bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viral infection induces the upregulation of MHC-1 expression in infected cancer cells
Authors: Kim Sang Hoon , Jung Yong Woo 
Published: January 2023

Abstract
Cancer cells can evade immune system by the downregulation of major histocompatibility complex-1 (MHC-1) molecules and upregulation of immunosuppressive ligands such as programmed death ligand 1 (PD-L1). In addition, cancer cells provide inhibitory cytokines so that the microenvironments of cancer maintain as an anti-inflammatory condition. However, it is not clear if cancer cells provide pro-inflammatory microenvironments to help clear viral infection, when they were infected with life-threatning viruses To test this question, we infected EL-4 cells, a lymphoma cell line, with lymphocytic choriomeningitis virus (LCMV) and examined if this infection causes the phenotypic change of cancer cells. On day 7 post infection, we observed that expressions of MHC-1 and PD-L1 molecules increased, while decreased PD-1 expression was found in virus-infected cancer cells. Since the overexpression of MHC-1 molecules was found on virus-infected cells, we further examined whether virus-specific CD8 T cells can recognize the antigen presented by these cancer cells and if these CD8 T cells can mount immune response. When LCMV-specific memory T cells were cultured with virus-infected EL-4 cells, we found that these CD8 T cells were able to produce IFN-γ and TNF-α, but the levels of these proteins were lower compared to positive controls. Altogether, these data suggest that cancer cells infected with viruses presented the viral antigens to CD8 T cells so that the delivery of viral antigen to cancer would be a novel therapeutic strategy.
Adrenergic stress impairs CD8+T-cell activation and effector function, limiting antitumor immune responses: an in vivo analysis
Authors: Qiao Guanxi , Chen Minhui , Bucsek Mark J , Mohammadpour Hemn , MacDonald Cameron R , Campbell Heather M , Hylander Bonnie L , Repasky Elizabeth A 
Published: January 2023

Abstract
CD8+T-cell activation requires a substantial up-regulation of both glycolysis and oxidative phosphorylation to support proliferation and immune effector functions. We have shown that chronic stress suppresses anti-tumor immunity and is associated with elevated levels of the sympathetic neurotransmitter norepinephrine (NE). NE signals through adrenergic receptors (ARs) present on all cells to coordinate a sympathetic stress response. We found that reducing or blocking AR signaling can significantly improve anti-tumor immune responses. Additionally, we discovered that triggering AR signaling during CD8+T-cell activation in vitro impairs metabolic reprogramming, primarily through the beta2-AR. We hypothesized that, in vivo, chronic stress would also impair metabolic reprogramming, leading to significant failure of intratumoral CD8+T-cell effector function. We found that the mitochondrial mass of CD8+T-cells isolated from B16-OVA tumors (melanoma) is decreased compared to CD8+T-cells from tumor draining lymph nodes; however, when tumor bearing WT mice are treated with propranolol, or in tumors grown in adrb2−/− mice, we found that tumor infiltrating CD8+T-cells have a higher mitochondrial mass. We also found that tumor infiltrating CD8+T-cells from mice treated with propranolol have higher CD28 expression, suggesting that adrenergic stress-induced signaling impairs metabolism of tumor infiltrating CD8+T-cells through a CD28-dependent pathway. Together, these data support the idea that in vivo, chronic stress inhibits the antitumor immune response through inhibition of CD8+T-cell metabolism.
Tumor-intrinsic PD-L1 regulates tumor initiating cell virulence and stemness genes, and TCF1+ stem-like T cells through Raptor in ovarian cancer, which correlates with survival in high grade serous ovarian cancer
Authors: Gupta Harshita B. , Murray Clare E , Deng June , Mohammad Tabrez AS , Zhang Xinyue , Wu Bogang , Clark Curtis A , Sareddy Gangadhara , Chen Yidong , Vadlamudi Ratna , Li Rong , Curiel Tyler J 
Published: January 2023

