenic Th17 cells or splenocytes from diabetic mice did not significantly alter disease progression in the recipient mice. Therefore, Th17 derived IL-22 is not directly pathogenic to beta cells. We conclude regulatory Treg17 cells induced by TGF-beta+IL-6 that express high levels of AhR are protective while Th17 cells with a very low level of AhR induced by IL-23 + IL-6 are pathogenic. Both EN and SMB equally contributed to this work.
Loss of tolerance due to post-translational modification of beta cell peptides (BA11P.124)
Authors: McGinty John , Chow I-Ting , Greenbaum Carla , Odegard Jared , Kwok William , James Eddie 
Published: January 2023

Abstract
Post-translational modification (PTM) of self-proteins generates neo-antigens that are clinically relevant to autoimmune disease and are increasingly implicated in T1D. Here we demonstrate that enzymatic transglutamination and citrullination of beta cell antigens enhances presentation by the high risk HLA class II alleles DR4 and DQ8. We show CD4+ T cells specific for these epitopes are present at elevated frequencies ex vivo in the peripheral blood of patients with long standing T1D and are of Th1 phenotype. Such neo-antigens can induce distinct T cell specificities, while others cross-react with wild type-specific T cells. In each case, autoreactive T cells preferentially recognize modified epitopes resulting in enhanced proliferation and cytokine production. Mechanistically, modification at key binding pockets enhanced peptide binding to HLA class II, creating a stable pMHC that could bind autoreactive CD4+ T cells. Alternatively, modification of residues outside of binding pockets altered TCR interaction to permit T cell recognition. In one instance, dual modification of HLA and TCR contact points was required to induce a T cell response. Interrogation of autoantibody positive, healthy “non-progressors” revealed an intermediate T cell frequency, representing a break in tolerance without progression to overt diabetes. These findings implicate an important role for PTMs in broadening the antigenic repertoire and exacerbating the evolving autoimmune response in T1D.
IL4RA regulates lymphocytes trafficking in sclerodermatous graft-versus-host disease. (CAM4P.154)
Authors: Urso Katia , Alvarez David , Cremasco Viviana , Tsang Kelly , Lafyatis Robert , von Andrian Ulrich , Aliprantis Antonios 
Published: January 2023

Abstract
Scleroderma is an autoimmune disease characterized by inflammation and fibrosis in skin and internal organs. We utilized a murine Graft Versus Host Disease (GVHD) model of Scleroderma (SclGVHD), in which lymphocytes are transferred from B10.D2 mice (graft) into MHC-matched, lymphocyte deficient Balb/c Rag2-/- mice (host, sclGVHD mice). Over the course of 6 weeks, sclGVHD mice develop skin inflammation and fibrosis. Previously, we identified IL13 pathway activation in the skin of sclGVHD mice and scleroderma patients. Accordingly, host mice lacking IL4RA, a functional subunit for the IL13 receptor complex, are protected from sclGVHD. Here, we show that sclGVHD-IL4Ra-/- mice display a defect in lymphocyte trafficking, with more activated T cells in subcutaneous lymph nodes (sLNs) but fewer T cells in lymph, blood and skin compared to control mice. In addition, sphingosine 1-phosphate (S1P) kinase 1 was decreased in the sLNs and in sorted lymphatic endothelial cells (LEC) from sclGVHD-IL4Ra-/- mice. Since S1P is the major regulator of lymphocyte egress from sLNs, these data suggest that IL4Ra promotes sclGVHD by inducing the production of this mediator from LECs, which drives activated T cells into the periphery. These experiments highlight a potential novel role for IL4RA in inflammatory diseases, and indicate that strategies which impede lymphocyte trafficking may be effective therapeutically in the context of GVHD and scleroderma.
Tissue-resident specialized T cells promote the migration of local tissue dendritic cells: immune regulation at the local tissue level (CAM4P.155)
Authors: Gutierrez Miguel-Angel , Eriksson Anna , Randhawa Darshan , Kim Peter , Singh Ram 
Published: January 2023

Abstract
Dendritic cells (DC) that primarily reside in tissues carry antigens to local lymphoid organs to induce immunity or tolerance. We posit that a defect in the migration of tissue-DCs may predispose to autoimmunity in a tissue-specific manner; and an improved migration of tissue-DC may ameliorate disease in the respective organ. Here, we demonstrate that treatment of lupus dermatitis-prone MRL-lpr and MRL+/+ mice that exhibit a profound defect in the migration of skin-DC with a glycolipid αGalCer reduced the severity of dermatitis and enhanced the migration of skin-DCs, more so in Langerhans cells (LC; p=0.004) than in Lang+dDC (p=0.03). This effect of αGalCer was independent of its effect on iNKT cells, but required the presence of CD1d. Furthermore, αGalCer treatment enhanced the numbers of epidermis-resident γδ T cells in MRL-lpr mice that had reduced numbers of γδ T cells as compared to MHC-matched control mice. Finally, gd T cell-deficient mice had reduced skin-DC migration, and isolated skin-gd T cells directly promoted the migration of LC via CD40L-CD40 interaction. These data elucidate a new mechanism of regulation of skin-DC homeostasis whereby skin-gd T cells normally facilitate LC migration from skin to cutaneous lymph node. Such ‘local’ control of migratory behavior of tissue-DC can regulate immune response in a tissue-specific manner. This mechanism of skin-DC homeostasis is disrupted in lupus dermatitis, but can be repaired by treatment with a glycolipid.
Adipokine-induced activation responses in vascular endothelial cells: An inflammatory trigger in adipose microenvironment (CAM4P.160)
Authors: Singh Manindra , Benencia Fabian 
Published: January 2023

