bluuebunny/crossref_metadata_2025_split huggingface dataset:
Title: HMGB1 both enhances and blocks myeloid-derived suppressor cell potency Katherine H. Parker, Suzanne Ostrand-Rosenberg Department of Biological Sciences, University of Maryland Baltimore County, Baltimore MD 21250 (162.40)
Authors: Parker Katherine , Ostrand-Osenberg Suzanne 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in individuals with cancer and inflammation and play a pivotal role in tumor immunity by suppressing T-cell activation and secreting proinflammatory molecules. MDSC potency is mediated by immune suppressive factors such as inducible NO synthase (iNOs), arginase, and reactive oxygen species (ROS). MDSC also impair tumor immunity through crosstalk with macrophages in which IL-10 production increases while IL-12 production decreases, causing a shift in innate and adaptive immunity towards a type 2 tumor-promoting phenotype. Nuclear protein, High Mobility Group Box1 (HMGB1) is the second most abundant protein within a cell and is released from myeloid cells as a danger response to sepsis, infection, or arthritis. It’s release promotes inflammatory responses. HMGB1 signals through a multitude of receptors including TLR4 and RAGE, which are expressed by MDSC. In contrast to other inflammatory mediators which increase MDSC potency, HMGB1 reduced the suppressive mechanisms of TLR4-\- and wildtype MDSC, by reducing ROS in TLR4-\- MDSC and iNOs levels in wildtype MDSC. Glycyrrhizin, an HMGB1 inhibitor, decreased IL-10 in co-cultures of macrophages and MDSC. These findings suggest that HMGB1 plays both anti- and pro-inflammatory roles in regulating MDSC suppressive activity.
Total body irradiation enhances the anti-tumor efficacy of adoptively transferred CD8+ T cells stimulated ex vivo with IL-12 (162.41)
Authors: Johnson C. Bryce , Cloud Colleen , Rubinstein Mark , Cole David 
Published: January 2023

Abstract
Stimulation of T cells with IL-12 improves their cytolytic capabilities and ability to persist in vivo. Despite these enhanced functional characteristics, we have found that these cells can only eliminate established tumors in mice preconditioned with cyclophosphamide (CTX). While this result demonstrates the importance of lymphodepletion in adoptive cell transfer (ACT) regimens, it is unclear if other forms of lymphodepletion would also enhance the efficacy of IL-12 primed cells. Since the most successful lymphodepleting regimen in metastatic melanoma clinical trials uses total body irradiation (TBI), we sought to determine if TBI preconditioning combined with ACT of IL-12 stimulated pmel-1 CD8+ T cells might be similarly synergistic. When we adoptively transferred pmel-1 CD8+ T cells primed with antigen and IL-12 (pmelIL-12) into mice preconditioned with TBI, we saw significantly elevated numbers of donor T cells compared with mice adoptively transferred with pmel-1 CD8+ T cells primed with antigen alone (pmelsham). Importantly, the increase in donor T cell numbers seen with the combination of TBI + pmelIL-12 translated to significant delays in melanoma outgrowth. Strikingly, the addition of pmelsham to TBI preconditioning resulted in no improvement in anti-tumor immunity compared to TBI alone. Thus both CTX and TBI host preconditioning greatly enhance the anti-tumor efficacy of transferred T-cells stimulated with IL-12.
Gut commensal bacteria promote anti-tumor innate immune responses in distant tumors after immunotherapy and chemotherapy (162.5)
Authors: Iida Noriho , Stewart Charles , Goldszmid Romina , Dzutsev Amiran , Trinchieri Giorgio 
Published: January 2023

Abstract
Experimental evidence in models of autoimmunity and infection indicated that systemic innate and adaptive immune responses are influenced by gut commensal bacteria and impaired by treatment with antibiotics. This study aimed to determine the effect of commensal flora on tumor-associated inflammation and responsiveness to immunotherapy and immunogenic chemotherapy. To deplete the gut commensal flora, C57BL/6 mice were administered an antibiotic cocktail including neomycin, vancomycin and imipenem in the drinking water, resulting in a 3-log reduction in fecal bacteria. In mice bearing subcutaneous MCA38 colon carcinoma or B16 melanoma, this antibiotic treatment suppressed immunotherapy-induced tumor necrosis following intratumoral CpG treatment in combination or not with systemic anti-IL-10R antibody injection. TNF is a key effector molecule for tumor destruction in CpG-based therapy. Antibiotic-treated mice showed reduced frequency of tumor-infiltrating TNF-producing myeloid cells after therapy. Administration of single antibiotics revealed that tumor TNF production correlated with the remaining number of gut bacteria. Oral administration of LPS restored TNF production in antibiotics-treated mice. Finally, the chemotherapeutic effect of the immunogenic cytotoxic drug oxaliplatin was impaired in antibiotic-treated mice. Altogether, these results suggest that optimal immunotherapeutic and chemotherapeutic responses against cancer may require an intact commensal flora.
Antigen persistence regulates the functional characteristics and stability of secondary Th1 responders (163.10)
Authors: Jay David , Kim Chulwoo , Williams Matthew 
Published: January 2023