Abstract
We reported that tumor intrinsic PD-L1 promotes tumor initiating cell (TIC) virulence and mTORC1. Others have focused on PI3K/AKT/mTOR in promoting TIC, but specific downstream mTOR regulators of tumor stemness are unknown. We knocked down Raptor (mTORC1 component, Rptorlo) in ID8agg cells (murine ovarian cancer). Rptorlo cells had reduced mTORC1 with no change in PD-L1 in total cells or CD44+CD24+ TIC. %TIC was reduced in Rptorlo cell cultures, and Rptorlo TIC were functionally defective for self-renewal by tumorosphere formation. Rapamycin (mTORC1 inhibitor) reduced ID8agg Rptor, tumorospheres, and the stemness and virulence genes Oct4 and Nanog. Oct4 knockin to PD-L1lo ID8agg restored TIC numbers and spheres. Together, data confirm PD-L1 drives stemness through Oct4 by increasing mTORC1. Rptorlo TIC formed significantly smaller tumors vs. control TIC in immunodeficient NSG mice, confirming TIC intrinsic Rptor drives immune independent virulence. In wild type mice, Rptorlo vs. control TIC produced less ascites and smaller tumors with lower %TIC in vivo (but similar PD-L1), significantly more recently-activated CD44hiCD62LloCD8+ cells in ascites and draining lymph nodes (DLN). CCR2+CD8+ T cells and CXCR5+TCF1+PD-1+Tim3− stem-like T cells were also increased in Rptorlo DLN. Thus, Rptorlo TIC influence systemic and tumor-associated immunity. In high grade serous ovarian tumors (The Cancer Genome Atlas) high Rptor expression predicted a significantly higher cancer stem cell signature, and lower median survival in late stage patients. Our work establishes tumor intrinsic Rptor driven by PD-L1 plays a key role in regulating TIC and stem like T cells and can be a prognostic marker for late stage ovarian cancer patients.
Longitudinal Phenotyping Studies of MRL/MpJ-Fas
lpr/J and NZBWF1/J Mouse Lupus Models
Authors: Schile Andrew , French Richard , Serrano Jason , Leighton Krystal 
Published: January 2023

Abstract
MRL/MpJ-Faslpr/J (MRL-lpr) and NZBWF1/J mice develop autoimmune diseases resembling systemic lupus erythematosus, a disease affecting &gt; 1 million Americans. MRL-lpr mice have a mutation (Faslpr) promoting survival of self-reactive lymphocytes and a strain background predisposed to autoimmunity. NZBWF1/J mice are a polygenic model with female disease bias. Cohorts of 40 mice/sex/strain were weighed and monitored weekly for clinical signs. Hematology, serum chemistry, and urinalysis was conducted on 10 mice/sex/strain every two weeks (MRL-lpr) or monthly (NZBWF1). Lymphoproliferation was greater in MRL-lpr females: white blood cell counts (×103/μL) increased from a median of 3.5 at 8 weeks to 9.2 at 18 weeks; median male counts increased from 3.2 to 6.1. At 38 weeks NZBWF1 WBC did not differ by sex, but red blood cells and platelets were significantly lower in females (14% & 55% reductions, respectively; P = 0.018 & P = 0.0001). MRL-lpr renal failure was progressive and greater in females: 9 of 10 females had urine albumin:creatinine ratios exceeding 100 mg/g by 17 weeks of age, while 2 of 10 males were in this range. Serum blood urea nitrogen increased by &gt;3X in 5 of 7 NZBWF1 females that reached endpoint by 38 weeks; values did not change in MRL-lpr. The first overt signs of disease were cervical lymphadenopathy in MRL-lpr females and body weight loss in NZBWF1 females. More than 50% of female NZBWF1 mice had lost &gt;10% of peak body weight by 38 weeks while all males were gaining weight. Median time to MRL-lpr study endpoint was 19 weeks for females and &gt;24 weeks in males; mice generally maintained or gained weight throughout. All data will be available from the Mouse Phenome Database to serve as references for disease progression in these models.
IL-4 synergizes with low-dose IL-2 to restore systemic lupus erythematosus B cells at the resting naive status
Authors: Hsu Hui-Chen , Liu Shanrun , Gao Min , Wu Qi , Yang PingAr , Chatham W. Winn , Mountz John D. 
Published: January 2023

