bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pulmonary vaccination against influenza virus induces a protective CD8 T cell response, which is regulated by APCs within the lungs (P6154)
Authors: Hemann Emily , Kang Sang-Moo , Legge Kevin 
Published: January 2023

Abstract
Recently there has been a renewed interest in the development of novel pulmonary influenza A virus (IAV) vaccines. CD8 T cells play an important role in clearance of IAV, and our prior studies demonstrate a key role for dendritic cells (DCs) in activation of IAV-specific CD8 T cells in the lymph nodes and maintenance in the lungs during IAV infections. Herein, we determined the role of pulmonary vaccine-induced CD8 T cells in protection from IAV challenge and the requirements for generation and maintenance of such CD8 T cell immunity. Our data demonstrates vaccination with IAV virus-like particles (VLPs) containing IAV HA and M1 leads to a significant increase in HA533-specific CD8 T cells. These VLP-specific CD8 T cells mediate protection of mice challenged with lethal doses of either homo- or heterosubtypic IAVs containing the HA533 epitope. Our preliminary results suggest interactions between DCs and effector T cells within the lungs are required following vaccination for maximal pulmonary VLP-specific CD8 T cell responses. Currently, we are investigating the contribution of inflammation and the APC subsets required in generation, boosting, and maintenance of vaccine-specific CD8 T cells during pulmonary vaccination. Collectively, our results highlight an important role for CD8 T cell mediated protection after i.n. vaccination and the seminal role pulmonary APCs play in activating and maintaining local vaccine-specific CD8 T cell responses against IAV in the lungs.
Age-associated cross-reactive antibody-dependent cellular cytotoxicity to 2009 H1N1 influenza prior to the pandemic (P6160)
Authors: Jegaskanda Sinthujan , Laurie Karen , Amarasena Thakshila , Winnall Wendy , Kramski Marit , De Rose Robert , Barr Ian , Brooks Andrew , Reading Patrick , Kent Stephen 
Published: January 2023

Abstract
During the 2009 H1N1 influenza pandemic (H1N1pdm) older individuals were partially protected from disease. Prior seasonal H1N1 infections likely played a role by the induction of neutralizing antibodies and T cell immunity towards 2009-H1N1pdm. Non-neutralizing antibodies with other effector functions such as antibody-dependent cellular cytotoxicity (ADCC) may have assisted in the immunity observed. We tested sera from a cohort of 177 individuals aged 1-72 years old for ADCC antibodies to H1N1pdm HA either immediately prior to, or following, 2009 H1N1 pandemic by our ADCC NK cell activation assay. Almost all individuals in the &gt;45 age group (28/30 subjects) had ADCC antibodies towards the H1N1pdm prior to the 2009 H1N1 pandemic, whereas approximately half of the individuals in the 1-14 (11/32) and 15-45 (9/16) had ADCC antibodies prior to the 2009 pandemic. The H1N1pdm-specific ADCC antibodies were able to mediate the killing of H1N1pdm-infected respiratory epithelial cells. Additionally, ADCC to H1N1pdm HA correlated with ADCC to the antigenically similar 1918 HA protein in subjects post-2009 influenza pandemic and subjects &gt;45 years had higher ADCC towards a range of seasonal H1N1 HA proteins compared to younger subjects. We conclude that ADCC antibodies may have contributed to the protection exhibited in older individuals during the 2009-H1N1 pandemic. This has significant implications for improved vaccination strategies against future influenza pandemics.
Cross-strain human TCR signatures and their importance in universal immunity against influenza (P6164)
Authors: Loh Liyen , Valkenberg Sophie , Wang George , Thomas Paul , Kedzierska Katherine 
Published: January 2023

Abstract
In contrast to the current antibody-mediated and strain-specific influenza vaccines, T-cells directed at conserved internal proteins elicit broad immunity against seasonal and pandemic influenza viruses. Here, we dissected the optimal human influenza-specific CD8+ T-cell populations across different HLAs, both at functional and clonal levels, to provide insights into universal immunity against influenza. We found that although sporadic variations can be found across many peptides, mutations ‘escaping’ T-cell recognition get fixed only for selected CD8+ T-cell populations. Using a human single-cell multiplex RT-PCR for TCRαβ, we found that specific TCRs can recognize multiple variants derived from different influenza strains. For example, a dominant public TCR clone found at high frequency within M158+CD8+ T-cell responses in all HLA-A*0201+ individuals can recognize the naturally-occurring variants of the peptide. This suggests that the globally common HLA-A2+ population have universal T-cell immunity to any M158 variant, which can, at least in part, explain high conservation level for M158. In addition, our current analyses across other HLAs including HLA-A*01, greatly extend these findings. Our study provides insights into the diversity of the CD8 T cell response against influenza and may help unravel beneficial targets needed for a successful universal vaccine against both season and pandemic influenza strains.
Altered T-bet dominance in interferon-γ decoupled CD4+ T cells with attenuated cytokine storm and preserved memory in influenza (P6144)
Authors: Dutta Avijit , Miaw Shi-Chuen , Yu Jhang-Sian , Chen Tse-Ching , Lin Chun-Yen , Lin Yung-Chang , Chang Chia-Shiang , He Yueh-Chia , Chuang Sheng-Hao , Yen Ming-I , Huang Ching-Tai 
Published: January 2023

