bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostaglandin E2 Receptor Signaling Induces IL-23p19 Expression through CREB and STAT-3 Transcriptional Regulation (98.2)
Authors: Kocieda Virginia , Adhikary Sabina , Emig Fran , Ganea Doina 
Published: January 2023

Abstract
Previously, we have shown that PGE2 inhibits IL-12p35 expression & promotes IL-23p19 expression in dendritic cells (DC) treated with LPS or Poly I:C. The effect is mediated through EP4 and to a lesser degree EP2 receptors and induction of cAMP. This study is focused on essential transcriptional factors and signaling pathways involved in PGE1-OH (EP4 agonist) induced p19 expression. Previous studies reported involvement of NFkB (c-Rel), ATF-2, SMAD-3 & AP-1. CREB is a target of cAMP-activated PKA and two CREB binding sites have been identified in the p19 promoter. Therefore, CREB is a potential transcription factor activated by PGE. Experiments with p19-luciferase constructs containing wt & CREB-mutated sites indicate the importance of CREB sites in p19 transcriptional activity. PGE2/PGE1-OH also induced STAT-3 tyrosine phosphorylation in DC and in the DC cell line. Blocking STAT-3 phosphorylation with the chemical inhibitor S3I-201 and the specific peptide inhibitor PpYLKTK-mts reduced p19 expression in DC. Although no STAT-3 binding site was found in the p19 promoter, STAT-3 was proposed to act as a co-activator for c-Rel to induce p19 expression. These data show for the first time that CREB and STAT-3 are important regulators of PGE2-induced p19 expression in DC. These observations show the versatility that prostaglandins have to differentially regulate expression patterns of cytokines that orchestrate an immune response.
The activation state of Ly-6Chi inflammatory monocytes determines their immune regulatory function (98.23)
Authors: Zhu Bing , Kennedy Jennifer , Wang Yue , Sandoval Garcia Carolina , Elyaman Wassim , Xiao Sheng , Khoury Samia 
Published: January 2023

Abstract
We reported that CD11b+Ly-6ChiLy-6G- inflammatory monocytes (IMCs) obtained after EAE immunization strongly induced apoptosis in pre-activated CD4 T cells through the production of nitric oxide. However, it was recently reported that transfer of wild type IMCs worsened EAE disease in GM-CSF-/- or CCL2-/- recipients, suggesting a pathogenic function of IMCs. We hypothesized that the immune function of IMCs depends on their activation state. We found that ex vivo purified IMCs induced antigen-specific proliferation of naïve TCR transgenic CD4 T cells, suggesting that these IMCs can function as antigen presenting cells. In contrast, when the same IMCs were first activated with IFN-γ, LPS and GM-CSF, they strongly suppressed T cell proliferation induced by professional APCs, which could be rescued by NOS2 inhibition. Similar dichotomy of T cell regulatory function was observed in inflammatory dendritic cells (IDCs) differentiated from IMCs with GM-CSF. In addition, IMCs isolated from the central nervous system (CNS) of MOG-immunized B6 mouse before EAE onset supported T cell proliferation, survival and Th1/Th17 differentiation, but CNS IMCs obtained at EAE peak suppressed T cell proliferation and differentiation. Furthermore, transfer of in vitro activated IMC and IDCs markedly suppressed EAE severity and reduced CNS inflammation. In summary, we demonstrate that the immune function of IMCs and IDCs is plastic and dependent on their activation state.
Requirement of voltage-gated calcium (Cav) channels in T cell receptor-mediated calcium response and effector functions of T lymphocytes (99.13)
Authors: Jha Mithilesh , Badou Abdallah , Flavell Richard 
Published: January 2023

Abstract
Calcium signals are required for the activation, differentiation and effector functions of T lymphocytes. However, the molecular machinery required for calcium influx upon TCR stimulation of T cells is not yet clear. Previously, we have shown that members of the Cav1 family of voltage-gated calcium channels are expressed in T lymphocytes and regulate calcium influx into these cells. Recently, we have demonstrated an essential role for the beta3 regulatory subunit of Cav channels in the maintenance of naive CD8 T cells since deficiency in beta3 resulted in a profound survival defect of naïve CD8 T cells. Here, we investigated the expression and function of Cav1 channels in differentiated CD4 T lymphocyte populations and discovered a novel role of Cav1 channels in effector helper T cell population. We found a selective expression of Cav1.3 in effector Th2 cells but not naïve CD4 T cells or effector Th1 cells. Both TCR-mediated calcium response and NFATs nuclear localization were severely impaired in Cav1.3-deficient Th2 cells. A profound and selective impairment of Th2 effector cytokine production was observed in vitro and in vivo after immunization of mice. Our data demonstrate a novel and essential role of Cav1 channels in different T cell functions. Therefore, Cav1 channels represent a specific and new therapeutic target for T cell-mediated inflammatory diseases.
Humoral responses require a multi-stage T:B lymphocyte interaction process (99.5)
Authors: Cannons Jennifer , Qi Hai , Lu Kristina , Ghai Mala , Gomez-Rodriguez Julio , Germain Ronald , Schwartzberg Pamela 
Published: January 2023

