bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human CD26hi Th17 cells eradicate large established mesothelioma (P2139)
Authors: Paulos Chrystal , Nelson Michelle , Huff Logan , Kundimi Sreenath , Goodyear Morgan 
Published: January 2023

Abstract
Human CD4+ T cells can differentiate into multiple effector subsets, but their role in anti-tumor immunity remains incompletely elucidated. Further, the costimulatory molecules that effectively bolster their antitumor activity are unknown. To uncover the role of CD28 versus ICOS costimulation, we sorted Th1 (CXCR3+), Th2 (CCR4+), or Th17 (CCR6+ or CD26hi) subsets from bulk human CD4+ T cells and stimulated them with CD3/CD28 or CD3/ICOS beads. We found that ICOS costimulation not only augmented human Th17 cells’ function, but also enhanced the function of human Th1 and Th2 cells superior to CD28 costimulation. Moreover, CD26hi Th17 cells were more polyfunctional than the other T cells subsets, as indicated by increased secretion of IL-17, IFN-γ, IL-22 and TNF-α. To determine the therapeutic potential of these subsets, we sorted Th1, Th2 and Th17 cells from human peripheral blood, expanded them with CD3/ICOS beads, and engineered them to recognize mesothelioma. We found that CD26hi Th17 cells mediated superior regression of large human mesothelioma in mice compared to CXCR3+Th1, CCR4+Th2 or CCR6+Th17 cells. The therapeutic effectiveness of CD26hi Th17 cells was associated with enhanced functionality and persistence in vivo. Taken together, these data indicate that the appropriate selection of effector CD4+ T cells is critical for successful tumor eradication. These findings will help guide next generation clinical trials for patients with advanced malignancies.
Adiponectin deficiency suppresses lymphoma growth in mice by modulating NK cells, CD8 T cells and myeloid-derived suppressor cells (P2141)
Authors: Yang Young , Han Sora 
Published: January 2023

Abstract
We previously found that adiponectin (APN) suppresses IL-2-induced natural killer (NK) cell activation by down-regulating IFN-γ-inducible tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand expression. Even though APN’s anti-tumor function has been reported in several solid tumors, with few controversial results, no lymphoma studies have been conducted. In this study, we assessed APN’s role in the function of immune cells, including NK cells, cytotoxic T-lymphocytes (CTL), and myeloid-derived suppressor cells (MDSC), using EL4 and B16F10-bearing C57BL/6J based APN-knockout (APNKO) mice. We observed attenuated EL4 growth in APNKO mice. Increased numbers of splenic NK cells were found under naive conditions and splenic CTLs under EL4-challenged conditions. Splenic NK cells in APNKO mice showed enhanced cytotoxicity, with and without IL-2 stimulation. In addition, decreased MDSC accumulation was found in EL4-bearing APNKO mice. Enforced MHC class I (MHC I) expression in B16F10 led to attenuated growth in APNKO mice. Thus, our results suggest that EL4 regression in APNKO mice is due to not only enhanced anti-tumor immune system but also to high level expression of MHC I.
Engagement of CD47 induces G1 arrest in EBV-transformed B cells by controlling CDK-cyclin-CDKi and activating p38 MAPK/JNK pathway (P2149)
Authors: Park Ga Bin , Choi Yunock , Kim Ja Young , Kim Hae Jin , Kim Seonghan , Kim Yeong-Seok , Lee Hyun-Kyung , Cho Dae-Ho , Lee Wang Jae , Bae Ki Won , Hur Dae Young 
Published: January 2023

Abstract
CD47 possesses a variety of anti-tumor, anti-angiogenic, and anti-metastatic properties in several tumors, but its roles on EBV-transformed B cells are still not fully understood. Here we first observed that EBV infection induced CD47 expression on B cells surface, and CD47 stimulation of EBV-transformed B cells with anti-CD47 mAb (B6H12) reduced cell proliferation and induced the cell cycle arrest at G1-phase. We showed that CD47-induced G1-phase arrest was mediated through increased expression of CDKi (p16INK4a, p21WAF1, and p53), a simultaneous decreased expression in CDK2, 4, 6 and cyclin D1, D2 and E and enhanced binding of CDKi-CDK. Among the relevant pathways, CD47 mAb induced outstanding activation of p38 MAPK and JNK, whereas phosphorylation of Akt and ERK1/2 were both reduced. In particular, p38 inhibitor SB203580 and JNK inhibitor SP600125 powerfully blocked the decreased expression of CDK and the increased expression of CDKi and dramatically suppressed binding of phospho-p38-CDKi. Accordingly, these data demonstrate that the p38 MAPK and JNK pathway participates in CDKi induction, subsequently leading to a decrease in the levels of cyclin D1-CDK4/6 and cyclin E-CDK2 complexes and CD47-dependent EBV-transformed B cell growth inhibition. In conclusion, these findings concerning the molecular mechanisms of CD47 signaling in EBV-transformed B cells provides a theoretical basis for clinical approaches for the use of therapeutic agents in treating EBV-associated tumors.
Colorectal tumor-specific regulatory and effector CD4+ T cell responses: translating laboratory results to the clinic (P2159)
Authors: Scurr Martin , Gallimore Awen , Godkin Andrew 
Published: January 2023