Abstract
CD4+ memory T cells exhibit a skewing towards high functional avidity during memory maintenance. We find that heterologous rechallenge of LCMV-induced CD4+ memory T cells from LCMV-immune mice with a recombinant Listeria monocytogenes that secretes the LCMV-derived glycoprotein peptide GP61-80 (Lm-gp61) preserves the high functional avidity of secondary Th1 effector cells and their subsequent stability within the memory pool. Conversely, adoptive transfer of CD4+ memory T cells into naïve mice prior to rechallenge results in a loss of functional avidity by secondary Th1 effector cells and poor maintenance of secondary memory. Loss of function is not due to the transfer itself, as transfer into LCMV-immune hosts allows secondary Th1 effector cells to maintain their enhanced function after Lm-gp61 challenge. LCMV-immune mice clear an Lm-gp61 infection more quickly than naïve mice, suggesting that the infectious environment of the secondary challenge is critical for the acquisition of secondary Th1 effector function. Artificially extending the inflammatory response alone following secondary challenge does not adversely affect the functional avidity of CD4+ memory T cells into LCMV-immune recipients. Instead, our findings indicate that upon rechallenge, secondary Th1 effector and memory cells are exquisitely susceptible to functional fine-tuning based on the persistence of infectious antigen.
T helper 17 cell lineage commitment is dictated by DC populations resident in priming tissues (163.23)
Authors: Hu Wei , Troutman Ty , Pasare Chandrashekhar 
Published: January 2023

Abstract
Activation of pattern recognition receptors on dendritic cells (DCs) and macrophages leads to secretion of cytokines that control activation and differentiation of CD4 T cells. While IL-12 is critical for Th1 lineage development, IL-6 and TGF-β play an important role in differentiation of Th17 cells in vitro. IL-1 has also been implicated in regulating Th17 differentiation. In the present study, we examined the relative contribution of IL-6 and IL-1 for in vivo Th17 differentiation and found that requirements for Th17 polarization depend entirely on the site of priming. We found that IL-6 plays a critical role in Th17 lineage priming in the skin and the mucosal tissue such as the gut and the lung, but is completely dispensable for Th17 priming in the spleen. IL-1 is however necessary for Th17 priming in all tissues. We discovered that differential cytokine requirements for Th17 lineage commitment are guided by differential population of DCs resident in different tissues. We found that CD103+ DCs that are present in the skin and intestinal lamina propria, but not in the spleen, favor the generation of iTreg cells while suppress Th17 priming, and IL-6 is required to overcome the effects of CD103+ DCs. Th17 lineage commitment is therefore differentially regulated in systemic and mucosal immune systems. Further work will focus on the dynamic regulation of CD103+ DC by the intestinal microbiota, and the role of CD103+ DCs in controlling intestinal immune homeostasis.
Detrimental effects of T regulatory cell-promoting IL-2-anti-IL-2 complexes in staphylococcal toxic shock syndrome. (164.13)
Authors: Rajagopalan Govindarajan , Tilahun Ashenafi 
Published: January 2023