Abstract
X-linked lymphoproliferative (XLP) disease is an immune disorder caused by mutations encoding SLAM-associated protein (SAP, Sh2d1a), an adaptor that facilitates Fyn recruitment to SLAM family of receptors, including 2B4, Ly9, SLAM, CD84 and Ly108. SAP-/- CD4 T cells exhibit a selective impairment in adhesion to antigen presenting B cells but not dendritic cells (DC), resulting in defective germinal centre (GC) formation. However, the nature of this selective adhesion defect is unclear. We provide evidence that while T:DC interactions are primarily integrin-dependent, T:B cell interactions have an early integrin-dependent component and a sustained phase that also requires SAP. We further demonstrate that T cells adhere to the SLAM family members, CD84 and Ly108, in a SAP-dependent manner. Both CD84 and Ly108 are highly expressed on T follicular helper (TFH) cells, a specialized subset of CD4 T cells that reside within GCs and are critical for their formation. Cd84-/- mice exhibit a partial defect in GC responses to T-dependent antigens. This defect correlated with impaired cognate T:B cell conjugate pairing observed in vivo by dynamic imaging as well as reduced TFH cell differentiation and function. Strikingly, the combined loss of CD84 and Ly108 markedly reduced T:B conjugate pairing in vitro. Thus, our results identify SLAM family members as critical receptors involved in the dynamic regulation of sustained T:B cell interactions.
Functional effects of ERAAP polymorphisms linked to ankylosing spondylitis (100.18)
Authors: Reeves Emma , Elliott Tim , James Edd 
Published: January 2023

Abstract
Optimal peptide loading on the MHC I molecule is essential for antigen presentation to CD8+ cytotoxic T lymphocytes. Endoplasmic Reticulum Aminopeptidase associated with Antigen Processing (ERAAP) is responsible for N-terminal trimming of peptides to optimal length for stable loading and presentation through MHC I. In humans, ERAAP is also known to play a role in pro-inflammatory cytokine receptor cleavage as well as regulating blood pressure and angiogenesis. Recently, a single nucleotide polymorphism (SNP) linkage analysis study has identified ERAAP as being associated with increased risk of the autoimmune inflammatory disorder, ankylosing spondylitis (AS). Here, we show that SNP mutation of ERAAP alters its ability to trim peptides. Transfection of ERAAP-/- cells with ERAAP molecules incorporating each of the SNPs identified in the linkage analysis show a hierarchy of reduced function. More pronounced functional phenotypes are revealed with additional mutations suggesting a cumulative effect. Although the mechanism for the effect of SNP mutation on ERAAP function is unclear, it appears that they cause a dramatic effect on peptide trimming.
Self-antigen peptidome carried by the human lymph (100.3)
Authors: Santambrogio Laura , Clement Cristina , Stern Lawrence 
Published: January 2023

Abstract
The pre-nodal afferent lymph is the fluid which directly derives from the extracellular milieu of every parenchymal organ collecting catabolic and metabolic products. A comprehensive qualitative and quantitative investigation of the self-antigenic repertoire transported by the human lymph was the goal of our investigation. A major difference between lymph and plasma could be visualized by FPLC and 2D gel in the amount of low molecular weight products corresponding to peptide fragments. Naturally processed peptides in normal pre-nodal human lymph were fractionated by HPLC and characterized by MS/MS. Analysis of more then 300 sequences, identified self-peptides derived from both intracellular and extracellular proteins, transported by the human lymph. Quantitative analysis established that some of these peptides are present in nanomolar concentration. The peptidome, generated by physiological tissue catabolism and transported by the pre-nodal lymph, is in addition to the self-peptidome generated in endosomal compartment. Unlike self antigen processed by local or nodal APC, which produce epitopes constrained by the endosomal processing activity, self antigens present in the lymph could derived from a wider variety of processing pathways; including caspases, involved in cellular apoptosis, ADAM and MMPs involved in receptors/cytokines editing and matrix remodeling. Altogether, expanding the tissue-specific self-repertoire available for the maintenance of immunological tolerance.
Preterm labor leads to activation and proliferation of maternal T cells which recognize the paternal alloantigen via the indirect pathway (100.46)
Authors: Wegorzewska Marta , Nijagal Amar , Le Tom , Tucker Andrew , Tang Qizhi , MacKenzie Tippi 
Published: January 2023

