bluuebunny/crossref_metadata_2025_split huggingface dataset:
A mouse model of transient diabetes; a new perspective on glucose homeostasis (123.24)
Authors: Girtman Megan , Pavelko Kevin , Pease Larry 
Published: January 2023

Abstract
We have induced acute diabetes following immune attack on the pancreas with islet specific CD8+ T cells, but surprisingly many animals subsequently recovered blood glucose homeostasis. The recovered animals exhibited nearly normal glucose tolerance and produced normal levels of blood insulin following glucose challenge. Remarkably very few islets were present in these animals and those remaining were virtually insulin free. In this model B6 RIP-OVAhi mice receive 100 to 600 naïve OT-1 CD8+ T cells prior to activation by an infection with Theilers murine encephalomyelitis virus encoding the SIINFEKL ovalbumin antigen. When greater numbers of T cells are transferred, this protocol causes acute and fatal diabetes. However, when limiting numbers of T cells are used, animals can recover from the acute phase of the disease. Under these limiting conditions, we find that the mice develop acute pancreatitis by day 5 following infection and stop producing insulin by day 8. By day 11 to 14 some animals begin to recover. Early in the recovery process, insulin positive beta cells are evident in islets. However, late after recovery (days &gt;56) animals that regulate blood sugar normally are found devoid of insulin producing beta cells, though insulin levels are near normal. This raises important questions about how these animals recover glucose homeostasis following cellular immune attack on their islets. Our hypothesis is that insulin is produced outside of the pancreas in these animals.
GILT modulates CD4+ T cell tolerance to cutaneous autoantigen TRP1 (123.32)
Authors: Rausch Matthew , Hastings Karen 
Published: January 2023

Abstract
Maintaining tolerance to skin-restricted antigens is critical for avoiding cutaneous autoimmunity. We have shown that gamma-interferon-inducible lysosomal thiol reductase (GILT) is essential for efficient MHC class II-restricted processing of the melanocyte differentiation antigen, tyrosinase-related protein 1 (TRP1). In GILT-/- TRP1-specific TCR transgenic (Tg) mice, CD4+ TRP1-specific T cells escape thymic deletion, but do not induce autoimmune destruction of melanocytes (vitiligo). GILT-/- Tg mice have fewer peripheral CD4+ TRP1-specific T cells compared to TRP1-deficient mice. CD4+ T cells in GILT-/- Tg mice have marked reduced IL-2 and IFN-γ production and a portion are antigen-experienced. Since tolerance is only partially mediated by an increased percentage of TRP1-specific regulatory T cells in GILT-/- mice, we sought to characterize other mechanisms that constrain the activity of TRP1-specific T cells, such as anergy, exhaustion and deletion. Here, we demonstrate that fewer TRP1-specific T cells were recovered from skin-draining lymph nodes following adoptive transfer of CD4+ T cells from GILT-/- Tg compared to TRP1-deficient Tg mice. Furthermore, TRP1-specific T cells from GILT-/- Tg mice underwent diminished antigen-specific proliferation in vitro compared to T cells from TRP1-deficient Tg mice. These findings suggest multiple peripheral tolerance mechanisms inhibit CD4+ T cell mediated autoimmunity to an endogenously expressed cutaneous autoantigen.
Transaldolase Deficiency Enhances the Development of Experimental Autoimmune Encephalomyelitis (123.46)
Authors: Perl Andras , Bartos Adam , Niland Brian , Fernandez David 
Published: January 2023

Abstract
Transaldolase (TAL) regulates mitochondrial hyperpolarization (MHP), a reversible step of T-cell activation. Here, we investigated the role of TAL in T-cell mediated experimental autoimmune encephalomyelitis (EAE), a mouse model multiple sclerosis. Direct immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) elicited EAE in TAL-deficient (TAL-/-) mice at an accelerated rate relative to wild-type littermates (TAL+/+; 2-way ANOVA, p=0.0005). Adoptive transfer of MOG35-55 peptide-immunized TAL-/- lymphoblasts triggered EAE in naïve Rag2-/- recipients at a 2.10±0.42 greater higher degree relative to TAL+/+ lymphoblast (p &lt; 0.0001). The increased potency of TAL-/- lymphoblasts was associated with an expansion of CD4+ T cells (62.74±4.48) as compared to TAL+/+ controls (57.34±4.48, p=0.007). In contrast, the frequency of CD4+/CD25+/Foxp3+ regulatory T cells was reduced in TAL-/- mice (2.91 ± 1.02%) relative to TAL+/+ littermates (3.64 ± 1.02%),; p=0.002) In vivo administration of N-acetylcysteine (NAC) reversed the skewing of CD4+ effector and regulatory T cells and ameliorated the EAE disease score in NAC-treated TAL-/- mice (p&lt;0.05). These data identify the metabolic control of MHP by TAL, as a novel checkpoint of T cells lineage specification that affects the expansion of effector and regulatory CD4+ T cells and thus modulates the onset and severity of EAE. This checkpoint is redox-controlled and represents a target for therapeutic intervention with NAC.
Improved identification of leukocyte sub-populations using new bright fluorochrome reagents in multi-color flow cytometric analysis. (124.11)
Authors: Stall Alan , Luan Feng-Jun , Edinger Mark , Jaimes Maria , Elia Jeanne , Chen Yu 
Published: January 2023