Abstract
The adaptive immune response to colorectal cancer (CRC) has a crucial role in prolonging host survival. Increased tumor infiltrates of CD3+ T cells can improve patient outcome, yet other T cell subsets exist that are capable of suppressing anti-tumor responses. Our lab has found that suppression of tumor-specific Th1 responses is associated with progression of CRC. Here, the phenotype and function of CD4+ T cells derived from PBMC, colon and tumor samples were analysed for suppressive markers by FACS, and anti-tumor responses by IFN-γ ELISPOT. CRC patients with more advanced tumors responded to fewer epitopes and generated a significantly weaker epitope-specific T cell response to the oncofetal antigen, 5T4 than healthy donors (p=0.0006). The mechanism of loss of T cell response is independent of HLA-DR subtype or patient age, but human depletion experiments both in vitro and in vivo indicates suppression by Foxp3+ regulatory CD4+ T cells. These cells were found in abundance amongst tumor-infiltrating lymphocytes; however, another equally prominent population of IL-10 and TGF-β-producing CD4+Foxp3- T cells were found to be &gt;100-fold more suppressive. Thus, a major caveat to cancer immunotherapy is the suppressive tumor microenvironment, which contributes to the selective decline of measurable anti-tumor CD4+ T cell responses as tumors progress. These responses are enhanced in CRC patients by depleting regulatory T cells.
HIF-1/2α mediates PAR-2-induced TGF-α expression, but not VEGF production, in human pancreatic cancer cells (P2163)
Authors: Pan Shiow-Lin , Chang Li-Hsun , Teng Che-Ming 
Published: January 2023

Abstract
Hypoxia-inducible factor (HIF) can influence tumor associated immune cells toward assisting in tumor progression and control of immune protection. In this study, we demonstrated that activated protease-activated receptor-2 (PAR-2) upregulated both HIF-1α and HIF-2α protein level, resulting in enhanced TGF-α. Downregulation of HIFs-α by siRNA or YC-1, a HIF inhibitor, resulted in depleted levels of TGF-α protein. Further, PAR-2 through integrin-linked kinase (ILK) signaling, including the p-AKT, promoted HIFs protein expression. Diminishing of ILK by siRNA decreased PAR-2-induced p-AKT, HIFs-α and TGF-α protein. Our results suggest that ILK is involved in the PAR-2-mediated TGF-α via a HIF-α-dependent pathway. Furthermore, the culture medium from PAR-2-treated pancreatic cancer cells enhanced HUVEC proliferation and tube formation, which was blocked by the MEK inhibitor PD98059. We also found that activated PAR-2 enhanced tumor angiogenesis through the release of vascular endothelial growth factor-A (VEGF-A) from cancer cells, independent of the ILK/HIFs-α pathways. Consistent with microarray analysis, activated PAR-2 induced TGF-α and VEGF-A gene expression. In conclusion, the activation of PAR-2 signaling induced human pancreatic cancer progression through the induction of TGF-α expression by ILK/HIFs-α, as well as through MEK/VEGF-A-mediated angiogenesis, and it plays a role in the interaction between cancer progression and cancer-related inflammation.
Modeling leukemia immunoediting in mouse-human chimeras (P2169)
Authors: Oliveira Giacomo , Toffalori Cristina , Garcia-Manteiga Jose Manuel , Camisa Barbara , Crucitti Lara , Lazarevic Dejan , Peccatori Jacopo , Bernardi Massimo , Bordignon Claudio , Bondanza Attilio , Stupka Elia , Ciceri Fabio , Fleischhauer Katharina , Bonini Chiara , Vago Luca 
Published: January 2023

