bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic identification of immunodominant CD8+ T cell responses to influenza A virus (P6170)
Authors: Chen Weisan , Wu Chao , Grant Emma , Zanker Damien , Valkenburg Sophie , Chan Kok-Fei , Eckle Sidonia , Bharadwaj Mandvi , Tan Bee , Kedzierska Katherine , Zou Quan Ming , Doherty Peter 
Published: January 2023

Abstract
Immunodominant T cell responses are important for virus clearance. However, the identification of immunodominant T cell peptide+HLA glycoprotein epitopes has been hindered by the extent of HLA polymorphism and the limitations of predictive algorithms. A simple, systematic approach has been used here to screen for new, immunodominant CD8+ T cell epitopes. The analysis targeted healthy HLA-A2+ and HLA-A2- donors. While M158A2 was consistently detected in all individual samples in our study, the response to this epitope was only immunodominant in three out of eight while, for the other five, prominent CD8+ T cell responses tended to focus on various peptides from the influenza nucleoprotein (NP) that were not presented by HLA-A2. In all the tested 7 A2- individuals, immunodominant responses all focused on NP. Importantly, most novel, immunodominant T cell epitopes identified by our study would not have been predicted by the current prediction programs as they are either too long or lacking typical HLA binding motifs. Our data stress the importance of systematic analysis for discovering HLA-dependent, immunodominant CD8+ T cell epitopes derived from viruses and tumors. Focusing on HLA-A2 and predictive algorithms may be too limiting as we seek to develop targeted immunotherapy and vaccine strategies that depend on T cell-mediated immunity.
Co-immunization induces tolerogenic response against asthma via generation of antigen specific iTreg (P5233)
Authors: Wang Bin , Geng Shuang 
Published: January 2023

Abstract
Asthma is a chronic inflammatory disorder caused by T cell-mediated inflammation within airways. No antigen specific treatment has been available. Using an Der p1 induced murine asthma model, we find that co-immunization of an Der p1 protein with a DNA vaccine encoding the same antigen is able to prevent this experimental asthma as evidenced in the marked reduction of infiltrations of eosinophils and lymphocytes into the site of the allergen challenge. We demonstrate that the prevention of experimental asthma was directly related to the induction of a population of Der p1 specific T regulatory (iTreg) cells exhibiting a CD4+CD25-FoxP3+ phenotype and expressing IL-10, and TGF-β following the co-immunization. Blockade of IL-10 and TGF-β of the iTreg cells by anti-IL-10 and TGF-β antibodies is partially able to reverse the suppression in vitro and in vivo, which caused the recurrence of the inflammation. Furthermore, adoptive transferred Der p1 induced iTreg cells is able to suppress the Der p1 induced asthma, but not to OVA induced asthma, and vice versa, suggesting that the iTreg exerts an inhibition in an antigen specific manner. To our knowledge, the co-immunization of protein with its cognate DNA vaccine protect/treat experimental asthma via the induced antigen specific iTreg cells may lead to a novel immunotherapy against asthma in humans.
Pegylated adenosine deaminase prevents immune cell migration and infiltration into the brain in experimental autoimmune encephalitis (P5171)
Authors: Kim Do-Geun , Krenz Antje , Bynoe Margaret 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a debilitating neuroinflammatory disease that is characterized by infiltration of inflammatory immune cells into the central nervous system (CNS). Currently, there is no cure for MS and the few available treatments only lessen symptoms in some patients, and can have debilitating side effects. Our lab has pioneered studies demonstrating that blockade of broad spectrum or A2A specific adenosine receptor signaling inhibits lymphocyte infiltration into the CNS and protects mice from a multiple sclerosis animal model called experimental autoimmune encephalomyelitis (EAE). Pegylated adenosine deaminase (PEG-ADA) is an FDA-approved drug used to treat patients with severe combined immune deficiency (SCID) due to a mutation in their adenosine deaminase (ADA) gene which converts adenosine into inosine. In this study, we used PEG-ADA to assess its therapeutic potential to protect progression and alleviate the severity of EAE. We hypothesized that similar to adenosine receptor blockade, depletion of extracellular adenosine by PEG-ADA may lessen the influx of inflammatory immune cells into the brain and protect mice from EAE. Our results showed that indeed mice treated with PEG-ADA developed significantly less severe EAE and had less immune cell infiltration in their brain. Because a common characteristic of MS in general is the invasion of pathogenic immune cells into the CNS, this study has the promising potential to benefit MS patients.
In vitro and in vivo anti-arthritic study of a novel histone deacetylase inhibitor YH508 (P5187)
Authors: Yang Chia-Ron , Hsieh I-Ni 
Published: January 2023

