bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isorhapontigenin shows strong anti-melanoma cell activity, and induces anti-tumor immunity
Authors: Song Yinhong , Yu Zouzou , Tong Chenxi , Liu Mei , Jiang Xiaoling , Zeng Yan , Chen Changrong 
Published: January 2023

Abstract

Background
Melanoma is one of the deadliest forms of skin cancer, and its incidence has continued to rise during the past decade. Isorhapontigenin (ISO) is a new derivative of stilbene compound, isolated from Chinese herb Gnetum Cleistostachyum with capability of antitumor.

Purpose
The potential anti-melanoma activity, impact on genes’ expression, as well as the influence of immune response against melanoma of ISO were detected in our studies in order to clarify its anti-melanoma effect and the corresponding mechanism.

Methods
Cytotoxicity of ISO on melanoma cell line B16F10 was studied by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Cell cycle analysis by flow cytometry, annexin V staining, RT-qPCR and Western blot were used to elucidate the mechanism of action of ISO at the cellular level. The in vivo anti-tumor ability of ISO was measured in C57BL/6 mouse syngraft models.

Results
ISO induced dose-dependent inhibitory effect on the proliferation of B16F10 cell by arresting cells at G0/G1 phase promoting the apoptosis of the cell, which was associated with an increase in the Bax:Bcl-2 ratio and decrease in the proliferative-related genes CYCLIN D1 and SURVIVIN in vitro. In addition, ISO could inhibit the tumor immune escape by promoting the expression of MHC molecules on the membrane of tumor cells, and decreased the infiltration of Tregs and MDSCs which involved in suppressing the anti-tumor effects of immune system. On the other hand, ISO increased the infiltration of T cells, NK cells and NKT cells, which was able to enhance the anti-tumor immune response.

Conclusion
Taken together, these findings indicate that ISO may be useful as a treatment for Melanoma and thus warrants further investigation.
CD122-selective IL-2 complexes treat ovarian carcinomas and melanoma, alter Treg differentiation and induce more CD8+CXCR5+TCF-1+ stem T cells when combined with αPD-L1
Authors: Deng Yilun , Gupta Harshita B. , Drerup Justin Michael , Reyes Ryan Michael , Mendez Jenny , Zhang Xinyue , Padron Alvaro S , Garcia Myrna , Curiel Tyler J 
Published: January 2023

Abstract
Anti-tumor T cells (Teffs) engage IL2 largely through CD122, vs. CD25 for regulatory T cells (Tregs). In ID8agg ovarian cancer (OC), CD122-selective IL2 complexes (IL2c, made from CD122-blocking ab+IL-2), increased Teff numbers and functions as expected but unexpectedly reduced tumor Treg function, with near-complete tumor rejection in OC. IL2c reduced lineage specific molecules (e.g., Tbet) and cytokines (e.g., IFNg) in tumor Tregs, suggesting IL2c improves Treg differentiation, but not explaining IL2c-driven Treg defects. In vitro, IL-2 and IL-2c produced similar Treg numbers and Foxp3 from naïve CD4+T cells, with functional data pending. αPD-L1 improved IL2c efficacy for full tumor rejection in OC and B16 melanoma. Increased CD8+CXCR5+PD1+Tim3−TCF-1+stem-like T cells (CXCR5+) are associated with favorable αPD-1 or αPD-L1 outcome in mice and humans. IL2c + αPD-L1 markedly increased CXCR5+in B16 melanoma and to a lesser extent in OC. IL2c + αPD-L1 increased tumor CXCR5+perforin expression in B16 vs. either single agent. Injecting tumor-infiltrating CXCR5+into RagKO mice produced CXCR5+Tim3− and CXCR5−Tim3+cells confirming tumor CXCR5+stem cell properties. These data demonstrate several novel IL2c mechanisms to exploit in distinct cancers and treatment combinations. Ongoing work tests IL2c, αPD-L1 and combo treatment effects on CXCR5+ stemness and mechanisms for CXCR5+ induction, and mechanisms for IL2c-driven Treg dysfunction.
An engineered vaccine encompassing an MHC class I antigen presenting molecule induces self-reacting CTL in a setting of profound tolerance
Authors: Pease Larry R , Parks Christopher A , Kranz David , Barry Michael 
Published: January 2023