Abstract
Acute Myeloid Leukemia (AML) can be recognized and eliminated by the immune system, as demonstrated by the clinical efficacy of allogeneic hematopoietic stem cell transplantation. Still, immune-resistant variants of AML can outgrow upon the selective pressure of the transplanted immune system and determine clinical relapse, in a process called “leukemia immunoediting”, the biological bases of which remain largely unknown. To unravel novel mechanisms of immunoediting, we engrafted primary human AML in immunocompromised NOD/SCID γ-chainnull mice and modeled immune pressure by serial infusions of human T cells, either autologous or allogeneic to the leukemic cells. HLA-mismatched allogeneic T cells eradicated AML from 6/6 treated mice, whereas HLA-identical T cells granted only temporary control in 3/3 mice and autologous T cells were completely inefficacious in 3/3 mice. To fine-tune immune pressure from HLA-mismatched T cells, and thus model a phase of equilibrium before leukemia immune escape, we genetically modified allogeneic T cells to express the HSV-Tk suicide gene. The activation of the suicidal machinery abated circulating T cell counts in 3/3 mice, halted the ongoing antileukemic response and resulted in leukemia outgrowth. Gene expression profiling of the AML blasts purified from the mice upon escape from immune pressure demonstrated the selective and significant deregulation of genes involved in immune processes, including antigen processing and presentation.
Systemic 4-1BB activation induces a novel T-cell phenotype driven by high expression of Eomesodermin (P2197)
Authors: Curran Michael , Geiger Theresa , Montalvo Welby , Kim Myoungjoo , Reiner Steven , Al-Shamkhani Aymen , Sun Joseph , Allison James 
Published: January 2023

Abstract
Following treatment with 4-1BB agonist antibody, a novel population of KLRG1+ T-cells infiltrate the tumors of mice. Compared to their KLRG1- counterparts, these T-cells express high levels of cytotoxicity associated genes in both the CD4 and CD8 lineages and also demonstrate enhanced tumor-specific killing in vitro. The phenotype of these KLRG1+ cells is dependent on high expression of the T-box transcription factor Eomesodermin (Eomes). The unique ability of α4-1BB to generate this phenotype stems from the expression of 4-1BB by antigen presenting cells (APC) which respond to its activation by producing cytokines which then drive the development of these Eomes+KLRG1+ T-cells. By analyzing changes in APC cytokine production in vivo, as well as by using a series of gene knockout mice we have begun to identify the factors necessary to generate this novel T-cell lineage. Among these factors, IL-27, IL-15, and IL-10 appear to be paramount. These T-cells represent a novel polarity we have termed ThEO (CD4) and TcEO (CD8) which resolves multiple questions associated with 4-1BB activation including how 4-1BB enhances tumor-specific cytotoxicity, and how 4-1BB can promote tumor immunity while repressing autoimmunity. Understanding the nature of this novel lineage of highly tumoricidal T-cells in both tumor and pathogen-specific immunity may provide critical information for converting sub-optimal anti-tumor responses to therapeutically successful ones.
Macrophage phenotypes influence lung cancer migration (P2221)
Authors: Rohrbach Timothy , Deshane Jessy , Steele Chad , Willey Christopher 
Published: January 2023

Abstract
Background: Lung cancer is the leading cause of cancer mortality. Studies have demonstrated that high macrophage density correlated with high microvessicle density and poor patient prognosis. Tumor associated macrophage are believed to predominantly possess an alternatively activated phenotype (M2). Hallmarks of this population include pro-angiogenesis, wound repair and extracellular matrix degradation. We investigated the role macrophage play in lung cancer migration. Methods: Human lung cancer lines A549, H1299, H1792, H1975 & H1650 were used. Murine bone marrow differentiated macrophages were stimulated with IFN-γ or IL-4 to achieve classically activated (M1) and M2 populations. Conditioned media (24 h) was collected and used in migration assays. Migration was assessed using BD 24 well FluoroBlok cell culture inserts. Results: qRT-PCR showed that stimulated M1 had a 344 fold increase (p&lt;0.01) of iNos and stimulated M2 had a 39 fold increase (p&lt;0.01) in Arg-1. Migration increased 20% (p&lt;0.01) in A549 cells when cultured in M2 conditioned media. However, when macrophage and lung cancer cells were co-culture, migration of H1299 and H1650 increased by 82% (p&lt;0.01) and 184% (p&lt;0.01) respectively. Conclusions: Our studies suggest that macrophage produce cytokines that influence the migratory abilities of lung cancer cell lines.
Control of T cell fates and immune tolerance by p38α signaling in mucosal dendritic cells (P3177)
Authors: Huang Gonghua , Wang Yanyan , Chi Hongbo 
Published: January 2023