Abstract
We have recently identified that down-regulation of interleukin-4 receptor (IL-4R) is a novel hallmark of B-cell dysregulation in SLE patients. Single cell transcriptomics analysis revealed that elevation of IL4R in pre-switched B cells is the opposing signature of increased type I interferon stimulated genes (ISGs) and double negative B cells (TBX21, ITGAX, FCRL3, FCRL5, and ZEB2). Flow cytometry analysis further confirmed that down-regulation IL-4R and upregulation of intracellular IFN-β correlated with the loss of CD21+IgD+CD27− resting naïve (rNVA) B cells and accumulation of CD21−IgD+CD27− activated naïve (aNAV) and double negative CD21−IgD+CD27− B cells in SLE patients (n=47). Interestingly, exposure of SLE B cells to IL-4 prior to treatment with low-dose IL-2 (0.2 ng/mL) blocks the anti-Ig, IL-21, IFN-gamma, TLR7 and BAFF-stimulated development of T-bet+CD11c+IgD−CD27− DN2 B cells and CD27+CD38+ plasmablasts (PBs) and preserves B cells in the rNAV state. Such effect was diminished in the absence of IL-4 or when low-dose of IL-2 was substituted with high-dose of IL-2 (20 ng/mL). Stimulation of B cells with IL-4 promoted the induction of CD25 (IL-2RA) on B cells. Together, our results suggest a mechanism of action underlying the synergism between IL-4 and low-dose IL-2. Specifically, the IL-4R signaling pathways upregulate CD25 on B cells, thereby promoting formation of the high affinity IL-2R complexes required for low-dose IL-2 signaling that induces a regulatory signal that restores SLE B cells to the rNAV stage. Our results suggest that the process of development of autoreactive B cells in SLE can be directly measured in a clinical lab, and can be directly abrogated using cytokine therapy available for clinical use.
Lupus-like disease in B6.Nba2 mice shows a biphasic disease progression
Authors: Keller Emma J , Campbell Nicole , Davison Laura M , Patel Neeva , Jorgensen Trine N 
Published: January 2023

Abstract
Lupus is an autoimmune disease with a diverse pattern of symptoms affecting approximately 1.5 million Americans. Over the past decade, new biologics (f.ex. Belimumab, Anifrolumab) have emerged targeting cytokines and/or cells known to be pathogenic in lupus, however, response-rates among varied patient populations remain low, supporting the heterogeneity of the disease. B6.Nba2 mice exhibit a constitutive progressive lupus-like disease pattern driven by type I interferons (IFNα). Using this model, ablation of plasmacytoid dendritic cells (pDCs) is effective if initiated before, but not after, 4 months of age, suggesting a biphasic disease pattern with pDCs/IFNα playing a role during the early phase only. To investigate the second phase, we compared disease manifestations in 4 and 9 month old B6.Nba2 mice. As expected, IFNα-induced gene transcripts diminished after 4 months of age as did levels of IL-6; another product of pDCs, while we saw no changes in IL-21 levels. In contrast, splenic BAFF levels increased over time both at the transcriptional and protein level as did levels of Irf4 and Bcl6 transcripts, supporting an upregulation in specific B cell subsets including germinal center B cells and plasma cells in aging mice. These data indicates that pDCs and their products, IFNα and IL-6, play a critical role in early lupus like disease progression, while BAFF and B cells are involved in the later stage of the disease progression. Thus, treatment with different biologics may be needed at different time points of disease. We suggest that investigating patterns of gene expression combined with obtaining an inclusive patient history is necessary to determine the treatment approach needed for each individual lupus patient.
Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus
Authors: Wang Xinghao , Goel Rishi R. , O’Neil Liam J. , Nakabo Shuichiro , Hasneen Kowser , Gupta Sarthak , Wigerblad Gustaf , Blanco Luz P. , Kopp Jeffrey B. , Morasso Maria I. , Kotenko Sergei V. , Yu Zu-Xi , Carmona-Rivera Carmelo , Kaplan Mariana J. 
Published: January 2023

Abstract
Type III interferon lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, remains to be determined. Here, we identify a non-redundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1)-deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys. Single-cell RNA sequencing in mouse and human immune cells revealed distinct and selective responses to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and drive tissue-specific inflammation. These data provide new insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.
B cell migration into skin limits local inflammation
Authors: Debes Gudrun , Aira Lazaro E , McGettigan Shannon E 
Published: January 2023

Abstract
Regulatory B cells (Bregs) limit inflammatory responses in various organs. While most studies suggest that Bregs exert their anti-inflammatory functions by virtue of IL-10 production in lymphoid tissues such as spleen and lymph nodes, we found that IL-10 producing B cells reside constitutively in skin and are preferentially recruited in inflammation in an α4β1 integrin-dependent manner. To address whether Bregs suppress inflammation at the effector site (i.e. inflamed skin), we employed mice with an inducible B-cell specific deletion of α4-integrin. Selectively blocking migration of B cells into the inflamed skin led to increased localized inflammation in mouse models of psoriasis and cutaneous hypersensitivity. The data support a model in which Bregs suppress inflammation not only in lymphoid tissues but also at effector sites.
Combined blockade of α4β7 and αEβ7 integrins leads to a greater reduction of gut proinflammatory T lymphocytes over either pathway alone
Authors: Dai Bingbing , Hackney Jason , Ichikawa Ryan , Elstrott Justin , Sun Kai-Hui , Modrusan Zora , Gogineni Alvin , McBride Jacqueline , Keir Mary E , Yi Tangsheng 
Published: January 2023