Abstract
Engineered antigen presenting molecules can promote allorecognition and activate CTL capable of recognizing weak or self-antigens in the context of self-MHC. Traditionally, allogeneic antigen presenting molecules differ from self MHC molecules in their interactions with the bound peptides and with TCR expressed in the immune repertoire to promote peptide dependent alloimmunity. Alloreactive T cells target their inducing alloantigens, as well as third-party alloantigens, but as a result of tolerance, generally not self-antigen presenting molecules. Certain residues located on the alpha-1/2 domains of class I antigen presenting molecules interface with TCR CDR loops and do not influence the nature or orientation of bound peptides. These residues are more conserved within and across species than are residues that determine peptide antigen binding properties. Class I variants designed with amino acid substitutions at key positions within the conserved helical structures at this MHC:TCR interface are found to provide strong activating signals to alloreactive CD8 T cells in the self tolerant immune repertoire. We demonstrate that CTL activated in this manner can break self-tolerance by reacting to self-peptides presented by native MHC. The ability to activate self-tolerant T cells capable of cross-reacting on self-peptide-MHC in vivo represents a novel approach for inducing autoimmunity, with possible application the development of cancer vaccines.
Single-cell RNA sequencing reveals different subsets of macrophage and dendritic cells in human skin
Authors: Xue Dan , Tabib Tracy , Morse Christina , Lafyatis Robert 
Published: January 2023

Abstract

Objective
Single-cell RNA sequencing(scRNA-seq) was performed to cells from whole human skin without pre-purifying to reveal the transcriptional landscape and heterogeneity of macrophages and dendritic cell (Mϕ/DC) subsets.

Methods
Single-cell RNA sequencing was implemented to ten enzymatically-digested human skin biopsies and analysis was performed with Seurat, then with gene ontology (GO) enrichment analysis and immunofluorescent staining.

Results
Upon scRNA-seq, 27869 cells from ten skin samples were analyzed in Seurat and 22 distinct clusters were identified using smart local moving clustering. One cluster highly specifically expressed MS4A4A, CD1C, HLA genes and other Mϕ/DC traditional markers, verifying as Mϕ/DC. Upon reanalysis of this cluster (988 cells), we identified three macrophage subsets, marked by high expression of CCR1, MARCO or TREM2; six dendritic cell subsets, marked by high expression of CXorf21, MCOLN2, CLEC9A, KIAA0101 or LAMP3 and one Langerhans cell subset. The KIAA0101 subset expressed a set of marking proliferation genes and all were in G2M phase, indicating represent a progenitor population. GO enrichment analyses indicated different putative functions of Mϕ/DC subsets. Then, the two major macrophage subsets could be defined immunofluorescently by CCR1 and MARCO double staining. And immunofluorescent staining of TREM2 and MS4A4A verified the existence of TREM2 macrophages.

Conclusion
Using scRNA-seq, we were able to uncover the transcriptional landscape and phenotypic heterogeneity of Mϕ/DC subsets in human skin, which will open up more opportunities to explore distinct immune cell populations and their roles in health and pathological conditions.
A single infection with a malaria parasite protects mice from lethal autoimmune glomerulonephritis
Authors: Amo Laura , Kole Hemanta K , Scott Bethany , Moore Ian N , Qi Cheng-Feng , Wu Juan , Wang Hongsheng , Bolland Silvia 
Published: January 2023

Abstract
The progression of autoimmune diseases such as Systemic Lupus Erythematous (SLE) can be altered by environmental factors, including parasitic infections. Epidemiological studies have shown a relative absence of SLE in West Africa (areas of endemic malaria), even though SLE is highly prevalent in populations of African descent living outside of Africa. We hypothesize that malaria infections might reduce the incidence of lupus. In the present work, we assess the effect of the non-lethal Plasmodium yoelii 17XNL in a well-characterized animal model of SLE (FcγRIIB−/−). Mice deficient in the inhibitory Fc receptor for IgG (FcγRIIB) develop spontaneous disease driven by the production of anti-nuclear autoantibodies, a broad immune activation, splenomegaly, anemia and lethal glomerulonephritis with a pathology similar to human SLE. We infected FcγRIIB−/− mice at 2 months of age with P. yoelii and followed the progression of autoimmune disease for 5 months. Infection with P. yoelii increased the titer of a broad range of autoantibodies, with concomitant immune-complex deposition and complement fixation in the kidney. While lupus-prone mice succumbed from renal disease detected by protein in urine, malaria-infected lupus-prone mice did not develop proteinuria or lethal disease. Infection with the parasite did not alter tolerance mechanisms leading to lupus but instead prevented end-point tissue pathology. P. yoelii infection seems to inhibit pathogenic leukocyte infiltration without affecting the autoimmune inflammation of glomeruli. These results indicate a possible route for lupus protection that specifically targets renal function, which remains a cause of the substantial morbidity and mortality in SLE patients.
Ikaros regulates chromatin landscape in mature B cells, and is critical for B cell tolerance
Authors: Rodriguez Princess D , Howell William , Amiel Eyal , Frietze Seth , Schjerven Hilde 
Published: January 2023