Abstract
With many cell surface markers expressed at very low levels the ability to identify (and sort) biologically relevant sub-populations by flow cytometry is often limited by the availability of fluorescent reagents sufficiently bright to resolve these markers. In the past year multiple new fluorochromes have been developed which have significantly improved brightness compared to previously available reagents. In particular, BD Horizon™ PE-CF594 and BD Brilliant Violet™ 421 reagents can be 2-5 times brighter than equivalent PE reagents which have typically been the brightest available. These brighter reagents, when used in multicolor analyses, provide multiple benefits including full resolution of small, dim sub-populations resulting in more accurate enumeration and enrichment via sorting. Data will be presented demonstrating this improved resolution using model systems including human T memory and Treg cell sub-populations and murine CD34+ bone marrow cells.
A proof-of-concept screen for identification of novel natural product modulators involved in mouse Treg/Th17 differentiation by using high-throughput Flow Cytometry (124.2)
Authors: Wang Zichun , Cheng Hongsheng , Shen Yongchun , Hansen Hans , Suh Ted 
Published: January 2023

Abstract
The recent discovery of two novel subsets of CD4+ T lymphocytes (Th17 and Treg) has led to a paradigm shift in the understanding of how autoimmune responses are mediated and regulated. Interestingly, both Th17 and Treg cells can develop from the same naïve CD4+ T cell precursors and in some circumstances they can convert to each other. Several recent publications highlight the role of the aryl hydrocarbon receptor (Ahr) in regulating Treg and Th17 cell differentiation and possible application to human diseases. Depending on the ligands, Ahr activation can control naïve CD4+ T cell differentiation towards either a Treg (TCDD) or a Th17 (FICZ) phenotype. Identifying novel agents that promote or inhibit differentiation of naïve CD4+ T cells to Treg or Th17 could be beneficial in the area of Oncology and autoimmune diseases. Here we describe an assay developed for identification of new modulators based on T cell differentiation by using high-throughput flow cytometry. With TGF-β or TGF-β/IL-6 stimulation isolated mouse naïve CD4 cells can be differentiated efficiently into Treg or Th17 lineages. Treg or Th17-specific expression was detected by intracellular staining of FoxP3 or IL-17, respectively. A proof-of-concept screening against 1600 pure natural products (NPs) was performed and seventeen Th17 specific hits were identified
Plasma ST2 predicts therapy-resistant graft-versus-host disease and survival (126.13)
Authors: Vander Lugt Mark , Braun Thomas , Ferrara James , Hanash Samir , Levine John , Harris Andrew , Couriel Daniel , Paczesny Sophie 
Published: January 2023

Abstract
Graft-versus-host disease (GVHD) is the primary limitation of allogeneic hematopoietic cell transplantation (HCT). Although we have validated a panel of 6 GVHD plasma biomarkers with diagnostic and prognostic value, current blood tests do not predict a patient's response to therapy. We compared plasma from responders (R) and non-responders (NR) using proteomics as a discovery engine, and high-throughput ELISA as validation. Five proteins significantly elevated in NR and 6 validated GVHD markers were measured at therapy initiation in 381 patients with acute GVHD and treated with steroids. In multivariate analysis including the clinical GVHD grade (the strongest clinical predictor), suppressor of tumorigenicity 2 (ST2), the IL33 receptor, significantly predicted response to GVHD therapy. Then, we compared ST2 and grade to predict mortality 180 days post-therapy, we found that patients with high grade and low ST2 had a good prognosis while patients with low grade and high ST2 had a poorer prognosis, suggesting that ST2 provides important prognostic information above the clinical grade. We then analyzed the ability of ST2 measured 14 days post-transplant to predict the occurrence of GVHD and mortality. Patients with high ST2 were 1.4 times more likely to develop GVHD by day 100 post-transplant and 3.2 times more likely to die 180 days post-transplant. Therefore, measurement of ST2 significantly enhances the accuracy of outcome prediction in allogeneic HCT recipients.
Memory T cells are resistant to depletion due to their intrinsic characteristics and anatomical location (126.22)
Authors: Ayasoufi Katayoun , Valujskikh Anna 
Published: January 2023