Abstract
Cytokine storm has been postulated as one of the major causes of mortality in patients with severe respiratory viral infections such as influenza. With the help of an influenza antigen- specific mouse experimental system, we report that CD4+ T cells contribute effector cytokines leading to lung inflammation in acute influenza. Although virus can no longer be detected from tissues 14 days after infection, virus-derived antigen continues to drive a CD4+ T cell response after viral clearance. Antigen specific CD4+ T cells proliferate and evolve into memory CD4+ T cells efficiently, but the production of effector cytokines is seriously hampered during this phase. This decoupling of proliferation and effector cytokine production doesn’t appear in conjunction with increased suppression by regulatory T cells or decreased induction of transcription factors. Rather, GATA-3 and ROR-γt levels are elevated when compared to cells that have effector cytokine production. T-bet dominance over GATA-3 and ROR-γt decreases with the disarmament of effector cytokine production. Importantly, upon re-infection, these decoupled cells produce elevated levels of IFN-γ and were effective in virus eradication. These results provide a mechanism through altered T-bet expression to dampen the cytokine storm without impeding the generation of memory T cells in influenza virus infection.
Targeting of antigens to dendritic cells via lentiviral vector induces tolerance of pre-activated T cells and protects mice from autoimmunity (P5215)
Authors: de Andrade Pereira Bruna , Ackermann Mathias , Dresch Christiane , Fraefel Cornel 
Published: January 2023

Abstract
Autoimmune disease is characterized by a breakdown of tolerance and activation of auto-reactive T cells. Current treatment is based on palliative drugs that attenuate or delay disease symptoms. The aim of this project was to develop a new strategy to induce permanent antigen-specific tolerance for treating autoimmune disease. The strategy includes the ex vivo modification of autologous hematopoietic stem cells (HSC) with lentiviral vectors that express myelin oligodendrocyte glycoprotein (MOG), an auto-antigen involved in experimental autoimmune encephalomyelitis (EAE). The MOG-transgene is under the control of a dendritic cell (DC)-specific promoter. After re-infusion, the modified HSC will give rise to MOG-expressing DCs. We have previously demonstrated that 100% of mice that received HSC transduced with MOG-lentiviral vectors were protected. Protection correlated with the depletion of MOG-specific T cells and generation of functional Foxp3+ regulatory T cells. Moreover, we showed that the tolerance induced was antigen-specific while the immune system was not generally suppressed. In the present work, we demonstrate that mice which have received HSC transduced with MOG-lentiviral vectors were also fully protected from EAE after adoptive transfer of pre-activated MOG-specific T cells. This result highlights the applicability of this strategy in a therapeutic model by reverting the pathogenic phenotype of effector MOG-specific T cells.
Proteasome inhibition with bortezomib depletes plasma cells and autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients (P5146)
Authors: Gomez Alejandro , Willcox Nick , Vrolix Kathleen , Hummel Jonas , Duimel Hans , Verheyen Fons , Molenaar Peter , Buurman Wim , Martinez-Martinez Pilar , De Baets Marc , Losen Mario 
Published: January 2023