Abstract
The zinc finger transcription factor Ikaros plays central roles in the gene regulatory programs associated with proper B cell development. While mutations in the IKZF1 gene have been implicated in autoimmune disease and various B cell malignancies, the resultant epigenetic and transcriptional alterations in Ikzf1-mutated B cells remain largely unknown. We recently found in mouse models that deletion of the fourth zinc finger domain in the Ikzf1 gene (Ikzf1ΔF4/ΔF4) results in a B cell hyper-reactive (HR) phenotype. We hypothesized that Ikaros is required to establish and maintain an epigenetic program for co-stimulatory activation of B cells. To test this hypothesis, we have generated genome-wide transcriptome and chromatin-accessibility profiles of wildtype and Ikzf1ΔF4/ΔF4naïve splenic B cells following ex vivo co-stimulatory activation. We found that Ikaros mutant B cells have an overall similar accessible chromatin landscape as wildtype, but Ikzf1ΔF4/ΔF4B cells exhibit deregulated chromatin structure at inflammatory gene pathways linked to B cell growth and survival. To then explore the direct Ikaros targets we determined the Ikaros chromatin binding sites by Cleavage Under Targets & Release Using Nuclease (CUT&RUN) in wildtype B cells. Integration of gene expression and chromatin binding data indicates that Ikaros has a role in the repression of gene targets associated with cell proliferation and inflammation. Our data supports the model that Ikaros antagonizes NFkB actions at inflammatory gene pathways. Overall, our results reveal distinct mechanisms of Ikaros in the regulation of inflammatory genes in mature B cells and defines altered pathways that may be responsible for the HR phenotype of Ikaros-mutated B cells.
Multiple Myd88-dependent Toll-like receptor signaling pathways mediate inflammation in a mouse model of primary Sjögren’s syndrome
Authors: Kiripolsky Jeremy , Kasperek Eileen M , Yu Guan , Kramer Jill M 
Published: January 2023

Abstract
Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by exocrine gland dysfunction and immune hyperactivity. The adaptor Myd88 is critical for immune function, as most TLRs utilize Myd88 for signal transduction. Previous work by our group found Myd88 is required for pSS disease. Our objective was to identify the specific Myd88-dependent TLR pathways that mediate salivary and systemic inflammation. We used the pSS mouse model NOD.B10Sn-H2b/J (NOD.B10), Myd88-deficient NOD.B10 mice (NOD.B10Myd88−/−), and C57BL/10 controls. For all experiments we used female mice that were at least 26 weeks old, the age that NOD.B10 females display clinical disease. We isolated spleens from NOD.B10 mice and C57BL/10 controls and performed RNA-sequencing. We then harvested salivary tissue or spleens from NOD.B10, NOD.B10Myd88−/−, and C57BL/10 mice. We performed qPCR and flow cytometry to assess expression of Myd88-dependent TLRs. We cultured salivary tissue from NOD.B10 and NOD.B10Myd88−/− mice and performed cytokine arrays on the supernatants. Finally, we treated salivary tissue with a TLR4 inhibitor and quantified spontaneous IL-6 secretion. We identified dysregulation of numerous TLR-related networks in pSS splenocytes. We found upregulation of Myd88 dependent-TLRs in both the spleen and salivary tissue from NOD.B10 mice. Salivary tissue from Myd88-sufficient NOD.B10 females exhibited spontaneous secretion of IL-6, MCP-1 and TNFa, and this was diminished in NOD.B10Myd88−/− mice. Finally, TLR4 blockade reduced IL-6 secretion in NOD.B10 salivary tissue. Our preliminary data suggest Myd88-dependent pathways contribute to the inflammatory landscape in pSS, and inhibition of such will likely have therapeutic utility.
Regulation of plasmacytoid dendritic cells function via ER stress pathway
Authors: chaudhary vidyanath , Barrat Franck J. 
Published: January 2023

Abstract
Systemic sclerosis is a life-threatening autoimmune disorder which causes fibrosis and chronic inflammation. One of the hallmarks of systemic sclerosis is production of high levels of type I interferon, which plays a significant role in the activation of B cells for antibody production. Plasmacytoid dendritic cells (pDCs) are the key immune cells producing high levels of interferon in autoimmune diseases such as systemic sclerosis. There is evidence suggesting that the microscopic structure of pDCs shows abundant levels of endoplasmic reticulum (ER) in their cytoplasmic compartment. Besides this, studies in patients with autoimmune diseases show that ER stress is induced in the peripheral blood mononuclear cells(PBMCs). We have observed that induction of ER stress in pDCs isolated from the PBMCs of healthy individuals markedly reduces the production of cytokines in TLR9-induced pDCs. This indicates that ER stress might be involved in the regulation of pDCs function. Hence, it is intriguing to further study the underlying mechanisms of how activation of ER stress in pDCs may be involved in the pathogenesis of autoimmune diseases.
Small numbers of T cells specific to different myelin-antigens cooperate to induce autoimmunity in a murine model of multiple sclerosis
Authors: Robinson Rachel R , Rojano Elba M , Forsthuber Thomas 
Published: January 2023