Abstract
The pathology of rheumatoid arthritis (RA) includes synoviocytes proliferation, expression of inflammatory mediators, and persistent recruitment of immune cell; these might result from dysregulation of epigenetic control by histone acetylase (HDAC). The aim of this study is to examine the anti-arthritic effect of YH508, a histone deacetylse (HDAC) inhibitor, by in vitro and in vivo models. The IC50 values of YH508 against enzymatic activity of HDAC1, 2, 3, 6, and 8 significantly lower than an approved HDAC inhibitor SAHA (Vorinostat), indicates that YH508 is more potent than SAHA. Treatment with YH508 showed dose-dependent inhibition of cytokines (IL-6, nitric oxide, PGE2) secretion in RAW264.7 macrophages and RA synovial fibroblasts. In addition, YH508 dramatically suppressed M-CSF/RANKL induced osteoclastogenesis from macrophages at low concentration. Furthermore, these inhibitory effects were reversed by overexpression class I/II HDAC. In vivo anti-arthritic effects of YH508 were evaluated in a M. butyricum-induced arthritis model in rats. Oral administration of YH508 significantly inhibited paw swelling, bone destruction and reduced serum cytokine levels. Our results demonstrate that HDAC inhibitor YH508 inhibits the development of arthritis, suggest that it provides a new therapeutic approach for the treatment of inflammatory arthritis.
FTY720 ameliorates murine Scl-cGVHD by promoting expansion of splenic regulatory cells and inhibiting immune cell infiltration into the skin (P5153)
Authors: Matsushita Takashi , Le Huu Doanh , Takehara Kazuhiko , Fujimoto Manabu 
Published: January 2023

Abstract
Objective: Murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) is a model for human Scl-cGVHD and systemic sclerosis (SSc). Sphingosine-1-phosphate (S1P) exerts a variety of activities in immune response, inflammation, and vascular systems. It was reported that regulation of S1P on fibrotic diseases as well as systemic sclerosis. FTY720, an oral S1P receptor modulator, has been shown to be a useful agent for the prevention of transplant rejection and the treatment of autoimmune diseases. In this study, the effects of FTY720 were investigated in Scl-cGVHD. Methods: FTY720 was orally administered to allogeneic recipients from day 0 to day 20 (short-term, early-treatment group), day 0 to day 42 (full-term, early-treatment group), or day 22 to day 42 (delayed-treatment group) after bone marrow transplantation (BMT). Results: Delayed-treatment of FTY720 attenuated and early-treatment inhibited Scl-cGVHD severity and fibrosis. In early-treatment, FTY720 induced expansion of splenic myeloid-derived suppressor cells, regulatory T cells and regulatory B cells. Vascular damages in Scl-cGVHD were inhibited by FTY720 through downregulating serum levels of S1P and sE-Selectin. Furthermore, FTY720 inhibited the infiltration of immune cells into the skin and diminished the expression of mRNA for proinflammatory cytokines in the skin. Conclusion: These results suggest that FTY720 could be a promising strategy for treating Scl-cGVHD and SSc patients.
Natura-alpha, a novel STAT3-Y705 inhibitor in treating systemic lupus erythematosus in NZB/W female mice (P5157)
Authors: Wang Longgui , Han Liying , Fallon John , Tsao Allen , Chiao Jen-Wei 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Increases in Th1/Th17 cells, and decreases in Treg cells, have been observed in patients with SLE. Natura-α, a synthetic small molecule inhibits STAT3-Y705 phosphorylation and regulates Th1/Th17 and Treg. The potential of Natura-α as a SLE therapeutics was explored. The SLE model NZB/W female mice which develops lupus nephritis were used after the disease was confirmed at week 19. One group (n=10) was given orally vehicle, and the other groups given Natura-α at 25 or 75 mg/kg, once/day, 5 days/week for 29 weeks. Mice were monitored until 52 weeks of age. Proteinuria in control mice was elevated at week 31, followed with sharp increase reaching greater than 1000 mg/dL at week 44. The levels in the two Natura-α-treated groups essentially maintained at stable lower level (150+100mg/dL at 25mg/kg, and 115+127mg/dL at 75mg/kg). Control mice began to die at week 38. At week 48, 60% of mice died in the vehicle group. In sharp contrast, all mice in the Natura-α-treated groups were survived (P&lt;0.001). Glomerular lesion in the control mice reached maximal at week 38, with over 85% exhibited severe lesions. The glomerular lesions in the Natura-α-treated groups were around the baseline level, i.e. approximately 20%. The treatments with the Natura-α significantly reduced proteinuria, prevented and reversed glomerular lesions, and improved survival, suggesting this novel STAT3-Y705 inhibitor is a potential SLE inhibitor.
Immune modulation and prevention of alloimmunization following transfusion with pathogen reduced platelets (P2144)
Authors: Jackman Rachael , Muench Marcus , Heitman John , Inglis Heather , Law Jacqueline , Marschner Susanne , Goodrich Raymond , Norris Philip 
Published: January 2023