Abstract
Menstrual or non-menstrual toxic shock syndrome (TSS), caused by the superantigen exotoxins of Staphylococcus aureus or Streptococcus pyogenes, is characterized by a robust activation of the immune system, systemic cytokine/chemokine storm, multiple organ failure and possibly death, if not treated promptly. We tested whether increasing the numbers of Treg in vivo by administration of IL-2-anti-IL-2 complexes (IL2C) could be beneficial in TSS. Administration of IL2C [prepared by incubating 1µg of IL-2 (Peprotech) and 5µg anti-IL-2 (eBioscience, clone-JES6-1A12) in a total 200 µl at 37oC for 30 min] on days 0, 1 and 2, caused a 3 to 4-fold increase in CD4+CD25+FoxP3+ Treg numbers in the spleens of HLA-DR3 transgenic mice by day 5. However, upon challenge with staphylococcal enterotoxin B (SEB, 50µg), compared to untreated HLA-DR3 transgenic mice, IL2C-treated mice produced significantly higher levels of IFN-γ (1714±1365 versus 6642±2253 pg/ml), MIP-1α (782±23 versus 2305±376 pg/ml,), MIP-1β, RANTES and TNF-α. SEB-induced mortality was also significantly increased in the IL2C treated group. While only 1/5 mice died in untreated group, 6/11 mice died in the IL2C treated group. In conclusion, even though administration of IL2C significantly increased the Treg numbers, such a treatment also increased their susceptibility to TSS. Hence, the benefits of T reg-promoting IL-2-anti-IL-2 complexes in TSS or related conditions need more stringent evaluation.
CD73-generated adenosine limits immunopathology during acute Toxoplasma gondii infection (164.17)
Authors: Mahamed Deeqa , Mills Jeffrey , Bynoe Margaret 
Published: January 2023

Abstract
As an obligate intracellular pathogen, the apicomplexan parasite Toxoplasma gondii elicits robust innate and adaptive immune responses that must be limited to prevent immunopathology. The breakdown of extracellular ATP to adenosine by the cell-surface enzyme CD73 plays an important role in the resolution of inflammation. The role of extracellular adenosine in the immune response to T. gondii infection has not been previously elucidated. In comparison to wildtype C57BL/6 mice, CD73-knockout mice infected with T. gondii by interperitoneal injection were highly susceptible to immune-mediated pathology, with significantly increased morbidity and mortality associated with marked infiltration of neutrophils and T cells into the peritoneal cavity. Peritoneal exudate cells from infected CD73KO mice generated higher levels of the inflammatory mediators nitric oxide, TNF-alpha, and IL1-beta, without enhanced parasite killing or clearance. The increased morbidity and mortality seen in CD73KO mice could be rescued by treating mice with the broad spectrum adenosine receptor agonist 5'-N-ethylcarboxamido adenosine. In addition, mice deficient in the adenosine receptor A2A were more susceptible to immunopathology during intraperitoneal infection with T. gondii compared to wildtype mice. Thus extracellular adenosine is a key molecule that regulates the immune response to an intracellular pathogen and promotes host survival.
The role of PKCθ in Francisella tularensis infection in mice (164.4)
Authors: Korzekwa Katy , Lovchik Julie , Wu Terry , Cannon Judy 
Published: January 2023

Abstract
Francisella tularensis is a facultative intracellular bacteria that causes tularemia in animals and humans. F. tularensis is highly virulent and can be lethal. T cells play a critical role in Francisella immunity. It has been shown that mice succumb to sublethal infections when all T cells are depleted; however individual subsets including CD4, CD8 and an unusual CD4-CD8-NK1.1- population can be protective. While T cells control infection by producing IFNγ and TNFα, other less well-characterized mechanisms also play a role. PKCθ is a protein kinase involved in T cell activation; PKCθ is important in IFNγ production and PKCθ-/- mice are protected against both TH1 and TH2 mediated diseases. To investigate the role of PKCθ in F. tularensis infection, we infected wild-type C57Bl/6 (WT) mice and B6.PKCθ-/- mice with a lethal dose of LVS (live vaccine strain) which is commonly used to study F. tularensis infection. While WT mice died within 2 weeks of infection, surprisingly, over 50% of the PKCθ-/- mice survived past 3 weeks. We found that infected PKCθ-/- mice had more CD4-CD8- T cells in liver and lung than WT mice. In contrast, PKCθ-/- mice had fewer CD4+ T cells in lymph nodes, spleen, liver, and lung. We found no difference in numbers of activated T cells in liver and lung of infected WT and PKCθ-/- mice. These results show that PKCθ may be important in the expansion of CD4+ and CD4-CD8- T cell subtypes and this shift in the absence of PKCθ may protect against LVS infection.
Combinational dasatinib and dendritic cell-based therapy improves therapeutic protection against melanoma growth (165.11)
Authors: Lowe Devin , Bose Anamika , Poudel Ravin , Taylor Jennifer , Storkus Walter 
Published: January 2023

