bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-kB is involved in abnormal BAFF signaling in peripheral monocytes of patients with primary Sjögren’s syndrome. (P6274)
Authors: Yoshimoto Keiko , Tanaka Maiko , Kojima Masako , Ogata Hideko , Suzuki Katsuya , Kameda Hideto , Abe Tohru , Takeuchi Tsutomu 
Published: January 2023

Abstract
Background and Purpose: We revealed that BAFF induced a robust increase in the production of IL-6 by monocytes from patients with primary Sjögren’s syndrome(pSS), and that the expression levels of a BAFF receptor (BR3) , NF-IL-6 and NF-kB2 were enhanced in pSS monocytes compared to the control. The purpose of this study is to elucidate the possible abnormalities of a BAFF signaling pathway in pSS monocytes. Materials and Methods: The expression level of BR3 on monocytes in whole blood from pSS patients or normal control was analyzed by FACS. Peripheral monocytes were stimulated with soluble BAFF (sBAFF), and the production of IL-6 by the cells was measured by ELISA. The expression levels of IKK-alpha and IKK-beta were analyzed by western blotting. Results and Discussion: FACS analysis showed that the expression level of BR3 was significantly elevated in pSS monocytes compared to the control. Interestingly, the expression level of BR3 on pSS monocytes was positively correlated with the amount of IL-6 produced by sBAFF-treated monocytes. Moreover, NF-kB activation inhibitor suppressed the IL-6 production by sBAFF-treated pSS monocytes in a dose-dependent manner. In addition, phosphorylation levels of IKK-alpha and IKK-beta in pSS monocytes were enhanced upon stimulation with sBAFF. These data suggest that sBAFF acts through BR3 to induce the expression of IL-6 in monocytes, and that IKK-alpha and IKK-beta are involved in the signal transduction pathway triggered by sBAFF.
Immunosurgical resection of host tissues mediated by a novel dendritic cell-based vaccine proficient in the promulgation of TH1 immunity by exploitation of the p43/sCTLA-4 axis (P4248)
Authors: Halpert Matthew , Cloud-Carstens Julienne , Collinson-Pautz Matthew , Liang Dan , Konduri Vanaja , Klump Sherry , Bhardwaj Ratan , Berens Michael , Paulter Robia , Spencer David , Levitt Jonathan , Decker William 
Published: January 2023

Abstract
The current understanding of TH1 polarization and the central role dendritic cells (DC) play in skewing such a response engender hope that DC-based vaccines may ultimately be capable of promoting therapeutic efficacy against recalcitrant pathogens and neoplastic self. However, to date the development of such a vaccine has been unsuccessful presumably because the full panoply of signals required for promulgation of bona fide TH1 immunity remains uncharacterized. Recently, our group demonstrated that synergistic loading of DC with homologous MHC class I and II antigens generates a powerful TH1 response significantly stronger and more specific than that generated by alternatively-loaded DC. Using this approach, we developed ‘TH1 DC’ vaccines against both autologous prostate and seminal vesicle (SV) in the wild type mouse. The data indicate that vaccines generated by homologous antigenic matching can overcome peripheral tolerance, producing a clinical result reminiscent of surgical resection. Translation of this platform to cancer immunotherapy has shown preliminary success against established tumors in inbred mouse models as well as spontaneous canine oligodendrocytomas. We demonstrate that these results are in part dependent upon the newly-characterized AIMp1(p43)/sCTLA-4 axis and comment upon the important role of this axis in the development of TH1 immunity as well as its applicability to cancer immunotherapy.
A novel quinazolin-derived reactive oxygen species-inhibitor suppresses influenza A virus-induced inflammatory mediators and leads to enhanced survival in mice (P4214)
Authors: Gangappa Shivaprakash , De La Cruz Juan , Ganesh Thota , Diebold Becky , Cao Weiping , Smith Susan , Taylor Andrew , Singh Neetu , Hofstetter Amelia , Kumar Amrita , Katz Jacqueline , Sambhara Suryaprakash , Lambeth J. David 
Published: January 2023