Abstract
In the autoimmune disease myasthenia gravis (MG), autoantibodies against the muscle AChR are mainly produced by both short- and long-lived plasma cells, which are resistant to standard immunosuppressive drugs (i.e. glucocorticoids). A novel therapy to eliminate plasma cells is the proteasome inhibitor bortezomib, which is used to treat patients with multiple myeloma (MM, a plasma cell malignancy). Previously, we demonstrated that bortezomib also reduced autoantibody titers in an animal model of MG (Gomez, A. M. J. Immunol. 2011). The thymus of MG patients is frequently enriched in germinal centers and contains plasma cells that produce autoantibodies in vitro, even after irradiation (which depletes B and T lymphocytes). We studied the in vitro effects of bortezomib in cultured thymus cells from MG patients undergoing therapeutic thymectomy. Treatment with a single dose of bortezomib blocked the production of these pathogenic autoantibodies, reduced the total IgG levels and eliminated plasma cells. Ultrastructural signs of apoptosis were detected in plasma cells as early as 8 h after addition of bortezomib; at 24 h, no plasma cells could be detected. Moreover, we demonstrated that the minimum concentration of bortezomib that eliminates plasma cells in vitro is 60-fold lower than the peak concentration found in MM patients treated with bortezomib, suggesting that low doses might be effective for eliminating plasma cells in patients with antibody-mediated autoimmune diseases.
Treatment with non-depleting T cell antibodies increases TGFβ levels in the diabetic pancreas and results in enhanced β cell function. (P5213)
Authors: Martin Aaron , Yi Zhouan , Wang Bo , Tisch Roland 
Published: January 2023

Abstract
A recent report from our laboratory detailed the reversal of recent-onset autoimmune diabetes in the NOD mouse following treatments with antibodies against CD4 and CD8. Treatment of mice with these particular antibodies does not deplete T cells, but transiently alters their function, culminating in long-lasting immune tolerance and a restoration of normal glycemic control. Consistent with observations made by other research groups, induction of diabetes remission was dependent on TGFβ, supported by two lines of evidence: 1 - co-administration of anti-TGFβ with anti-T cell antibodies resulted in a failure of remission induction, and 2 - elevated levels of TGFβ RNA and protein can be detected in the pancreata of remission mice. Within one week of antibody treatment, T cells are purged from the pancreas and the draining lymph node in a process that was found to be independent of TGFβ, suggesting that effects of elevated TGFβ are not limited to T cell function. Furthermore, treatment of recent-onset diabetic mice with a reduced dose of antibody resulted in a purging of T cells from the pancreas and draining lymph node, but not a restoration of glycemic control. Normal glycemic control could be achieved at this dose when exogenous TGFβ was administered. Together, these data indicate that TGFβ may directly affect the insulin-producing pancreatic β cells. Recent observations support the notion that TGFβ enhances insulin production and/or induces β cell proliferation.
Immunological studies on promising and selective anti-arthritic effects of Euphorbia hirta (P5155)
Authors: Ahmad Sheikh , Albakheet Saleh 
Published: January 2023

Abstract
Euphorbia hirta L. (Euphorbiaceae) is a tree locally used as a traditional medicine in Africa and Australia to treat numerous diseases such as hypertension, respiratory ailments, tumors, wounds, antipyretic, anti-inflammatory activities etc. In the present study we investigated the anti-arthritic effects of fresh leaves of E. hirta ethanol extract, that was found to inhibit the production of inflammatory mediators and cytokines of adjuvant arthritis in mice. The production of the Th1 and Th2 cytokine was estimated by flowcytometric assay by using cytometric bead array (CBA) analysis in adjuvant induced arthritis in mice treated with E. hirta at graded oral doses. CBA uses the sensitivity of amplified fluorescence detection by flowcytometer to measure soluble analytes in a particle based immune assay. This assay can accurately quantitate five cytokines in a 50 µl sample volume. Oral administration of E. hirta at doses of 25-200 mg/kg showed significant inhibition of Th1 (IL-2, IFN-γ & TNF-α) and up regulation of Th2 (IL-4 and IL-5) cytokines. Also, E. hirta significantly down regulated LPS induced production of nitric oxide production in peritoneal macrophages. These results suggest that E. hirta exhibit an improvement in adjuvant induced arthritis through down regulation of activated macrophages and T lymphocytes functions such unique effects of E. hirta shown on adjuvant arthritis mice model may be advantageous to the long term treatment of clinical rheumatoid arthritis.
Effects of valproic acid and dexamethazone in acute kidney ischemia-reperfusion injury model (P2216)
Authors: Speir Ryan , Andrews Jared , DeHart Mary , Gelnett Mary , Brand Timothy , Salgar Shashikumar 
Published: January 2023