Abstract
Purpose: Multiple tolerance mechanisms protect the semi-allogeneic fetus from attack by the maternal adaptive immune system. We hypothesize preterm labor (PTL) may represent a breakdown of tolerance to the allogeneic fetus. Methods: B6 females were bred to BALB/c males and CFSE-labeled TCR transgenic T cells (TCR75 CD4, indirect; 4C CD4, direct; 2C CD8, direct) which recognize BALB/c antigen were adoptively transferred on E12.5 to study the roles of indirect and direct antigen presentation. PTL was induced by LPS on E13.5 and mice were analyzed at E18.5 for expression of CD44, CD62L, and CFSE. Controls included syngeneic matings with PTL and allogeneic matings without PTL. Results: 4C and 2C T cells did not proliferate during PTL. TCR75 cells proliferated and upregulated CD44 in allogeneic pregnancies with PTL compared to those without PTL (p&lt;0.05) or syngeneic pregnancies with PTL (p&lt;0.05). Although TCR75 cells proliferated in all allogeneic pregnancies, they only accumulated in animals undergoing PTL, suggesting that apoptosis of alloreactive T cells maintains maternal-fetal tolerance in normal pregnancies. Conclusions: PTL leads to proliferation, activation, and accumulation of maternal T cells that recognize the paternal alloantigen via the indirect pathway, indicating these cells participate in the pathogenesis of the disease. Understanding their role may uncover novel pathways for therapeutic intervention in PTL.
Myosin 1c participates in B cell cytoskeleton rearrangements, is recruited to the immunological synapse and contributes to antigen presentation. (100.48)
Authors: Maravillas-Montero Jose , Gillespie Peter , Patiño-Lopez Genaro , Shaw Stephen , Santos-Argumedo Leopoldo 
Published: January 2023

Abstract
Myosin 1c (Myo1c) is a member of the unconventional class I myosins of vertebrates, which directly link the plasma membrane with the microfilament cortical web. Although this molecular motor has been implicated in cell functions such as cytoskeleton organization, cell motility, nuclear transcription and endocytosis; its role in the hematopoietic cells is largely unknown. We found that Myo1c is abundantly expressed in murine B lymphocytes and is preferentially located at the plasma membrane, especially in peripheral processes such as microvilli. It was observed not only that this motor concentrates at the growing membrane protrusions generated during B cell spreading, but also that is actively recruited to the immune synapse. Interestingly, Myo1c was detected in the lipid rafts of B cells and showed a strong colocalization with MHC-II, particularly after crosslinking of these molecules. By transfecting a dominant negative form of Myo1c, we also detected alterations in spreading and antigen presentation ability of these cells. All these data suggest that Myo1c could be involved in the B lymphocyte cytoskeleton dynamics and membrane protein anchoring and/or sorting, during cell-cell contacts, including those related with CD4+ T cell activation.
Superimposed viral infection recruits CD8+ T cells to the CNS that exacerbate EAE (101.13)
Authors: Rainey-Barger Emily , Rao Praveen , Segal Benjamin , Irani David 
Published: January 2023

Abstract
Epidemiological data support a link between viral infection and multiple sclerosis (MS), but the underlying cellular and molecular mechanisms through which such infections might initiate or alter the disease remain unknown. Likewise, few studies have examined the effects of a superimposed viral infection on experimental autoimmune encephalomyelitis (EAE), an important mouse model of MS. We find that an otherwise asymptomatic alphavirus infection introduced directly into the brains of mice during the pre-clinical phase of active immunization EAE significantly accelerates disease progression compared to sham-inoculated controls. While peripheral T cell responses and the proportions of CD4+ T cells in spinal cords of infected and sham-inoculated EAE mice are similar, the CD8+:CD4+ ratio and the total number of CD8+ T cells increase in the spinal cords of infected EAE hosts. Furthermore, this infection does not exacerbate EAE symptoms compared to sham inoculation in CD8-deficient hosts. These findings suggest that CD8+ T cells activated by a superimposed alphavirus infection promote autoimmune mechanisms that drive EAE pathogenesis, possibly via production of pro-inflammatory cytokines or cytotoxic molecules. Our dual disease paradigm will allow us to determine how acute viral infection influences peripheral and central nervous system (CNS) immune responses during EAE as well as to clarify the role of CD8+ T cells in autoimmune CNS demyelination.
Monocytes promote the formation of autoreactive Th17 cells in inflammatory arthritis (101.23)
Authors: Simons Donald , Oh Soyoung , Garcia Victoria , Mroz Lori , Caton Andrew 
Published: January 2023