Abstract
The solid tumor microenvironment (TME) is characterized by an abnormal vasculature system that promotes interstitial pressure, hypoxia, and acidity - diminishing the efficacy of standard single agent therapeutics. We hypothesize that combinational strategies that effectively target cancer cell growth and vasculature development will improve the clinical outcome of patients with malignant disease such as melanoma. To address this hypothesis, C57BL/6 mice were challenged subcutaneously with B16 melanoma cells and tumors allowed to progress 7 days. Animals were left untreated or received daily doses of dasatinib (an FDA-approved receptor tyrosine kinase inhibitor drug [TKI]) for one week with/without intratumoral injections of dendritic cells (DCs) transduced with IL-12 (DC.IL12) on days 7 and 14 post-tumor inoculation. Our pre-clinical results indicate synergistic benefits from co-treatment with dasatinib/DC.IL12 therapy based on the magnitude of anti-tumor immune responses promoted and the level of protective T cells recruited into treated tumor lesions. Dasatinib modified the aberrant TME in vivo by diminishing Treg (CD4+Foxp3+) and MDSC (CD11b+Gr1+) frequencies and reducing expression of markers associated with hypoxia, angiogenesis, and cancer stem cells. Overall, these data highlight the advantage of “sensitizing” the host using an anti-vasculature drug to instill an environment conducive to recruiting and sustaining vaccine-initiated anti-tumor immune effector cells.
Enhanced MHC Class I and II expression induced following staggered combination treatment of human tumor cells with Hsp90 inhibitors and Interferons. (165.16)
Authors: Kurnick James , Haggerty Timothy , Rose Lenora , Dunn Ian , Newton Estelle , Pandolfi Franco 
Published: January 2023

Abstract
We have previously shown that Hsp90 inhibitors (iHsp90) can enhance both differentiation antigens and MHC Class I in melanomas and gliomas. To extend these findings, we treated a series of tumors including cancers of the breast, cervix, osteosarcoma and lymphomas to examine the effects of iHsp90 on both Class I and II MHC. Class I MHC was enhanced in most tumors, but induction of MHC Class II antigens was NOT induced in MHC Class II-negative tumors. Since both Types I and II interferon’s (IFN) are known to enhance MHC antigen expression, we wished to determine they would synergize with iHsp90s. However, since iHsp90s can inhibit IFN-signaling, we varied the time of exposure of the tumor cells to the IFNs and iHsp90s to determine if we could circumvent the counteracting effects. While IFN-gamma stimulated strong Class II MHC expression, the simultaneous addition of iHSP90 largely prevented this MHC Class II expression. However, pretreatment for 24 hrs with IFN-gamma allowed iHsp90 to further enhance MHC Class II expression. Similarly, synergistic enhancement of MHC Class I expression was noted if either IFN-beta or IFN-gamma were added prior to addition of iHsp90. Staggering treatment with interferon’s and iHsp90s yielded strong induction of both Class I and II MHC antigens. As both IFN and iHsp90 increased differentiation antigens and MHC, the further increase in MHC expression from the drug combination could be of particular utility in cancer immunotherapy.
Effects of age on the immune response in baboons to the Y. pestis F1 vaccine antigen. (166.24)
Authors: Bonnel Caroline , Arteaga-Cortes Lourdes , Ench Yasmin , Leland M. , Dube Peter , Kraig Ellen 
Published: January 2023

Abstract
The ability to mount effective immune responses declines with age, which correlates clinically with decreased vaccine efficacy and increased susceptibility to infection and cancer. As a result, new vaccines should be tested for efficacy in older individuals. Towards this end, young (5-6 years of age) and old (17-22 years) baboons were immunized with the LcrV candidate vaccine antigen from Yersinia pestis. Surprisingly, older baboons had a strong humoral response [JI 181:109] suggesting either that the baboon immune system is less affected by aging or that LcrV acts like a recall antigen. Thus, a second Y. pestis vaccine antigen, the F1 protein, was tested; F1 is unique to this bacterial species and would be seen as a “new” antigen. The antibody response to F1 did decline with age, but the T cell response did not. Thus, an analysis of the effects of aging on T cell fine specificity was undertaken. T cell proliferation and IFN-γ ELISpots were used to map which of 32 overlapping synthetic F1 peptides stimulated T cells from the immunized baboons. A Th1 response was observed for a few individual animals in response to whole both F1 antigen and specific peptides. ELISpots specific for IL-4 and IL-5 cytokines are currently being used to follow Th2 cells specific for F1. Future efforts will focus on generating F1-specific T cell clones using herpesvirus papio transformed B cell lines as antigen presenting cells.
A novel human Neonatal Tissue Construct (NTC) models age-specific immune responses to Bacille Calmette-Guérin (BCG) vaccine (166.27)
Authors: Sanchez-Schmitz Guzman , Stevens Chad , Baecher-Allan Clare , Levy Ofer 
Published: January 2023