Abstract
Dendritic cells (DCs) bridge innate and adaptive immunity. Our previous studies have shown that DCs employ the intracellular p38 and MKP-1 signaling axis to instruct T cell lineage choices and T cell-dependent autoimmune and infectious diseases (Huang et al. Immunity 2011; Huang et al. Nature Immunology 2012). Aside from launching protective adaptive immunity, DCs also play a crucial role in maintaining immune tolerance. To further explore the intracellular signaling pathways that program DCs to promote tolerogenic responses, we used a combination of approaches including mouse genetics, cellular immunology and biochemistry, as well as models of immune tolerance. We found that p38α signaling in mucosal DCs reciprocally regulated the differentiation of anti-inflammatory induced regulatory T (iTreg) cells and proinflammatory Th1 cells from naïve precursors, and promoted mucosal tolerance. Deficiency of p38α in mucosal DCs inhibited the generation of iTreg cells while promoting Th1 cell development in a TGF-β-dependent manner. Consequently, loss of p38α in DCs prevented induction of mucosal tolerance in vivo. Moreover, p38 signaling was constitutively activated in mucosal DCs and p38α activity was required for the expression of retinoid acid-metabolizing enzymes and imprinting gut homing receptors on responding T cells. Our studies identify a key mechanism of DC-mediated coupling of T cell differentiation and trafficking that orchestrates mucosal immune tolerance.
CD4+Foxp3+CD25+ regulatory T cells differentiate into IL-17-producing cells and promote immunopathology during Chlamydia genital tract infection (P3211)
Authors: Wang Jun , Moore-Conners Jessica , Halperin Scott 
Published: January 2023

Abstract
CD4+FoxP3+CD25+ regulatory T cells (Tregs) have been shown to promote de novo Th17 differentiation and to themselves convert into IL-17-producing cells in certain inflammatory settings. However, whether Tregs can potentiate IL-17/Th17 responses to intracellular bacterial infection has not been established. Using a murine model of Chlamydia, we found that Tregs produced IL-17 upon Chlamydia infection and promoted IL-17 production by conventional CD4+ T cells in vitro. Correspondingly, in vivo depletion of Tregs by anti-CD25 antibody dramatically reduced the induction of IL-17-producing CD4+ T cells during Chlamydia genital tract infection. Consistent with reduced IL-17 responses, Treg-depleted mice displayed striking amelioration of neutrophil infiltration and pathology in genital tract tissue relative to control mice, despite comparable bacterial burden throughout the course of infection. Collectively, our data demonstrate an important role for Tregs in promoting IL-17/Th17 responses during intracellular bacterial infection.
Goblet cells deliver luminal retinoids and imprint CD103+ lamina propria dendritic cells (P3223)
Authors: McDonald Keely , Wheeler Leroy , Knoop Kathryn , Miller Mark , Newberry Rodney 
Published: January 2023

Abstract
The intestinal lamina propria (LP) underlies the villous epithelia and contains a large population of CD103+ myeloid DCs. CD103+ LP-DCs generate the vitamin A metabolite all-trans retinoic acid (ATRA) and promote intestinal type responses including generating Foxp3+ T regulatory cells, imprinting gut homing expression on lymphocytes, and facilitating IgA production. In vivo studies demonstrated that luminal retinoids from the diet or bile are required to condition intestinal LP-DCs to generate ATRA. How luminal retinoids confer this capacity is not known. Goblet cell associated antigen passages (GAPs) provides a portal for CD103+ LP-DCs to acquire soluble luminal substances and goblet cell (GCs) proteins, suggesting a role for GCs and GAPs in imprinting CD103+ LP-DCs. Using an in vivo two-photon (2P) imaging approach, we found that GAPs delivered luminal retinoids and the enzyme required to metabolize pro-vitamin A to LP-DCs. In the absence of GCs, LP-DCs are not imprinted with ALDH activity. We observed that LP-DCs express CCR6, which was required for LP-DCs to associate with the small intestine epithelium. CCR6 deficient LP-DCs do not acquire GC proteins or luminal antigens, do not become imprinted with ALDH activity, and are impaired at inducing ATRA dependent events. These findings demonstrate that GAPs deliver luminal retinoids and the enzymes required to metabolize these retinoids to CD103+ LP-DCs, and accordingly play a critical role in imprinting CD103+ LP-DCs.
Modulation of intestinal macrophages for control of Type 1 diabetes (P3183)
Authors: Acharya Nandini , Basu Sreyashi 
Published: January 2023