Abstract
T cells play a crucial role in many autoimmune diseases including multiple sclerosis (MS). Despite this, mechanisms of peripheral tolerance and dysregulation of these mechanisms during autoimmunity remain elusive. Myelin-reactive T cells are present in the blood of both healthy controls and patients with MS and T cells from patients with MS react to many different myelin peptides. The strongest genetic risk factor for developing MS is the HLA-DRB1*1501 haplotype, indicating that peptide binding to this MHC aids in disease induction. It is unlikely and not supported by current human studies that patients exhibit large populations of T cells specific for a single myelin-antigen. In contrast, a quorum of 2–5 low avidity autoreactive T cells specific for one epitope might suffice to induce autoimmunity. We hypothesized that a quorum could be established and induce autoimmunity by small numbers of antigen-specific T cells recognizing different myelin antigen peptides, particularly in genetically susceptible individuals. We utilized wild-type C57BL/6 mice and transgenic mice expressing the human MHC HLA-DRB1*1501 allele to assess the effect of inducing experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis, with low numbers of different myelin peptide-specific T cells or myelin peptides at suboptimal doses. In this proof-of-principle study, we found that EAE can be initiated by the cooperation of small numbers of myelin peptide-specific T cells reactive against different myelin epitopes. The results support the hypothesis that a quorum of T cells could be reached by multiple antigen-specific T cells and could suffice to initiate autoimmune disease.
Clinicopathological and Prognostic Significance of CCR5/CCL5 axis in Hepatocellular Carcinoma
Authors: Singh Santosh Kumar , Mishra Manoj K , Lillard James W. , Singh Rajesh 
Published: January 2023

Abstract
Hepatocellular carcinoma (HCC) is one of the world’s most devastating malignancy which accounts for more than 90% liver cancer. The poor diagnosis of HCC lead’s scientists to search for novel treatment options to improve patient survival rates. There is accumulating evidence that chemokines and chemokine receptors (CCRs) contribute to tumor development and progression, as well as metastasis. Chemokine CCL5 (RANTES) has been reported to facilitate tumor progression and metastasis in various cancers, including liver cancer. However, the function of CCR5/CCL5 interaction in HCC proliferation and migration is poorly understood. Hence, the present study was undertaken to investigate the expression and role of the CCR5/CCL5 axis interface in the progression and invasiveness of HCC. In vitro study of liver cancer cell lines SNU387, PLC/PRF 5, and SK-HEP-1 showed higher expression of CCR5. Flow cytometry, RT-PCR, western blot, immunofluorescence techniques were used to quantify the expression of chemokine CCR5 and CCL5 in liver cancer cells. To determine the clinical significance of CCR5 expressed by HCC cell lines, a microarray of liver cancer tissues stained for CCR5 and CCL5 were analyzed. Our results show significantly (p&lt; 0.001) higher expression of CCR5 and CCL5 in cancerous tissues compared to normal liver tissues. Furthermore, in order to delineate the role of CCR5/CCL5 interaction in HCC cell proliferation and migration, we pre-treated the HCC cell lines with the Maraviroc (CCR5 antagonist) in presence of CCL5. This data demonstrates both biological and clinical significance of CCR5 and CCL5 expression that may contribute to HCC metastasis, thus inhibition of its axis could be a promising avenue to treat liver cancer.
Transcriptomic analysis of human IL-7 receptor alphalow and higheffector memory CD8+ T cells reveals an age-associated signature linked to influenza vaccine response in older adults
Authors: Park Hong-Jai , Shin Min Sun , Kim Minhyung , Bilsborrow Joshua , Mohanty Subhasis , Montgomery Ruth R , Shaw Albert , Yoo Sungyoung , Kang Insoo 
Published: January 2023