Abstract
Therapeutic approaches to treat inflammatory bowel diseases (IBD) include targeting integrins that mediate adhesion and migration of lymphocytes to the gastrointestinal (GI) tract. Etrolizumab is a humanized monoclonal antibody that selectively binds the β7 subunit of the heterodimeric integrins of α4β7 and αEβ7. The relative contribution of α4β7 and αEβ7 integrin family members to lymphocyte migration and retention in GI tractremains to be characterized. Here we applied single-cell technologies to healthy and IBD patient biopsies and found that αEβ7 is highly expressed in a subset of proinflammatory CD4+T cells and majority of cytotoxic intraepithelial CD8+T cells. In order to understand the role of αEβ7 in gut T cell accumulation, we used a photo-convertible reporter system to determine that concurrent inhibition of α4β7 and αEβ7 together led to a greater reduction of polyclonal or antigen specific T cell accumulation in the intestinal mucosa and epithelium compared to single blockade of either α4β7 or αEβ7. Further intra-vital two-photon microscopy and photo-specific labeling experiments revealed that blockade of αEβ7 reduces T cell interactions with basolateral epithelial surface, increases the migratory speed of activated T cells in the intestinal mucosa, and facilitates effector T cell egress from the intestinal mucosal through lymphatic vessels. Our data suggests co-blockade of α4β7 and αEβ7 together offers a superior inhibition of T cell accumulation in gastrointestinal tissues through a stepwise inhibition of T cell migration and subsequent tissue retention.
Full-length gasdermin-B (GSDMB) regulates epithelial adhesion and migration, and is increased in patients with IBD
Authors: Rana Nitish , Maywald Rebecca , Kondolf Hannah , Abbott Derek W , Heaney Jason , Ivanov Andrei , Pizarro Theresa 
Published: January 2023

Abstract
Resolution of inflammation at mucosal surfaces is a process critical for patients with IBD. GWAS revealed variant SNPs within the gene encoding gasdermin-B (GSDMB) that associates with an increased susceptibility to IBD and elevated GSDMB expression. The aim of this study was to determine the expression pattern and function significance of GSDMB in the pathogenesis of IBD. Primary intestinal biopsy and isolated intestinal epithelial specimens from IBD patients and non-IBD controls were evaluated for mRNA and protein expression. Using the human intestinal epithelial cell line, HT-29, CRISPR-cas9 knockout cells lacking GSDMB were generated, and used for in vitro XTT, cell-death and cell migration assays. Additionally, human epithelial cells transfected with GSDMB constructs and/or stimulated with methotrexate (MTX) were employed for relevant functional assays. We report for the first time a dramatic increase in full-length epithelial-specific GSDMB in IBD patients compared to healthy controls, which unlike other gasdermin family members, does not partake in program-mediated cell death. Additionally, we describe a functional decrease in in vitro proliferative activity, wound repair and an increase in focal adhesion proteins in epithelial cells lacking GSDMB, phenotypically rescued via transfection or MTX treatment. Importantly, GSDMB expression is decreased in IBD patients in remission, to that of levels of non-IBD controls. Taken together, our data suggests that increased epithelial-derived GSDMB during IBD is protective in function and promotes epithelial-specific adhesion and migration, providing rationale for the potential therapeutic use of GSDMB to optimize gut mucosal healing and restoration to homeostasis.
Spatiotemporal Dynamics of Regulatory T Cells and Th17 Cells in the Leptomeninges During Autoimmune Neuroinflammation
Authors: Othy Shivashankar , Jairaman Amit , Dynes Joseph , Dong Tobias X , Tune Cornelia , Yeromin Andriy V , Zavala Angel , Akunwafo Chijioke , Chen Fangyi , Parker Ian , Cahalan Michael D 
Published: January 2023