Abstract
We have previously reported that oral administration of Capsaicin (CP), the pungent component of chili peppers inhibits proliferation and activation of auto-reactive T cells and protects mice from development of Type-1 diabetes (T1D) in a dose dependent manner. Here, we demonstrate that orally administered CP leads to induction of CX3CR1+ macrophages specifically in lamina propria and in the pancreatic lymph nodes. CX3CR1+ macrophages also known as regulatory macrophages (Mregs) play a critical role in maintenance of immune homeostasis in the gut. Inflammation hampers the differentiation of monocytes into CX3CR1+ macrophages in the gut. However, the factors responsible for facilitating the differentiation into Mregs remain elusive. Using mice deficient in Vanilloid Receptor 1 (VR1), the receptor for CP, we report that VR1 is important for the differentiation of macrophages into Mregs, which subsequently play a key role in tolerance induction via the induction of immune-suppressive CD4+IL10+FoxP3- Tr1 cells. This process culminates in providing protection from T1D in NOD mice. This study elucidates how a common food additive, CP, can act as a potent immune-modulatory agent and ameliorate autoimmune disease like T1D.
Critical role for PGI2 in the regulation of IL-22 production by intestinal innate immune cells (P3191)
Authors: Simons Bryan , Ferrini Maria , Jaffar Zeina , Roberts Kevan 
Published: January 2023

Abstract
Our previous studies have shown that prostacyclin (PGI2) plays an important role in regulating mucosal inflammatory responses and the development of IL-17-producing innate T cells. Using mice lacking the PGI2 receptor, IP, we have investigated the role of this prostanoid in innate immune responses in the intestine. IL-22 belongs to the IL-10 family of cytokines and targets innate immune pathways due to the restricted expression of IL-22 receptors on innate cells critical to maintaining barrier function, such as epithelial cells. Our results revealed that IP receptor deficient mice (IP-/- mice) had a marked increase in intestinal IL-22 production by innate lymphoid cells, but a clear defect in IgA production. Importantly, the number of CD3-NKp46+ lymphoid cells was dramatically increased in the Peyer’s patch of IP-/- mice compared to wild-type animals and the cells produced high levels of IL-22 in response to IL-23 exposure. Concomitant with the enhanced IL-22 production, altered intestinal mucus production and reduced number of inter-follicular cells in the Peyer’s patch was observed in IP-/- mice compared to wild-type mice. Collectively, these results demonstrate that PGI2 plays a critical role in regulating IL-22 production and limiting NKp46+ lymphoid cell responses in the intestine. Since expression of IL-22 is induced in several human gut inflammatory conditions including Crohn’s disease, these findings may have implications in inflammatory bowel disease.
Enhanced apoptosis of NOD.H2h4 thyrocytes by low concentrations of iodide: an intrinsic susceptibility factor in iodide-accelerated thyroiditis? (P4148)
Authors: Kolypetri Panayota , Carayanniotis George 
Published: January 2023

Abstract
Enhanced iodide intake in NOD.H2h4 mice accelerates the onset and severity of spontaneous autoimmune thyroiditis (ISAT) via an unknown mechanism. In this study, we have tested two hypotheses: 1) that NOD.H2h4 thyrocytes exhibit increased susceptibility to iodide-mediated apoptosis vs that of thyrocytes from other strains of mice; and 2) that progression of ISAT is associated with a reduction in the number of Treg cells in lymphoid tissues. We report that NOD.H2h4 thyrocytes cultured in vitro for 24 hr with 1-16 μM of NaI exhibited total numbers of apoptotic cells (ranging from 7.2 -32.9% above background) which were significantly higher than similarly treated CBA/J thyrocytes (ranging from 1.5 - 6.3% above background) upon staining with fluorescent caspase inhibitors. In addition, we report that flow cytometry of Treg cells in thyroid-draining lymph nodes (7.6-9.9% of CD4+ cells) or spleens (18.5 -19% of CD4+ cells) of NOD.H2h4 Foxp3-gfp mice did not reveal a significant alteration in their frequency, 7, 11 and 15 days following the initiation of enhanced iodide-intake (0.05 % NaI in drinking water). These results indicate that ISAT is not associated with a decrease of Treg frequency in lymphoid organs during the initial stages of the disease but support the view that an intrinsic high susceptibility of NOD.H2h4 thyrocytes to iodide-mediated apoptosis may be one of the triggering factors in ISAT.