Abstract
Introduction: Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this study was to ameliorate kidney IR injury and identify novel biomarkers for AKI. Methods: Left renal ischemia was induced in Wister rats by clamping the renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n=8/group) received Valproic Acid (150 mg/kg; VPA), Dexamethasone (3 mg/kg; Dex) or Vehicle (Saline) IP. Animals were sacrificed at 3h, 24h or 120h IR and blood, urine and kidney were collected. Results: At 3h IR, urine albumin was lower (P&gt;0.05) in VPA (0.84±0.62) and Dex (1.04±0.73) compared to Vehicle (1.47±1.02 mg/ml) group; and Lipocalin-2 was lower (P&lt;0.006) in Dex (0.42±0.15) and higher (P&lt;0.01) in VPA (1.21±0.32) compared to Vehicle (0.77±0.31 µg/ml) group. Osteopontin was higher (P&lt;0.05) at 24h IR in VPA and Dex . TIM-1 did not differ. Serum creatinine (mg/dL) at 24 h IR in VPA (2.7±1.8) and Dex (2.3±1.2) was reduced (P&lt;0.05) compared to Vehicle (3.8±0.5). Histopathology at 3h IR demonstrated reduced (P&lt;0.04) ischemic changes in the renal cortex in VPA (27± 32 %) compared to Vehicle (56±27%) group. Tubular necrosis in the outer medulla was lower (P&lt;0.02) in Dex and VPA (43-45%) compared to Vehicle (70%) at 24h IR. BCL-2 as determined by RT-PCR did not differ. Conclusion: The VPA administration prior to surgery appears to offer renal protection from IR injury.
Bim regulates allogeneic immune responses and transplant arteriosclerosis through opposing effects on T cell activation and death. (P2218)
Authors: von Rossum Anna , Enns Winnie , Shi Yu , Choy Jonathan 
Published: January 2023

Abstract
T cell responses towards allograft arteries are responsible for the development of transplant arteriosclerosis (TA), a vascular condition characterized by intimal thickening of graft arteries. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses by inducing effector T cell death, but its role in regulating allogeneic T cell responses is poorly understood. We compared allo-activation and death of T cells from Bim+/+, Bim+/- and Bim-/- mice as well as the development of TA in these animals. Unexpectedly, Bim was required for alloantigen-induced proliferation of both CD4 and CD8 T cells, as well as IL-2 production. Partial reduction in Bim expression was sufficient to attenuate T cell activation while complete elimination was required to prevent T cell death driven by cytokine deprivation in vitro. When TA was examined in aortic interposition grafts, intimal thickening was significantly reduced in Bim+/- but not Bim-/- recipients. There was significantly less CD4 T cell accumulation in the intima of arteries from Bim+/- as compared to Bim+/+ recipients, but this effect was not observed in Bim-/- mice. Further, T cell proliferation was significantly reduced in both Bim+/- and Bim-/- mice in response to allograft arteries but T cell death was attenuated only in Bim-/- animals. Taken together, our findings show that Bim controls both T cell activation and death in TA, and that these processes are differentially susceptible to reductions in Bim expression.
ERAAP associates with MHC I molecules for generation of optimal MHC I peptide repertoire. (APP3P.100)
Authors: Yang Soo Jung , Shastri Nilabh 
Published: January 2023

Abstract
Endoplasmic reticulum (ER) aminopeptidase associated with antigen processing (ERAAP) plays a critical role in the generation of the peptide repertoire presented by MHC I by trimming precursor peptides to optimal length. How ERAAP carries out this function and whether ERAAP activity is influenced by MHC I or other molecules in the ER is unknown. Here, we show that ERAAP physically associates with MHC I during peptide trimming events in the ER. ERAAP or its truncated domains II/III interacted with empty MHC I in the ER, but this interaction was independent of the peptide-loading complex. Most importantly, overexpression of domain II/III interrupted ERAAP function in wild-type cells resulting in altered-peptide presentation by MHC I. Thus, ERAAP function can be regulated by its association with MHC I and perhaps other key ER molecules.
Intradermal immunization with polyguanine conjugated antigens enables targeted and sustained delivery of protein antigens to dendritic cells in vivo. (APP3P.111)
Authors: Ciccotelli Jo Erika , Toussaint Helene , Erdos Geza , Carey Cara , Watkins Simon , Falo Louis 
Published: January 2023