Abstract
Obesity is a global epidemic and leads to premature death due to its association with metabolic diseases. Evidence suggests that a low-grade, chronic inflammation of adipose tissue contributes to metabolic disorder of visceral adipose tissue. Adipose tissue-derived hormones, also called as adipokines, regulate variety of homeostatic functions, including metabolism and inflammation. We examined the function of adipokines: visfatin, vaspin and leptin, and tested the hypothesis that adipokines regulate immunoinfiltration of adipose tissue by inducing activation of endothelium in the adipose microenvironment. A large scale microarray was performed for the identification of soluble chemokines produced by adipokine-treated endothelial cells, and a decrease in the levels of chemokine ligand-17 was observed (n=5). Further, ELISA analysis confirmed significant upregulation for pro-inflammatory chemokines: Monocyte chemoattractant protein-1 (MCP-1) and granulocyte monocyte-colony stimulating factor (p&lt;0.05, n=5). RNA was isolated from the adipokine-treated endothelial cells and real-time PCR analysis confirmed significant upregulation of pro-inflammatory genes interleukin-6 and MCP-1 in response to visfatin treatment (p&lt;0.05, n=5). The surface expression of adhesion markers was measured by flow cytometry, and vascular cell adhesion protein-1 was found upregulated in response to visfatin. Overall, our results suggest that the studied adipokines are functional link for ECs and leukocyte crosstalk in the context of the adipose tissue.
Atheroprotective potential of CXCR4 on B1 cells (CAM4P.145)
Authors: Upadhye Aditi , Morris-Rosenfeld Samuel , McSkimming Chantel , Taylor Angela , McNamara Coleen 
Published: January 2023

Abstract
Atherosclerosis is a chronic inflammatory condition in which lipid deposition in arteries leads to the recruitment, activation, and accumulation of immune cells in the artery wall. Immune cells can have protective or detrimental effects on disease development. Existing evidence demonstrates that B1 cells hinder atherosclerotic lesion formation by secreting natural IgM antibodies that recognize modified self-epitopes present in diseased arteries. However, the mechanisms underlying B1 cell migration to arteries require further study. Our lab utilizes flow cytometry of circulating human immune cells in patients undergoing intravascular ultrasound of coronary arteries, in order to identify key surface markers that are associated with plaque burden. Expression of the chemokine receptor CXCR4 on human CD20+ CD3- CD27+ CD43+ B1 cells associated with reduced plaque burden in coronary arteries. No correlation was found between plaque volume and CXCR4 expression on naïve or memory B cell subsets. Prior evidence demonstrates that the helix-loop-helix transcription factor Id3 regulates B cell homing to the aorta and B cell-mediated atheroprotection. Loss of Id3 in the Apoe-/- mouse model of atherosclerosis led to systemic increase in surface expression of CXCR4 on B1 cells. Loss of Id3 additionally led to attenuated lesion formation, as measured by immunohistochemical lesion analysis of the aorta. These data suggest a potential atheroprotective function of CXCR4 on B1 cells.
The role of interleukin-17 in type I interferon mediated renal damage associated with lupus nephritis (CCR5P.202)
Authors: Ramani Kritika , Maers Kelly , Biswas Partha 
Published: January 2023

Abstract
Lupus nephritis (LuN) is a major clinical manifestation of systemic lupus erythematosus (SLE) resulting in significant morbidity and mortality. SLE is type I interferon (IFN-I) driven where IFN-I plays a critical role in irreversible damage in LuN. More recently, studies have implicated interleukin-17A (IL-17) in the pathogenesis of LuN. Little is known about the cross talk between IFN-I and IL-17 in mediating LuN. The objective of this study is to define the role of IL-17 in IFN-I mediated LuN. IFN-I driven LuN was induced with polyinosinic: polycytidylic acid (poly I:C) in lupus prone C57BL/6-Faslpr/lpr mice (B6.lpr). We show that renal damage is reduced in the absence of IL-17 receptor A (IL-17RA) signaling. Diminished renal pathology in B6.lprIL-17RA-/- mice correlated with diminished number of kidney infiltrating M2 macrophages implicated in the pathogenesis of poly I:C induced LuN. Kidneys of IL-17RA-/- mice also displayed reduced expression of osteopontin (Opn) produced by M2 macrophages and mediates Th17 regulation via IFN-I. Opn is involved in macrophage recruitment to sites of tissue damage. Finally, we showed that IFN-I and IL-17 could synergistically upregulate Opn gene expression in bone marrow derived macrophages. Therefore, these findings for the first time reveal a synergistic role for IL-17 and IFN-I in the pathogenesis of LuN. These studies may inspire development of novel therapeutic strategies for the treatment of LuN and other chronic kidney disorders.