Abstract
Acute lung injury (ALI) and its more severe form acute respiratory distress (ARD) can result from infectious agents, including several strains of influenza A virus. Recent evidence suggests that excessive production of reactive oxygen species (ROS) is a major contributor to ALI caused by influenza. We evaluated the effects of TG6-44, a novel inhibitor of ROS production, in in vitro and in vivo models of influenza A virus infection. In vitro, using the monocytic cells (THP-1) and human PBMC infected with influenza A virus (X31), we found that TG6-44 treatment decreased virus-induced ROS and inflammatory markers in THP1 (IL6, IFNγ , MCP1, TNFα , MIP1β) and in PBMC (IL6, IL8, TNFα , MCP1). Also, in influenza A virus-infected THP1 cells, TG6-44 treatment led to a reduction in virus-induced cell death as evidenced by decreased Caspase3 activation, decreased proportion of Annexin V+/PI+ cells, and increased Bcl2 phosphorylation. Notably, TG6-44-treatment decreased the proportion of THP1 cells expressing viral nucleoprotein and delayed its translocation into the nucleus. Moreover, mice infected with a lethal dose of influenza A virus (PR8) and given TG6-44 had both reduced levels of virus-induced inflammatory markers in lungs and a higher survival rate compared to controls. Taken together, our results demonstrate anti-inflammatory and anti-infective effects of TG6-44, and suggest ROS-inhibitors as valuable adjunct therapeutics to reduce ALI/ARD caused by influenza A virus infection.
Nanolipoprotein delivery enhances immunostimulatory properties of innate immune agonists and provides protection against lethal influenza challenge (P4218)
Authors: Weilhammer Dina , Alam Shabnam , Blanchette Craig , Fischer Nicholas , Loots Gabriela , Corzett Michele , Thomas Cindy , Hwang Mona , Lychak Cheri , Sant Andrea , Rasley Amy 
Published: January 2023

Abstract
Therapies targeting the innate immune system have the potential to provide transient, non-specific protection from a variety of infectious organisms. As such, we have employed a nanolipoprotein (NLP) platform to enhance the efficacy of synthetic innate immune agonists. NLPs are discoidal, nanometer-sized particles comprised of self-assembled phospholipid membranes and apolipoproteins. We demonstrate that the synthetic Toll-like receptor (TLR) ligands monophosphoryl lipid A (MPLA) and CpG oligodeoxynucleotides (CpG ODNs) can be readily incorporated into NLPs. Further, conjugation of both MPLA and CpG ODNs to NLPs significantly enhances their immunostimulatory profiles in vivo compared to administration of agonists alone. Specifically, conjugation to NLPs promotes agonist trafficking to secondary lymphoid organs, enhances and prolongs stimulation of innate immune cells, significantly increases cytokine production, and enhances upregulation of myriad immunoregulatory genes in vivo. Importantly, enhancement of cytokine production by agonists conjugated to NLPs was also observed in primary human dendritic cells. Strikingly, BALB/c mice pretreated with NLP-CpG constructs prior to a lethal influenza challenge were protected from weight-loss induced death, whereas pretreatment with CpG alone had no effect on survival. Taken together, these data suggest that NLP:agonist conjugates potentially represent a novel therapeutic measure against emerging pathogens.
pSTAT3: A target biomarker to study the pharmacology of the anti-IL 21R antibody ATR-107 in human whole blood (P4194)
Authors: Zhu Ming , Pleasic-Williams Susan , Lin Tsung , Wunderlich David , Cheng John , Masferrer Jaime 
Published: January 2023

Abstract
IL-21 has been shown to play an important role in autoimmune diseases. ATR-107 is an antibody which directly targets the IL-21 receptor. To aid the clinical development of ATR-107, there is a need for understanding the mechanism of action of this antibody when assessing target engagement in human subjects. To determine ATR-107 biological activity and potency in human blood, its inhibitory function against IL-21 induced STAT3 phosphorylation in human peripheral T and B cells was measured. The data show that IL-21 induces STAT3 phosphorylation in a dose-dependent manner, consistent with its translocation to the nuclear. Using a flow cytometry based functional whole blood assay, the data also show that ATR-107 is a potent IL-21 pathway inhibitor. It competes with IL-21 for receptor binding in a competitive manner, but once it binds to the receptor it behaves like a non-competitive inhibitor, most probably due to the long observed koff. The dose-dependent inhibition observed with ATR-107 correlates inversely with the levels of receptor occupancy, both in ex vivo whole blood assays and directly in human blood when ATR-107 was given to healthy volunteers. Altogether, IL-21 induced pSTAT3 in T and B cells can be used as a biomarker to evaluate the target engagement of ATR-107 in human whole blood. The non-competitive feature of this antibody reveals by pSTAT3 assay may help with the translation of preclinical information and dose selection towards ATR-107 clinical efficacy.
SIGN-R1 confers susceptibility to West Nile Virus encephalitis (P6036)
Authors: Chandran Ramakrishna , Srivastava Ruchi , Cantin Edouard 
Published: January 2023