Abstract
Effective vaccine design depends on the ability to target specific antigens to antigen presenting cells (APCs), including dendritic cells (DCs). Conjugation of proteins antigens to polyguanine (Poly(dG)) molecules is a novel immunization approach capable of transforming soluble antigens into aggregated particulates with exposed scavenger receptor (SR) ligands. We have previously shown that Poly(dG) conjugation to protein antigen results in increased antigen-specific helper and cytotoxic T cell responses, memory T cell induction, and antibody titers. Here, we specifically investigate mechanisms of Poly(dG)-conjugated antigen delivery and internalization. Compared to soluble OVA, Poly(dG)-OVA is rapidly and more efficiently internalized by bone marrow derived DCs in vitro, and this internalization is inhibited by scavenger receptor blockade. Importantly, in a mouse model intradermally injected Poly(dG)-OVA results in antigen persistence in the skin for up to 7 days. This is accompanied by increased antigen uptake by skin resident DCs and persistent migration of antigen loaded DCs to the draining lymph nodes. DCs exposed to Poly(dG)-OVA had increased expression of CCR7 and secretion of MCP-1, TNF-α, and IL-6. These results suggest that coupling Poly(dG) to protein antigens enables efficient DC targeting through SRs, prolonged delivery of antigens in vivo, and activation of innate immunity. This approach may be used to design more efficient antiviral and antitumor vaccines.
RBP4 activates antigen-presenting cells leading to adipose tissue inflammation and systemic insulin resistance (APP4P.116)
Authors: Vieira Pedro , Yore Mark , Dwyer Peter , Syed Ismail , Aryal Pratik , Kahn Barbara 
Published: January 2023

Abstract
A major cause of Type 2 diabetes is impaired insulin action which is a critical risk factor for cardiovascular disease and early mortality. Insulin resistance in obesity is highly associated with adipose tissue (AT) inflammation. RBP4, a retinol-transporter, is elevated in insulin resistance and contributes to increased diabetes risk. We aimed to determine the mechanisms for RBP4-induced insulin resistance. Here we show that RBP4 elevation causes AT inflammation by activating innate immunity which elicits an adaptive immune-response. RBP4-overexpressing mice (RBP4-Ox) are insulin-resistant and glucose-intolerant and have increased AT macrophage and CD4 T-cell infiltration. In RBP4-Ox, AT CD206+ macrophages express pro-inflammatory markers and activate CD4 T-cells while maintaining alternatively-activated macrophage markers. These effects result from direct activation of AT antigen-presenting cells (APCs) by RBP4 through a JNK-dependent pathway. Transfer of RBP4-activated APCs into normal mice is sufficient to induce AT inflammation, insulin resistance and glucose intolerance. Thus, RBP4 causes insulin resistance, at least in part, by activating AT APCs which induce CD4 T-cell Th1 polarization and AT inflammation.
Pulmonary dendritic cells require cis-activation to cross-prime T cells (APP4P.117)
Authors: Jakubzick Claudia , Desch A. Nicole , Gibbings Sophie , Clambey Eric , Janssen William , Slanskey Jill , Kedl Ross , Henson Peter 
Published: January 2023

Abstract
Dendritic cells (DCs) are required for the induction of cytotoxic T cells (CTL). In most tissues, including the lung, the resident migratory DC fall into two types, respectively expressing the integrin markers, CD103 and CD11b. The current supposition is that DC function is predetermined by lineage, designating the CD103+ DC as the major cross-presenting DC able to induce CTL. Here we proposed that DC function might also be determined by the nature of the pathogen associated molecular pattern (PAMP) that stimulates it and to which it is able to respond. Thus, in the presence of a TLR3 (CD103+) or a TLR7 (CD11b+) agonist respectively we demonstrated in vivo that both DC subtypes did exhibit the capacity to orchestrate a CTL response. This selectivity did not extend to antigen cross-presentation for T cell proliferation but was required for induction of cytotoxicity and protection in a model of tumor metastasis.
Role of Integrins in mediating Th17 Pathogenesis (CAM3P.203)
Authors: McGeachy Mandy 
Published: January 2023

Abstract
IL-23 plays a key role in autoimmune pathology, as evidenced by the resistance of IL-23 deficient animals to many models of autoimmune disease; susceptibility SNPs in the IL-23 receptor have also been identified in human disease including inflammatory bowel disease and psoriasis. We have previously demonstrated that IL-23 drives effector differentiation and proliferation of primary and memory Th17 cells in vivo. We have now identified a novel integrin that is expressed by Th17 cells in an IL-23-dependent manner. Inflammatory Th17 cells (generated in vitro in the presence of IL-23, IL-6 and IL-1) express high levels of this integrin, while ‘regulatory’ Th17 cells do not, as TGFβ suppresses expression in a dose-dependent manner. Integrin blockade rendered mice resistant to experimental autoimmune encephalomyelitis (EAE), and knockout mice were also resistant to EAE. T cells specifically require integrin expression for EAE induction. While effector functions such as IL-17 are not impaired, integrin knockout cells have reduced migration out of LN and into CNS. Together these data highlight a novel Th17-specific integrin that is regulated by IL-23, and may promote effector Th17 functions and/or proliferation.