Abstract
Memory T cells are known to be less sensitive to depletion therapies than naïve T cells. We tested whether anatomical location of memory T cells determines their resistance to depletion. We injected naïve B6 mice with rabbit anti-mouse lymphocyte serum, ALS. Two days after the last injection, more than 95% of CD8 and 60-80% of CD4 T cells were depleted from lung, liver, bone marrow, peripheral blood and spleen, but not from the thymus, with the residual cells being predominantly CD44hi. The in vivo binding of rabbit IgG to T cells in ALS-treated mice did not necessarily correlate with the depletion efficiency. Residual CD4 T cells were isolated from various organs and intravenously injected into groups of ALS-treated or control IgG-treated B6 mice. The distribution of injected cells in the adopted hosts was similar regardless of their origin. The CD4 T cells from lung, liver and thymus were further depleted when relocated into circulation, suggesting that their location is critical in the depletion resistance. The greatest depletion was observed within spleen and liver of the ALS-treated adopted hosts implicating these organs as possible sites of depletion. However, CD4 T cells obtained from BM and spleen were not further affected by relocation suggesting that they are intrinsically resistant to depletion. Understanding the phenotype and functions of depletion-resistant memory T cells from different organs may guide the use of lymphodepletion in transplant patients.
Tracking natural antitumor T cell responses at primary and metastatic tumor sites (127.6)
Authors: Dong Haidong , Liu Xin , Gibbons Rachel 
Published: January 2023

Abstract
Spontaneous antitumor immunity remains challenging to detect and monitor largely due to the absence of established biomarkers. We selected the integrin CD11a as a biomarker to define antitumor T cell responses. CD11a is up-regulated on effector and memory T cells and is involved in the killing of tumor cells by cytotoxic T lymphocytes. In primary (subcutaneously inoculated) and metastatic (intravenously injected) tumors, CD11a high CD8 T cells were detected in the primary (skin) or metastatic (lung) tumor sites, but not in secondary lymphoid organs. Once tumors were established, CD11a high CD8 T cells were identified in tumor draining lymph nodes and peripheral blood. Phenotype analysis revealed that CD11a high CD8 T cells were proliferating (Ki67+) activated T cells (CD62L low, CD69 high, PD-1 high). CD11a high CD8 T cells expressed the transcription factor T-bet but not Foxp3. Live, but not dead, tumor cells, induced expansion of CD11a high CD8 T cells in the lung, suggesting that the access of tumor cells to target tissues is required to induce CD11a high CD8 T cell responses. Our results suggest that CD11a may provide a new T cell biomarker to measure ongoing natural tumor-reactive T cell responses and to predicate the efficacy of tumor immunotherapy.
Antigen reactivity of B cells from patients at risk to develop Multiple Sclerosis demonstrates a specific somatic mutation pattern. (159.28)
Authors: Ligocki Ann , Rounds William , Li Min , Courtney Ardith , Frohman Elliot , Greenberg Benjamin , Stowe Ann , Ward E. , Monson Nancy 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is the leading disease of the central nervous system and a significant, costly cause of disability in young adults. Patients at risk for MS often present with a single demyelinating event, typically called a “clinically isolated syndrome” (CIS). A CIS can occur in the brain, spinal cord (Acute Partial Transverse Myelitis, APTM), or optic nerve (Optic Neuritis, ON). Our laboratory discovered a unique pattern of antibody gene mutation accumulation (i.e. antibody gene signature, or “AGS”) that is exclusive to B cells from the cerebrospinal fluid (CSF) and brain lesions of MS patients and CIS patients that develop MS in the future. Our goal for this study was to determine whether CIS and MS patient B cells that carry this pattern of somatic hypermutation accumulation in their antibody genes react to brain tissue. Thirty-four antibody genes of B cells isolated from the CSF of MS and CIS patients carrying this AGS pattern were cloned into antibody expression vectors to generate recombinant full-length human antibodies (rhAbs). Preliminary DAB staining using a subgroup of these rhAbs on cryo-sectioned mouse brain demonstrates binding to CNS tissue. Cortical staining of varied intensities was found among the rhAbs tested. Patterns of staining and details of antigen reactivity will be presented. This result provides promise in continuing to identify the auto-antigens that are recognized by the AGS B cells shared among patients at risk to convert to MS.
Interferon beta-1a modulation of B cells (161.12)
Authors: Huang Hui , Ito Kouichi , Dangond Fernando , Dhib-Jalbut Suhayl 
Published: January 2023