Abstract
DC-SIGN is a critical determinant of susceptibility to flaviviral infections. To study its role in immunity to West Nile Virus (WNV), we used mice that lacked the murine homolog SIGNR1. Following infection with a lethal dose of WNV, knockout (KO) but not wildtype (WT) mice were resistant to WNV; all WT mice succumbed by day 9 pi. CNS inflammation in WT and KO mice was similar. CD45high infiltrates in brains were similar at day 6-8 pi; macrophages and DCs were predominant in both KO and WT mice at day 6 pi but Ly6Chigh inflammatory macrophages was significantly increased in WT compared to KO brains (45% Vs 23%). T cell infiltrates were increased in WT compared to KO brains at day 8 pi, yet they did not protect. Analysis of T cell activation revealed increased CD62Llow CD44high effector CD4+ (40% Vs 10%) and CD8+T cells (35% Vs 5%) in the spleens of KO compared to WT mice. Enhanced T cell activation was supported by an increase in IFN-γ secreting T cells in the KO spleen. Higher levels of PD-1+ CD4+ and CD8+ T cells observed in WT compared to KO spleens possibly contributed to the reduced activation. Treatment of WT mice with a blocking mAb 22D1 and an RNA aptamer selected for binding to SIGNR1 that transiently reduces surface SIGNR1 expression significantly protected mice from mortality. These data suggest that SIGN-R1 plays an inhibitory role in activating WNV specific T cells and is a potential target for immunotherapeutic approaches for WNV and other flaviviral infections.
Deletion of Bim compromises the quality of CD8 T cell memory after acute infection (P6060)
Authors: Sharma Shalini , Sturm Oliver , Milasta Sandra , Dillon Christopher , Green Douglas , Thomas Paul 
Published: January 2023

Abstract
One important feature of T-cell memory formation is the process of cell death during the contraction phase of the immune response. CD8 T-cell contraction after acute infections is mediated by the intrinsic apoptosis pathway, regulated by the interaction of anti-apoptotic BCL2 with pro-apoptotic Bim. In a murine model of influenza A virus infection, we found that Bim-deficient animals experienced a total ablation of the CD8+ T cell contraction phase leading to the significant accumulation of antigen-specific cells. While these cells displayed typical memory phenotypes, in vivo adoptive transfer and in vitro functional studies show that Bim-deficient memory CD8 T cells are non-responsive to stimulation by antigenic peptides and fail to expand properly on secondary challenge, indicating an intrinsic defect of this spent effector population. These functional deficiencies begin to emerge even at the peak of the primary response. Taken together, these results demonstrate that efficient memory generation entails the generation of a distinct, productive memory lineage that is capable of evading Bim-mediated apoptosis.
Highly stable CD8 populations are maintained by systemic, low level division across multiple clones during MCMV memory inflation. (P6067)
Authors: Smith Corinne , Turula Holly , Snyder Christopher 
Published: January 2023