Abstract
Newborns have a distinct immune system that impairs immune responses to many conventional pediatric vaccines rendering them susceptible to preventable infections. Since birth is a reliable point of healthcare contact worldwide, effective single-dose birth immunization could help reduce global morbidity and mortality. However, vaccine development has been largely ad hoc and empiric. Modeling age-specific human immune responses could help predict safety and efficacy of adjuvants and vaccines targeting the newborn. Using human primary endothelial cells, human extracellular matrix, newborn monocytes and 100% autologous intact plasma we assembled the Neonatal Tissue Construct (NTC). In this tri-dimensional micro-vascular interstitium extravasated CD33+ monocytes autonomously differentiated into HLA-DRhigh CD86high and CCR7+ mature Dendritic Cells (DCs) in response to the live mycobacterial BCG vaccine known to be safe and effective at birth, and to induce effector T cell responses. BCG-pulsed NTC-derived DCs induced autologous naïve CD4+ T cell proliferation and activation (CD45RO+, TNF-α), as efficiently as DCs from an Adult Tissue Construct. While newborn and adult DC:T cell co-cultures secreted IL-2 and TNF-α in response to BCG, only newborn cells demonstrated constitutive IL-4 production and a marked impairment in IFN-γ production. In recapitulating neonatal responses to BCG, the NTC demonstrates its potential as a novel platform to study age-specific vaccine responses.
Interferon-γ-activated human leukocyte antigen-G gene expression in placenta-derived multipotent cells involves the epigenetic control and transcriptional regulation (167.12)
Authors: Chen Pei-Min , Hsu Pei-Ju , Wei Chung-Fan , Liu Ko-Jiunn , Sytwu Huey-Kang , Hsu Ping-Ning , Yen B. Linju 
Published: January 2023

Abstract
Placenta-derived multipotent cells (PDMCs) are progenitor cells isolated from the human term placenta with differentiation capacity for all three germ layers as well as strong immunomodulatory properties. The placenta is central to maintaining fetomaternal tolerance, and one of the most important immunomodulatory molecules involved is the human leukocyte antigen-G (HLA-G). HLA-G is a non-classical major hisotocompatibility complex (MHC) class I molecule which exhibits a restricted tissue-specific expression and exerts multiple immuneregulatory functions for maintaining the tolerance of placenta. We have shown that PDMCs can resist natural killer (NK) cell-mediated cytotoxicity by interferon-γ (IFN-γ)-induced surface HLA-G expression, suggesting that the expression of HLA-G may be involved the cis-acting epigenetic control and transcriptional regulation. Recently, we found that IFN-γ induces the expression of IFN regulatory factor 1 (IRF-1) and phosphorylation of STAT-1 in PDMCs. We speculate that the control of HLA-G in PDMCs involved not only the IFN-γ cis-acting regulatory elements including the IFN-stimulated response element (ISRE) and IFN-γ activation site (GAS), but also DNA-methylation which synergistically render the HLA-G gene promoter highly responsive to IFN-γ. Taken together, our results indicate that IFN-γ-activated HLA-G gene expression in PDMCs is involved the cis-acting epigenetic control and transcriptional regulation through JAK/STAT-1 signaling pathway.
Engagement of Glucocorticoid-induced leucine zipper (GILZ) with Infectious Bursal Disease virus (IBDV) VP4 suppresses type I interferon expression and enhances IBDV growth in host cells (168.13)
Authors: Zheng Shijun , Wang Yongqiang , Li Zhonghua , Li Xiaoqi , Cao Hong 
Published: January 2023

Abstract
Infectious Bursal Disease (IBD) is an acute, highly contagious and immunosuppressive avian disease caused by IBD virus (IBDV). Although IBDV-induced immuno-suppression has been well-established, the exact molecular mechanism for such induction is unclear. We report here that IBDV VP4 is an interferon-suppressor by interacting with the Glucocorticoid-induced leucine zipper (GILZ) in host cells. We found that VP4 suppressed the expression of type I interferon in HEK293T cells with Tumor Necrosis Factor(TNF)-α treatment or Sendai virus (SeV) infection, and this suppression could be completely abolished by knockdown of GILZ by siRNA. Furthermore, knockdown of GILZ significantly inhibited IBDV growth in host cells. Thus, VP4-induced suppression of type I interferon is mediated by interacting with GILZ, a protein that appears to inhibit cell responses to IBDV infection.