Abstract
Th17 cells have been implicated in a number of autoimmune diseases and their animal models including inflammatory arthritis. How these cells arise in the context of autoimmunity is not well understood. We recently described a mouse model of autoimmune arthritis in which mice expressing influenza hemagglutinin (HA) as a self-antigen under the control of a MHC Class II promoter (HACII), and co-expressing an HA-specific CD4+ TCR (TS1), spontaneously develop inflammatory arthritis by an IL-17-dependent mechanism. Here we have used these TS1xHACII mice to investigate the role of specific cell types in the activation of autoreactive CD4+ Th17 cells. We have found that monocytes are selectively enriched in the spleens and LNs of arthritic TS1xHACII mice relative to mice expressing the HACII transgene alone. Moreover, monocytes purified from the spleens of arthritic TS1xHACII and HACII mice had profound differences in their abilities to activate HA-specific T cells in vitro: monocytes from HACII mice were potent inducers of Th1 cells, whereas those from TS1xHACII mice were significantly more efficient at inducing Th17 cells. Monocytes from TS1xHACII mice also had an enhanced capacity to induce Th17 cells relative to B cells and cDCs isolated in parallel from the same organs. Collectively, these data suggest that monocytes can play an important role in the development of Th17 cells in vivo, and can participate in an autoimmune response that results in inflammatory arthritis.
Pathogenesis of rheumatoid arthritis in a fibrinogen-induced mouse model of autoimmunity (101.8)
Authors: Cordova Kristen , Baker Rocky , Barbour Gene , Haskins Kathryn , Holers V. 
Published: January 2023

Abstract
Citrullinated proteins, derived from the conversion of peptidyl-arginine to peptidyl-citrulline, are present in the joints of rheumatoid arthritis (RA) patients who also produce high levels of anti-citrullinated protein antibodies (ACPAs). T cells also have a role in RA and are thought to be involved in initiating, controlling and driving antigen-specific immune responses. We and others found that mice immunized with human fibrinogen (HF) or human citrullinated fibrinogen (HCF) develop mild inflammatory arthritis and peripheral T cells proliferate in response to HCF and HF. To determine if HCF-reactive T cells contribute to disease, DBA1/J mice were immunized with HCF and at various time points, T cells were assessed directly ex vivo or cultured in vitro. T cells were evaluated ex vivo for the presence of activation markers and cytokine production after antigen stimulation; T cell lines were cultured in vitro with antigen and IL-2 and evaluated in the same manner. Following two immunizations, mice produced CD4 T cells with an activated phenotype (CD44hi+CD62L-); TNFα and IL-17 were produced by CD4 T cells in response to HCF. T cell lines produced high levels of TNFα, IL-17, and IL-6 when stimulated by HCF, and one line also produced IFNγ. In sum, CD4 T cells are activated during disease progression and exhibit an inflammatory phenotype that may be pathogenic. T cell lines are being evaluated in vivo to determine if they can precipitate or accelerate disease.
Type I IFN signaling controls T lymphocyte transmigration into the airways (102.10)
Authors: McNally Beth , Ye Fang , Willette Meredith , Partida-Sanchez Santiago , Durbin Joan , Flano Emilio 
Published: January 2023

Abstract
Our current understanding of how T lymphocytes enter the airways in response to respiratory tract infections is limited. Here we show a role for type I interferon (IFN) signaling in regulating T lymphocyte transmigration into the airway mucosa. IFNα receptor (IFNAR) deficiency led to a reduction in the number of T lymphocytes that entered the airways but not the lung parenchyma. This effect was mediated both at the T lymphocyte and epithelial cell level. IFNAR-deficient airway epithelial cells failed to express the chemoattractants CCL3-5, CCL8 and CXCL9-11, and did not up-regulate the adhesion molecules ICAM1 and VCAM1. Lack of IFNAR signaling on T lymphocytes impaired Ly-6C expression and lymphocyte function-associated antigen-1 (LFA-1) clustering, which resulted in reduced cell adhesion. Finally, we show that IFNAR-deficiency inhibited T lymphocyte recruitment to the airways during respiratory syncytial virus (RSV) infection.
Shear forces and high affinity LFA-1 drive PMN recruitment (102.18)
Authors: Dixit Neha , Yamayoshi Itsukyo , Nazarian Ari , Simon Scott 
Published: January 2023