Abstract
Here we investigated the relationship of the age-associated expansion of IL-7 receptor alpha low (IL-7Rαlow) effector memory (EM) CD8+ T cells with the global transcriptomic profile of peripheral blood cells in humans. We found 231 aging signature genes of IL-7Rαlow EM CD8+T cells that corresponded to 15% of the age-associated genes (231/1,497) reported by a meta-analysis study on human peripheral whole blood from approximately 15,000 individuals, having high correlation with chronological age. These aging signature genes were the target genes of several transcription factors including MYC, SATB1, and BATF, which also belonged to the 231 genes, supporting the upstream regulatory role of these transcription factors in altering the gene expression profile of peripheral blood cells with aging. We validated the differential expression of these transcription factors between IL-7Rαlow and high EM CD8+ T cells as well as in peripheral blood mononuclear cells (PBMCs) of young and older adults. Finally, we found a significant association with influenza vaccine responses in older adults, suggesting the possible biological significance of the aging signature genes of IL-7Rαlow EM CD8+T cells. The results of our study support the relationship of the expansion of IL-7Rαlow EM CD8+ T cells with the age-associated changes in the gene expression profile of peripheral blood cells and its possible biological implications.
IL-2 Signals Program the Fate of Exhausted CD8 T cells
Authors: Kalia Vandana , Xiao Hanxi , Yuzefpolskiy Yevgeniy , Sarkar Surojit 
Published: January 2023

Abstract
The high affinity IL-2 receptor (IL-2Ra, CD25) is a key activation marker, which is transiently and heterogeneously expressed during the priming . While IL-2 signals are deemed critical for expansion of antigen-specific CD8 T cells, the role of IL-2 in programing the fate of exhausted CD8 T cells in vivo is poorly understood. Exhausted CD8 T cells are broadly divided into 2 subsets: one with brightest levels of inhibitory receptors such as PD-1, and lower mitochondrial spare respiratory capacity (SRC) – these cells are terminally exhausted and are largely unresponsive to PD-1 checkpoint blockade immunotherapy. The other subset has intermediate levels of inhibitory receptors and retains higher mitochondrial SRC – these are the clinically relevant cells that are highly responsive to PD-1 blockade. Based on the ability of IL-2 signals to drive glycolytic burnout in T cells, we hypothesized that the stochastic heterogeneity in in vivo assimilation of IL-2 signals during priming drives distinct CD8 T cell fates late during exhaustion. We sorted in vivo primed CD8 T cells based on their heterogeneity in CD25 expression, and adoptively transferred them into infection-matched chronically infected recipients. We observed that the exhausted CD8 T cells generated from CD25Hi donor cells phenotypically and functionally resembled terminally exhausted cells. Furthermore, knocking down the expression of CD25 or Special AT-rich sequence binding protein 1 (SATB1), which is known to regulate CD25 expression, resulted in better survival and function of exhausted CD8 T cells. Our data underscores the critical role of IL-2 signals in the exhaustion of CD8 T cells and has clinical significance in current combination checkpoint blockade immunotherapies.
IL-21 produced by CD4+ T cells drives differentiation of CD8+ T cells during polyomavirus encephalitis
Authors: Ren Heather , Mockus Taryn , Shwetank  , Lauver Matthew , Netherby Colleen , Jin Ge , Lukacher Aron 
Published: January 2023

Abstract
The demyelinating brain disease Progressive Multifocal Leukoencephalopathy (PML), caused by JC polyomavirus (JCV), is a life-threatening complication for patients with HIV/AIDS, hematologic malignancies, rheumatologic diseases, and those receiving long-term immunomodulating therapies. Using mouse polyomavirus (MuPyV), our laboratory developed a robust model of polyomavirus-associated demyelinating leukoencephalitis, complete with viral infection and T cell infiltration. Increasing evidence supports the importance of CD4+ T cells in controlling JCV in the brain and thereby preventing PML. Recent studies in our laboratory show that CD4+ T cells are essential for differentiation and maintenance of MuPyV-specific brain-resident memory CD8+ T cells (bTRM). We find that the help CD4+ T cells are provide to virus-specific CD8+ T cells for their appropriate bTRM differentiation is IL-21. PD-1hiCXCR5hi MuPyV-specific CD4+ T cells are the primary sources of brain IL-21 and co-localize with CD8+ T cells in the brain. Brain MuPyV-specific CD8+ T cells have increased expression of the IL-21 receptor (IL21R) 15 days post-infection, which correlates to the time-point when they begin to express CD103, a canonical TRM marker. TRM maintenance is independent of circulating cells. In line with this property, we show that MuPyV-specific CD8+ T cells are not depleted by parentally administered anti-CD8. In addition, brain CD8+ T cells from IL21R−/ − mice have decreased expression of CD103 and are susceptible to depletion from peripheral anti-CD8. These data indicate that during polyomavirus infection, IL-21 by CD4+ T cells drives CD8+ T cells to differentiate into tissue resident memory in the brain.