Abstract
Clinical studies have shown that IFNβ-1a reduces relapses and slows disease progression in relapsing multiple sclerosis (MS). Although the effect of IFNβ-1a on T cells has been extensively investigated, its effects on B cells are poorly understood. We examined the effect of IFNβ-1a on IL-10 production in B cells. B cells isolated from healthy donors were cultured with IFNβ-1a, and production of IL-10 was measured. IFNβ-1a enhanced IL-10 production in B cells in a dose dependent fashion. We also found that IFNβ-1a treatment increased the percentage of B-cells expressing B7.2 (CD86). To examine how IFNβ-1a mediated increase of B7.2 affects the proliferation of CD4+ T cells, CD4+ T cells were cultured with IFNβ-1a-treated or non-treated B cells, with or without anti-CD3. Anti-CD3 mAb-mediated T-cell proliferation was partially suppressed when B cells were treated with IFNβ-1a. Addition of anti-CTLA-4 mAb partially reversed the IFNβ-1a-mediated suppression of T-cell proliferation. These data suggest that IFNβ-1a-induced increase of B7.2 in B-cells may reduce the proliferation of CD4+ T cells through increased interaction of B7.2 with CTLA-4. In conclusion, in in vitro experiments, IFNβ-1a increases IL-10 production in B cells and can indirectly inhibit T-cell proliferation through up-regulation of B7.2 on B cells. These findings shed light on the mechanism of action of IFNβ-1a in MS.
Increase in natural killer T (NKT) Cell activation in hypoxic environments via the induction of HIF1alpha (162.16)
Authors: East James , Travis Candice , Webb Tonya 
Published: January 2023

Abstract
Tumors often experience hypoxic microenvironments due to poor vascular access in the early stage of neoplastic growth and continue to experience oxygen deficits in late stage progression despite the increase in neovascularization to the primary tumor or metastasis. This persistent hypoxic state selects for tumors cells that are able to compensate for low oxygen levels by increasing use of the glycolytic cycle under aerobic conditions (The Warburg Effect), suppressing apoptosis and inducing decreased genomic stability. These effects have been shown to be mediated, at least in part, by the transcription factor hypoxia inducible factor (HIF)-1alpha. Natural Killer T (NKT) cells are a subset of T cells that recognize a wide range of lipid antigens presented by the MHC Class I-like CD1d molecule. In this study, we sought to investigate the effects of hypoxia induction on CD1d-mediated NKT cell responses. Pharmacological agents were used to induce HIF-1a in LCD1d, and then we assessed their ability to present endogenous antigen to NKT cells. It was found that the induction of HIF-1a resulted in a significant increase in CD1d-mediated NKT cell activation, as assessed by IL-2, GM-CSF, and IL-13 production. The increase in NKT function was not due to with an increase in cell surface expression of CD1d. These results suggest that hypoxia in tumor cells may alter the repertoire of endogenous lipids presented in the context of CD1d which permits their recognition by NKT cells.
Ym1 is a stem cell secreted factor that augments NK cell killing of tumor cells (162.31)
Authors: Manzar Gohar , Kim Eun-Mi , Tabayoyong WIlliam , Zavazava Nicholas 
Published: January 2023

Abstract
We previously observed that embryonic stem cell-derived hematopoietic progenitor cells (HPCs) were resistant to NK cells in vitro despite their poor expression of MHC antigens. In contrast, HPCs were readily deleted by NK cells in vivo. This discrepancy led us to study protein expression by HPCs pre and post-transplantation using proteomics. The rationale was that in response to serum cytokines in vivo, HPCs likely upregulated certain proteins that enhanced NK cell cytotoxicity. Upon sequencing, most of these proteins were determined to be housekeeping proteins except for one protein, which we identified as Ym1, also known as chitinase 3-like protein 3. Subsequently, recombinant Ym1 was generated in E. coli. Ym1 strongly enhanced NK cell cytotoxicity to HPCs in vitro by activating NK cells into the highly cytotoxic Mac1hi subsets. This process was APC-dependent, suggesting cross-presentation of IL-15 to NK cells by APCs. In vivo, Ym1 induced the emergence of mature CD27loMac1hi peripheral blood NK cells, which have been found to be most effective at lysing tumor cells. Further, Ym1 caused a significant increase in the production of IFN-γ, perforin and granzyme B. Indeed, Ym1 remarkably enhanced target cell killing by 3-4 fold, which is a novel finding that has promising implications for the application of Ym1 in cancer treatment.
Enhancement of NK cell activity and Th1 immunity in healthy subjects by orally administered fucoidan mix. (162.35)
Authors: Miyazaki Yoshiyuki , Nakamizo Masaji , Tsuji Hiromitsu , Kirino Tomomi , Saito Yuzu , Kawahara Kazuhiro , Otsuka Ken , Tachibana Hirofumi , Yamada Koji , Fujii Makoto , Tachikawa Daisuke 
Published: January 2023