Abstract
Acute inflammation triggers the innate immune response of neutrophils that efficiently traffic from the blood stream to concentrate at high numbers at the site of tissue infection or wounding. A gatekeeper in this process is activation of β2-integrins, which forms bond clusters with ICAM-1 on the endothelial surface. These bond clusters serve dual functions of providing adhesive strength to anchor neutrophils under the shear forces of blood flow and directional guidance for cell polarization and subsequent transmigration on inflamed endothelium. We hypothesized that shear forces transmitted through high affinity LFA-1 facilitates their cooperation with the calcium release activated channel (CRAC) Orai1 in directing localized cytoskeletal activation and directed migration. Employing vascular mimetic microfluidic channels we observed neutrophils arresting on a substrate of either ICAM-1 or allosteric antibodies that stabilize a high or low affinity conformation of LFA-1. Neutrophils captured via low affinity LFA-1 did not exhibit intracellular calcium flux, F-actin polymerization, cell polarization, or directional migration under shear flow. In contrast, high affinity LFA-1 provided orientation along a uropod-pseudopod axis that required calcium flux through Orai1. We demonstrate how the shear stress of blood flow can transduce distinct outside-in signals at focal sites of high affinity LFA-1 that provides contact mediated guidance for neutrophil emigration.
CD8+ T cell trafficking post primary Influenza A virus infection (102.26)
Authors: Miao Hongyu , Topham David , Wu Hulin , Zand Martin 
Published: January 2023

Abstract
An important model for studying influenza A virus (IAV) infection is the acute antiviral immune responses. It is of a great interest to understand the growth and migration of virus-specific CD8+ T cells post IAV infection. However, the biological parameters that determine the kinetics of immune cells currently cannot be directly measured by experiments techniques. In this work, we developed mechanistic and semi-mechanistic mathematical models to infer the expansion, trafficking, and disappearance of CD8+ T cells in lymph node, spleen and lung from mice with primary influenza A infection. It was found that the spleen is a major contributor of effector CD8+ T cells to the lung in comparison with the lymph node. In addition, it is veryfied that the death of CD8+ T cells in lung follows a time-varying pattern. Tissues other than the lung and lymphatic organs notably contribute to the response in the lung, but not dominate the contributions from spleen. Our efforts provide a better understanding of the primary CD8+ T cell response to influenza infection.
Immunologic profile changes associated with aging in rhesus macaques (104.2)
Authors: Didier Elizabeth , Sugimoto Chie , Bowers Lisa , Bohm Rudolf , Gilbert Margaret , Barnes Mary , Pattison Melissa , Slisarenko Nadia , Falkenstein Katherine , Kuroda Marcelo 
Published: January 2023

Abstract
Immunosenescence is a public health concern. This study was to characterize the peripheral immune system in rhesus macaques of varying ages. Flow cytometry and multiplex cytokine levels were evaluated in blood from 35 monkeys (3.2-20 years old). Linear regression was used to define statistically significant changes (i.e. P&lt;0.05) with age. Significant declines were observed in numbers of neutrophils, eosinophils, basophils, and lymphocytes in blood with increasing age. No changes in numbers of monocytes, dendritic cells (DC), RBCs, or platelets were noted. Among lymphocytes, B cell numbers declined while NK cells and T cells were unchanged with increasing age. Within the T cell population, however, significant declines in naive CD4+ and CD8+ T cells, and γδ+T cells were seen with increasing age, whereas the number of CD8+ effector-memory T cells increased with age. Numbers of DCs did not change with advancing age, but the turnover rate of pDCs was higher in the 18-20 year-old group compared to younger groups. Of the cytokines tested in plasma using the Milliplex non-human primate cytokine (23-mer) kit, TNF-α, IL-2, MCP-1, sCD40L, TGF-α, VEGF, and IL-18 levels significantly increased with increasing age whereas IL-5 was the only cytokine tested that decreased with increasing age. These early results provide a basis to further characterize immunosenescence in a non-human primate model.