Abstract
Murine cytomegalovirus (MCMV) establishes a persistent/latent infection that induces a characteristic “memory inflation” of CD8 T cells specific for some viral epitopes. The inflationary CD8 populations are maintained at high numbers for life in spite of the fact that inflationary effectors turnover with a half-life of 45-60 days. The current model to describe memory inflation suggests that waves of memory CD8s divide in the lymph nodes to produce effectors that migrate to the tissues to control viral activity. We used an adoptive transfer of two congenically marked OT1 populations to show that, in spite of the constant turnover, two inflationary populations were maintained in parallel with minimal fluctuation over time. Likewise, within the endogenous antigen population, different clones identified by V-beta staining divided at a similar frequency. Division of antigen specific CD8s occurred at a low level systemically, including lymph nodes, spleen and non-lymphoid organs, as measured by Ki67 expression and BrdU incorporation. Although the frequency of division was the highest in draining lymph nodes, large numbers of dividing cells were still found in non-lymphoid organs, even when lymphocyte egress was blocked from lymph nodes with FTY720 treatment. These results suggest that inflationary populations are maintained by systemic, stable, low-level division across multiple clones and that division is not restricted to small numbers of cells dividing in the lymph nodes.
Increased frequency of Tim-3+ T cells is associated with symptomatic WNV disease clinical outcome (P6085)
Authors: Lanteri Marion , Diamond Michael , Govero Jennifer , Pinto Amelia , Law Jacqueline , Chew Glen , Wu Shiquan , Niki Toshiro , Inglis Heather , Hirashima Mitsuomi , Busch Michael , Norris Philip , Ndhlovu Lishomwa 
Published: January 2023

Abstract
After a five-year period of steady annual cases, the 2012 West Nile virus (WNV) season was marked by a 4-fold resurgence with 5387 diagnosed infections, 2734 neuroinvasive cases and 243 deaths. Currently, no treatment or approved human vaccine is available for WNV infection. Understanding factors contributing to anti-WNV immunity and protection is therefore mandated. The present study investigates the surface expression patterns of negative T cell regulatory molecules over the course of WNV infection in a cohort of 32 WNV+ blood donors enrolled in longitudinal follow-up after initial WNV RNA+ blood donation (index) in those with asymptomatic (n=24) or symptomatic (n=8) disease outcome. We observed increased frequencies of Tim-3+CD4+ T cells during acute WNV infection (&lt;90 days post-index) compared to uninfected controls (GEE P&lt;0.0001). WNV+ donors had elevated frequencies of Tim-3+PD-1+ events in CD4+ and CD8+ T cells (P&lt;0.05). Frequencies of Tim-3+ events in CD4+ and CD8+ T cells were higher in symptomatic than in asymptomatic subjects in the acute phase of infection (P=0.0009 and 0.033 on day 14 post-index, respectively), and symptomatic subjects had higher frequencies of Tim-3+CD4+ T cells throughout infection (GEE P&lt;0.005). Our study highlights key mechanisms of immune vulnerability and reveals that T cell negative regulation is linked to symptomatic WNV disease and may serve as a novel target for improving protective responses or dampening inflammation and symptoms.
Induction of pathogenic Th17 cells by inducible salt sensing kinase SGK1 (P1145)
Authors: Wu Chuan , Yosef Nir , Thalhamer Theresa , Zhu Chen , Xiao Sheng , Kishi Yasuhiro , Regev Aviv , Kuchroo Vijay 
Published: January 2023

Abstract
Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens and induction of multiple autoimmune diseases. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions. IL-23 has been shown to reinforce the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R). However, the molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions is unclear. Here we used unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1) is critical for regulating IL-23R expression and for stabilizing the Th17 cell by deactivation of Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and homeostasis. We show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is critical for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation.
Characterization of the in vivo function of RGC-32 in T-cells (P1151)
Authors: Tegla Cosmin , Cudrici Cornelia , Nguyen Vinh , Danoff Jacob , Vlaicu Sonia , Rus Violeta , Badea Tudor , Rus Horea 
Published: January 2023