Abstract
Blood transfusion is the most commonly performed allogeneic transplant, and results in alloimmunization of a number of recipients, potentially complicating subsequent transfusions as well as solid organ transplants. The use of a pathogen reduction method using riboflavin and UV light has been shown to induce changes in WBCs that result in a failure to stimulate allogeneic PBMCs in vitro. We assessed the degree of alloimmunization in vivo using mice given pathogen reduced versus untreated allogeneic platelets. WBC-enriched platelet rich plasma (PRP) was prepared from C57Bl/6 and Balb/cJ donor mice and either left untreated or pathogen reduced before transfusion via tail vein into Balb/cJ mice. Two weeks after transfusion circulating alloantibodies were measured, as were splenocyte cytokine responses to challenge with donor type cells ex vivo. Pathogen reduction treatment of allogeneic PRP prior to transfusion blocked alloimmunization. Mice that were transfused with untreated PRP following previous transfusion with pathogen reduced PRP had a normal alloantibody response, but their splenic lymphocytes had a reduced cytokine response to allogeneic challenge ex vivo. This immune modulation required the presence of WBCs in the transfused PRP and was donor specific. These results imply that UV treatment of blood products has the potential to modulate subsequent exposure to alloantigens, with implications for tolerance and organ transplantation.
Innate recognition of allogeneic non-self by monocytes initiates the rejection of transplanted organs (P2128)
Authors: Oberbarnscheidt Martin , Zeng Qiang , Williams Amanda , Rothstein David , Lakkis Fadi 
Published: January 2023

Abstract
It is generally assumed that inflammation or ‘danger’ at the time of transplantation triggers rejection. Here we tested the alternate hypothesis that the innate immune system distinguishes between self and allogeneic non-self, causing DC maturation and initiation of adaptive immunity. B6 Rag-/-γc-/- CX3CR1-GFP+/- reporter mice, which lack T, B, and NK cells, received syngeneic (B6) or allogeneic (Balb/c) vascularized heart grafts. &gt;90% of DCs present in the grafts by d.1 after Tx were derived from host monocytes. Mono-DC (GFP+lineage-Ly-6G-CD45+CD11b+CD11c+F4/80lo) were observed in greater numbers in allo than syn grafts at early time points and persisted at later time points (&gt;21d) only in allografts. Mono-DC in allografts were mature (MHCII+CD80+), expressed IL-12p40, and presented endotoxin-free OVA to CD4+ (OT-II) and CD8+ (OT-I) cells, causing proliferation and IFNγ production. Mono-DC from syn grafts were less mature, did not express IL-12p40, and failed to induce IFNγ production. In vivo exposure of monocytes to allogeneic non-self precipitated T cell-mediated rejection of single minor Ag-mismatched grafts that are otherwise accepted by the host. Transient depletion of host CD11b+ cells in WT mice abrogated T cell accumulation and IFNγ production in heart allografts and prevented acute rejection. Therefore, sensing allogeneic non-self by monocytes is a key, and previously unrecognized, innate pathway by which alloimmune responses are initiated.
Epitopes involved in indirect recognition of pocine MHC molecules induce potent T cell responses in HLA transgenic mice (P2184)
Authors: Lee Chong-Kil , Park Chan-su , Kim Ki-Hyang , Im Sun-A , Kim Narae , Song Sukgil 
Published: January 2023