Abstract
Multiple sclerosis is a devastating autoimmune disease of the central nervous system (CNS) affecting more than 2.5 million people worldwide. Regulatory T cells (Tregs) and T-helper 17 (Th17) cells orchestrate anti- and pro-inflammatory responses that underlie autoimmune diseases. We used two-photon microscopy to elucidate spatial organization, interstitial motility, cellular interaction and signaling of endogenous cells within the spinal leptomeninges in an autoimmune model of neuro-inflammation (EAE). Th17 cells arrive early, distribute uniformly during peak, and decline in numbers during later stages of EAE. In contrast, Tregs arrive before the peak of EAE, co-localize with Th17 cells and persist during later stages. Th17 cells meander widely, whereas Tregs adopt confined, repetitive-scanning motility along the surface of antigen-presenting cells. Notably, Th17 cells exhibit robust Ca2+ signals at the disease onset that are suppressed in the presence of Tregs in the later phases, and Th17 cells co-existing with Tregs remain partially refractory to TCR-activation in-vitro. These findings indicate that interactions with Tregs impart long-lasting suppression of Ca2+ signaling on Th17 cells. Altogether, our results demonstrate choreography-based evidence for Treg control over encephalitogenic T cells to limit neuroinflammation during EAE.
IL-13 promotes precancerous epithelial cell changes during autoimmune gastritis
Authors: Noto Christine N , Bockerstett Kevin A , Jackson Nicholas M , Ford Eric L , DiPaolo Richard J 
Published: January 2023

Abstract
Individuals with chronic autoimmune diseases have an increased risk of cancer development in the affected organ. Cytokines released during chronic inflammation regulate tissue repair processes and can contribute to an increased risk of carcinogenesis. However, the identities and mechanisms by which cytokines regulate cancer development is poorly understood. In these studies, a TCR transgenic mouse model of autoimmune gastritis (AIG) was used to determine the cellular sources of IL-13 and the molecular mechanisms by which IL-13 promotes precancerous epithelial cell changes in a setting of chronic inflammation. Using this model, we identified IL-13 secreting CD4+ T cells, ILC2s, and mast cells present in the mucosa of chronically inflamed stomachs. The use of both murine and human 3D gastric organoid cultures established that IL-13 acted directly on the gastric epithelium and regulated epithelial cell survival, growth, and differentiation. Neutralizing IL-13 in mice with AIG prevented many of the precancerous cellular changes associated with gastric carcinogenesis. Finally, single-cell RNA sequencing of gastric epithelial cells with and without IL-13 receptors identified the transcriptional responses of mucosal epithelium to IL-13 during chronic autoimmunity. These studies have identified that tissue-specific IL-13 production during autoimmunity acts directly on the gastric epithelium to induce cellular changes associated with gastric cancer.
An engineered IL-2 partial agonist promotes CD8+ T cell stemness and anti-tumor efficacy
Authors: Mo Fei , Yu Zhiya , Li Peng , Oh Jangsuk , Spolski Rosanne , Zhao Liang , Glassman Caleb R. , Yamamoto Tori N. , Chen Yun , Golebiowski Filip M. , Hermans Dalton , Marjri Sonia S. , Picton Lora , Liao Wei , Ren Min , Zhuang Xiaoxuan , Mitra Suman , Lin Jian-Xin , Gattinoni Luca , Powell Jonathan D. , Restifo Nicholas P. , Garcia K. Christopher , Leonard Warren J 
Published: January 2023

Abstract
Adoptive cell transfer of antigen specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in a subset of patients. To achieve effective responses, both the number of transferred T cells and their cell differentiation state are critical determinants. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and IL-2 but this can also lead to T cell differentiation into effector T cells, resulting in diminished therapeutic efficacy, whereas maintenance of a more stem-like prior to adoptive transfer is beneficial. Here, we show that an engineered IL-2 partial agonist generated on the super-IL-2 background promoted T-cell expansion without driving terminal differentiation. The partial agonist exhibited altered signaling and mediated distinctive downstream transcriptional, epigenetic, and metabolic programs. Moreover, it sustained expression of transcription factor TCF-1 (T cell transcription factor 1) and promoted mitochondrial fitness, facilitating the maintenance of a stem cell-like state. Accordingly, TCR transgenic and CAR-modified CD8+ T cells expanded with this engineered molecule displayed robust anti-tumor activity in vivo in established models of melanoma and acute lymphoblastic leukemia. Thus, tempering cytokine signaling with the IL-2 partial agonist provides a strategy for enhancing therapeutic efficacy by limiting exhaustion while preserving stemness. Moreover, our findings demonstrate the distinctive power of generation cytokine partial agonists with distinctive activities.