Abstract
We have previously shown that RGC-32 is involved in cell cycle regulation in vitro. To define the in vivo role of RGC-32, we generated RGC-32 knockout mice. These mice develop normally and do not spontaneously develop overt tumors. To assess the effect of RGC-32 deficiency on cell cycle activation in T cells we determined the proliferation rate of CD4 and CD8 from spleens of RGC-32-/- mice compared to wild type (WT) mice. CD4 T cells from RGC-32-/- mice display a significant increase in 3H-thymidine incorporation when compared with WT mice after stimulation with anti-CD3/anti-CD28. In addition, both CD4 and CD8 T cells from RGC-32-/- displayed a significant increase in the proportion of proliferating Ki67+ cells, indicating that in T cells, RGC-32 has an inhibitory effect on cell cycle activation. Furthermore, Akt and FOXO1 phosphorylation induced in CD4 from RGC-32-/- were significantly higher indicating that RGC-32 inhibits cell cycle activation by suppressing FOXO1 activation. To further examine the effect of RGC-32 on T cell functions we investigated the effect of RGC-32 on T regulatory (Treg) cells differentiation. A significantly lower percentage of CD4+ FoxP3+ Treg cells was found in unstimulated cells from RGC-32-/- compared to WT mice. Significantly fewer CD4+ FoxP3+ Treg cells are induced by TGF-β in RGC-32-/- compared to WT mice. Thus, RGC-32 is involved in controlling cell cycle in vivo, and in addition seems to play a role in the differentiation of Treg cells.
mTOR regulates CD4 and CD8 effector T cell differentiation via serum- and glucocorticoid-regulated kinase 1 (P1161)
Authors: Heikamp Emily , Patel Chirag , Collins Sam , Waickman Adam , Scharma Archna , Naray-Fejes-Toth Aniko , Fejes-Toth Geza , Sen Jyoti , Horton Maureen , Powell Jonathan 
Published: January 2023

Abstract
The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of T cell differentiation. mTOR integrates various signals in the immune microenvironment, including costimulatory ligands, cytokines, and the availability of nutrients to determine the outcome of T cell differentiation. Recently, we identified the serum- and glucocorticoid-regulated kinase 1 (SGK1) as a downstream target of mTORC2 that is a critical regulator of CD4 effector differentiation into Th1 and Th2 subsets. Specifically, SGK1 promotes Th2 differentiation by negatively regulating the NEDD4-2 E3 ligase mediated destruction of JunB. Simultaneously, SGK1 represses the production of IFN-γ by controlling the expression of the long isoform of TCF-1. Consistent with these functions, mice lacking SGK1 specifically in T cells fail to generate a Th2 response and are resistant to experimentally induced asthma. Likewise, such mice generate robust levels of IFN-γ in response to vaccines and more readily reject tumors. In addition, loss of SGK1 in CD8 T cells promotes memory differentiation by regulating the expression of CD127, CD62L, and eomesodermin. In summary, our findings reveal a novel role for SGK1 as an essential component of the mTOR pathway that guides differentiation of both CD4 and CD8 T cells. Targeting SGK1, therefore, may be a useful strategy for fine-tuning immune responses by manipulating T cell differentiation.
Androgens modulate anti-tumor immunity through interference with the T lymphocyte differentiation program (P1169)
Authors: Arredouani M. Simo , Kissick Haydn , Dunn Laura , Sanda Martin 
Published: January 2023

Abstract
Androgen modulation of immunity to tumor antigens have implications on designing novel prostate cancer immunotherapy regimens. However, the mechanisms governing androgen action are largely unknown. Herein we compared mouse castrate and non-castrate CD4 T cell transcriptomes and revealed major perturbations in gene regulation. Ingenuity pathway analysis identified dysregulations in key pathways, including Th cell differentiation, TCR signaling, Interferon signaling, and p38 MAPK signaling. Interestingly, nearly half of the genes that constitute the T cell differentiation pathway were affected. These genes include key transcription factors such as STAT1, Tbet, Foxp3, ROR-γ, costimulatory molecules CD40L and ICOS, and T helper cytokines such as IFN-γ, IL-17, TNF-α, and IL- 2. Transcription factors driving Th1 and Th17 differentiation as well as Th1 and Th17 cytokines and costimulatory receptors were upregulated. More CD4 T cells from castrated mice produced IFN-γ than did non-castrated ones. Conversely, exposure of activated CD4 T cells to IL-12 in the presence of androgens inhibited IFN-γ production and reduced Th1 differentiation genes like T-bet and IL-12-Rβ. This was concurrent with inhibition of STAT4 phosphorylation and upregulation of Ptpn22 and Ptpn1, both of which exhibit the ability to dephosphorylate STAT proteins. This suggests androgens’ negative effects on Th1 differentiation might be partly induced through Ptpn22- and Ptpn1-dependent dephosphorylation of STAT4.