Abstract
Indirect xenorecognition has been implicated as the major mechanism of chronic rejection, but precise definition of the epitopes involved has been limited. We identified swine leukocyte antigen (SLA)-derived immunogenic peptides that are presented in the context of human HLA molecules. The SLA class I-derived peptides that bind to HLA-DRB1*0401, a representative of the DR4 supertype, were predicted using a computer-assisted algorithm. The candidate peptides were synthesized, and their binding capacities to HLA-DRB1*0401 were compared in a competitive ELISA using biotinylated hemagglutinin reporter peptides [HA307-319]. Peptide-11 (LRSWTAADTAAQISK) was determined to exhibit the most potent binding capacity to HLA-DRB1*0401 in vitro and thus selected for in vivo immunization. Immunization of HLADRB1*0401-transgenic mice with peptide-11 elicited potent CD4+ Th1 responses. Peptide-11 shares homology to α2 domains of three SLA-1 alleles, six SLA-2 alleles, and 14 SLA-3 alleles. Additionally, we predicted HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) epitopes of SLA, and then performed peptide/HLA-A*0201 affinity and complex stability assays. Of candidate peptides, we selected two peptides that have high affinity and stability. Collectively, the present study identifies indirect xenorecognition epitopes shared by diverse SLA alleles.
Human iPS cell-derived CD34+ hematopoietic progenitor cells induce T cell anergy in alloreactive CD8+ T cells (P2188)
Authors: Kim Eun-Mi , Manzar Gohar , Zavazava Nicholas 
Published: January 2023

Abstract
Human induced pluripotent stem (iPS) cells have emerged as an alternative source of pluripotent stem cells that can be used in regenerative medicine. However, knowledge about the immunological characteristics of their derivatives remains enigmatic. Here, human iPS cells were differentiated into CD34+ hematopoietic progenitor cells (HPCs).These iPS cell-derived HPCs poorly express MHC class-I antigens, and are MHC class-II negative. They also lack expression of costimulatory molecules CD80 and CD86, but show relatively high expression of PD-L1. To investigate whether these HPCs stimulate CTLs, we generated CD8+ T cells against HLA-A2. Subsequently, HPCs were used as target cells for the CTLs. Interestingly HPCs were not susceptible to alloreactive CTL killing in a cytotoxicity assay. HPCs also failed to trigger release of IL-2 by CTLs as a sign of their activation. This lack of CTL activation was partially due to low MHC class I expression by the HPCs because HPC cell lysis was partially restored after MHC class I upregulation by treatment with IFN-γ. Interestingly, the CTLs became anergic when incubated with HPCs. As expected, T cell anergy was abrogated by treatment with rIL-2. Collectively, anergy was a result of low expression of CD80 and CD86 and high expression of PD-L1. These data indicate for the first time that human iPS cell-derived CD34+ HPCs induce T cell anergy, a property that could be exploited for cellular allo-transplantation of iPS cell-derived tissues.
Donor CD19-targeted T cells exert potent graft versus lymphoma activity without GVHD (P2134)
Authors: Ghosh Arnab , Davila Marco , Young Lauren , Jenq Robert , Sadelain Michel , van den Brink Marcel 
Published: January 2023

Abstract
We evaluated the relative effects of donor CD19-targeting chimeric antigen receptors (CAR)+T cells on the elimination of CD19+B cells and endogenous TCR-mediated GVHD in mouse models of allo-HSCT. We generated a panel of retroviral vectors encoding mouse CD19-specific CARs: CD19-delta, a tail-less CAR lacking the CD3ζ signaling and CD19-CAR signaling through CD28 and CD3ζ. CD19-CAR+T cells mediated specific lysis of CD19+tumors in vitro, while CD19-delta+T cells did not. We next transferred the transduced donor T cells into lethally irradiated recipients of T cell-depleted allografts and CD19+lymphoma A20-TGL (B6→BALB/c+A20-TGL). CD19-CAR+T cells mediated clearance of A20 tumor leading to significantly improved tumor free survival (p&lt;0.01), while mediating significantly less acute GVHD, resulting in improved survival (p&lt;0.001). Donor CD19-delta+T cells caused lethal GVHD, indicating persistent endogenous TCR mediated alloreactivity in the absence of CAR signaling. Compared to controls, fewer alloactivated CD19-CAR+T cells were found in the lymphoid organs of allo-HSCT recipients. This was accompanied by a lower expression of IFN-γ and lower frequencies of phenotypically activated T cells (p&lt;0.05). LPAM, associated with increased gut GVHD, was also significantly lower on CD19-CAR+T cells. CAR stimulation did not inhibit TCR-mediated killing. These results provide the first preclinical evidence suggesting that CAR+ donor T cells may be safely applied in an allogeneic context.
Bcl-xL regulates CD1d-mediated antigen presentation to NKT cells (APP3P.114)
Authors: Subrahmanyam Priyanka , Webb Tonya 
Published: January 2023