Abstract
Fucoidan is a sulfated polysaccharide derived from brown seaweeds which mainly consist of L-fucose. In Asian countries such as Japan, Korea and China, peoples eat seaweeds willingly as nourishing health foods. We previously showed that the tumor formation by transplanted Sarcoma180 cells was suppressed in mice fed 2% fucoidan mix containing diets, and NK cell activity was enhanced in the fucoidan-fed mice. The results suggest that the activated NK cells participated in elimination of the tumor. However, in human, immune enhancing activities of fucoidan have hardly been proved. Therefore, we performed an open-label trial in this study. Five healthy volunteers (47 ± 6 years old, 2 male and 3 female) took 2.5 g fucoidan mix per day for 30 days. There were no abnormal observations in the values of WBC, RBC, platelet count and blood profile. On the other hand, NK cell activity was augmented by 1.42 times in the average at end of the trial than the initial value. The ratio of IFN-gamma-producing (Th1) cells also increased to 114% for the initial value by the day 30 by the fucoidan mix intake, whereas IL-4-producing (Th2) cells decreased to 77%. As a result, the rise of Th1/Th2 ratio by 1.46 times in the average was observed with 4 subjects among 5 examinees. Furthermore, CD8+ cells tended to expand with the all subjects. These results suggest that intake of fucoidan is effective to augment anti-tumor immunity in human.
Hematopoietic progenitor kinase 1 (HPK1) influences regulatory T cell functions (163.26)
Authors: Sawasdikosol Sansana , Alzabin Saba , Cary Chris , Zha Ren Yuan , Burakoff Steven 
Published: January 2023

Abstract
HPK1 is a negative regulator of TCR-initiated signal transduction. HPK1-/- mice are more susceptible to experimental autoimmune encephalomyelitis, suggesting that the ability to enforce peripheral tolerance may have been compromised. Paradoxically, we observed that more natural regulatory T cells were found in the periphery of HPK1-/- mice than in wild type C57BL/6. We determined whether HPK1-/- Foxp3+ Tregs retained their ability to suppress TCR-induced effector T cell proliferation and found that they lack the ability to suppress. Because the ability to suppress T cell proliferation is a function conferred to Tregs by Foxp3-dependent suppression of IL-2 transcription, we assessed whether HPK1-/- Foxp3+ Tregs retain the ability to repress TCR-induced IL-2 production. We found that HPK1-/- Tregs produce a significant amount of IL-2 in response to TCR engagement, suggesting that Foxp3 is unable to carry out transcriptional repression. This aberrant phenotype implicates HPK1 as an important regulator of Treg functions.
IL-15 restores defective NK anti-fungal activity in a primary Hemophagocytic lymphohistiocytosis Patient (164.1)
Authors: Li Shushun , Kyei Stephen , Wright Nicola , Mody Christopher 
Published: January 2023

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially fatal clinical syndrome caused by various congenital defects that result in defective perforin-dependent cytotoxicity of NK cells. This leads to increased T cell activation and proliferation and excessive cytokine production including IL-1, IL-6, IFN-γ, TNF-α and GM-CSF that causes sustained activation of macrophages that is manifest as extensive inflammation and tissue damage. One study showed that 50% of deaths from familial HLH were due to invasive fungal infections. We sought to investigate whether NK cells from a patient with HLH have defective anti-fungal activity and seek a potential therapeutic approach. NK cells (CD56+/CD3-) were isolated from a two-month-old boy with c1090-1091del of the perforin gene resulting in p.Leu364&gt;Stop consistent with the FHL-2 form of HLH. Defective NK killing was observed for both Cryptococcus neoformans and Candida albicans. Remarkably, the defective anti-Candida activity of NK cells could be restored within 24 hours by IL-15 treatment that was similar to the enhanced anti-Candida activity of NK cells from healthy donors. We speculate that IL-15 enhances antifungal activity by stimulating NK cells to employ an alternate microbicidal effector mechanism. This result is the first to show that IL-15 can restore defective cytotoxic activity of NK cells from an HLH patient, and further studies might be considered to explore the mechanism and potential form of immunotherapy.