Abstract
Natural killer T (NKT) cells are a unique subset of T cells that recognize glycolipid antigens presented by CD1d molecules. Once activated, NKT cells can mount strong anti-tumor responses. However, little is known about the regulation of CD1d-mediated antigen processing and presentation to NKT cells, particularly in the context of B cell lymphoma. Pro-survival factors of the Bcl-2 family, such as Bcl-xL are often upregulated in B cell lymphomas, and are associated with changes in the endocytic pathway, which is paramount for CD1d-mediated antigen presentation. We hypothesized that Bcl-xL regulates this process, and found that over-expression or induction of Bcl-xL led to increased antigen presentation to NKT cells. Conversely, inhibition or knockdown of Bcl-xL led to decreased NKT cell activation. Knockdown of Bcl-xL also resulted in the loss of CD1d trafficking to LAMP1+ compartments. Furthermore, Rab7, a late endosomal marker was upregulated following Bcl-xL knockdown, and CD1d molecules accumulated in the Rab7+ compartment. These results demonstrate that Bcl-xL regulates CD1d-mediated antigen presentation to NKT cells by altering the intracellular localization of CD1d. Thus, we have identified a new pathway involved in antigen presentation that can impact current therapies targeting the Bcl-2 family, as well as emerging NKT cell based cancer immunotherapeutic strategies.
Increased expression of IL-15 and IL-15Ra in the islets of patients with T1D (CCR3P.217)
Authors: Chen Jing , Feigenbaum Lionel , Awasthi Parirokh , Butcher Donna , Anver Miriam , Golubeva Yelena , Bamford Richard , Zhang XiaoJie , St. Claire Mark , Thomas Craig , Discepolo Valentina , Jabri Bana , Waldmann Thomas 
Published: January 2023

Abstract
We previously showed that transgenic mice with islet expression of IL-15 and IL-15Ra developed diabetes that mimics early human T1D. Inhibiting IL-15 signaling with anti-IL2/IL15Rβ (anti-CD122) or with the JAK 2/3 inhibitor tofacitinib reversed the diabetes. This suggested a causative role of IL-15 and IL-15Ra in the induction of insulin dependent diabetes in mice. To further investigate whether IL-15 and IL-15Ra play a role in the pathogenesis of human type 1 diabetes, we investigated the expression of IL-15 and IL-15Ra in the islets of patients with type 1 diabetes, anti-insulin autoantibodies and normal donors. Immunohistochemistry demonstrated IL-15 expression in the islets in all T1D patients examined whereas IL-15 was detected only in the pancreatic islets in one out of four normal donors and two out of five autoantibody positive donors. Interestingly, in two cases where IL-15 was positive, we also detected islet expression of MxA, a GTPase induced by type 1 IFN (α/β) that has been reported to interfere with virus multiplication and spread. Furthermore, IL-15 and IL-15Rα mRNA levels were also higher in the islets from T1D patients compared to that from autoantibody positive donors or normal donors. Moreover, the serum sIL-15Rα levels were significantly higher in patients with T1D compared with those of normal controls. Taken together, our data suggest that disordered IL-15 and IL-15Rα may be involved in the pathogenesis of human T1D.
Histone H2A deubiquitination by 2A-DUB/Mysm1 regulates critical checkpoints in early T cell development (HEM4P.226)
Authors: Gatzka Martina , Hainzl Adelheid , Tasdogan Alpaslan , Maity Pallab , Singh Kamayani , Wilms Christina , Wlaschek Meinhard , Scharffetter-Kochanek Karin 
Published: January 2023

Abstract
Developmental processes rely on collaboration of epigenetic modifications and sequence-specific transcription factors for timely activation and silencing of lineage-specific genes. Because histone H2A deubiquitination by 2A-DUB/Mysm1 was recently shown to affect hematopoiesis, in this investigation, we used 2A-DUB-deficient mice to systematically characterize the function of this epigenetic regulator in early T cell development. Thymi of 2A-DUB-/- mice were severely hypoplastic with &gt;10-fold decrease in total cell numbers and increased fraction of apoptotic thymocytes compared with wild-type littermates. Diminished cell numbers resulted from a reduction of early thymocyte progenitors (ETPs) in context with defective HSCs, a partial block at the double-negative (DN)1-DN2 transition and increased apoptosis of double-positive (DP) thymocytes. In qPCR and IF analyses, we identified p19ARF and other genes involved in early T-cell development and protection from apoptosis as potential 2A-DUB target gene. ChIP analyses were conducted to explore binding of 2A-DUB to the Ink4a/Arf promoter in thymocytes. In addition, genetic approaches are used to validate the interaction of 2A-DUB/Mysm1 with known regulators of apoptosis and T cell development. We conclude that 2A-DUB/Mysm1 is critical for early T cell development via regulation of lineage-specific genes and that insufficient histone H2A deubiquitination induces apoptotic programs in HSCs, thymocytes and potentially other cell types.