bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eradication of tumors containing MHC class I deficient cells by inducing adaptive and innate immune responses
Authors: Seo Hyungseok , Jeon Insu , Bae Eun-Ah , Song Boyeong , Shin Kwang-Soo , Koh Choong-Hyun , Kang Chang-Yuil 
Published: January 2023

Abstract
During cancer immunoediting, tumor cells with spontaneous loss of MHC class I expression tend to gradually increase in tumor microenvironment by preferentially escaping from immune surveillance by cytotoxic T cells, although the MHC class I-deficient tumors have been historically considered to be susceptible to NK cell-dependent cytotoxicity. In line with this idea, recent studies demonstrated that most NK cells found in tumor microenvironment of advanced cancers are defected, releasing the malignant MHC class I-deficient tumors from NK cell-dependent immune control. Here we described that NKT cell-ligand loaded tumor-antigen expressing APC-based vaccine effectively eradicated these advanced tumors which have not been curable by an immunotherapy. In this process, we found that co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumors, and that MHC class I down-regulation in tumors was closely associated with the induction of NK cell exhaustion in tumor-bearing mice as well as in cancer patients. Furthermore, recovery of NK cell function by NKT cell driven cytokines was critical for the anti-tumor effect of the vaccine against these advanced tumors. These results uncover the mechanisms involved in the induction of NK cell dysfunction in advanced cancers and provide a guidance to develop new strategies for cancer immunotherapy.
The lymphomagenic molecule LMP1 sequesters TRAF3 to induce enhanced B cell survival.
Authors: Stunz Laura L , Bangalore-Prakash Pradeep , Mambetsariev Nurbek , Bishop Gail A. 
Published: January 2023

Abstract
The human TRAF3 gene is frequently mutated in multiple myeloma and lymphoma. TRAF3 restrains homeostatic B cell survival. B cell TRAF3 deficiency promotes enhanced viability and over-expression of the anti-apoptotic molecules NIK, Mcl1 and Pim2, enhanced nuclear CREB, and increased pSTAT3 in response to IL6 signaling. We assessed TRAF3 protein expression in human lymphoma samples. The number of TRAF3low DLBCL was higher than predicted based on genetic loss, so we speculated that cellular TRAF3 can be depleted through other means. The oncogenic Epstein Barr virus protein LMP1 binds TRAF3 with much higher avidity than do CD40 or BAFF receptors, so we hypothesized that LMP1-sequesters TRAF3, causing functional depletion. We found evidence of induction of survival pathways in TRAF3 sufficient B cells expressing LMP1 consistent with those in B cells genetically lacking TRAF3.
B lymphoma cell lines stably transfected with inducible LMP1 were stimulated via CD40 or BAFFR. TRAF3 binding was studied via CD40/BAFFR immunoprecipitation and Western blotting. We also examined levels of cellular NIK, and used confocal fluorescence microscopy to assess nuclear CREB expression. We found LMP1 expression sequesters cellular and nuclear TRAF3, decreasing its availability to CD40 and BAFFR, and increases survival-promoting NIK, CREB and pSTAT3. LMP1 mutated at the major TRAF binding site only marginally induced TRAF3 sequestration and NIK. Thus, B cell LMP1 expression can enhance survival by functionally reducing TRAF3 availability.
Antigen-presenting tumor B cells impact the phenotype of CD4 tumor infiltrating T cells in lung cancer patients
Authors: Bruno Tullia Carmela , Ebner Peggy , Moore Brandon , Squalls Olivia , Waugh Katherine , Eruslanov Evgeniy B , Singhal Sunil , Mitchell John , Franklin Wilbur , Merrick Daniel , McCarter Martin , Palmer Brent E , Kern Jeffrey , Vignali Dario , Slansky Jill E 
Published: January 2023

Abstract
The focus of immunotherapy has been on CD8 and CD4 tumor infiltrating lymphocytes (TILs), however, tumor infiltrating B cells (TIL-Bs) are understudied with no focus on their role as antigen presenting cells. We hypothesize that TIL-Bs help generate potent, long-term immune responses against cancer by presenting tumor antigens to CD4 TILs.
Using un-manipulated, primary human B cells from fresh tumor, we generated a specific in vitro antigen presentation assay and observed three types of CD4 TIL responses when TIL-Bs presented autologous tumor antigens. There were activated responder CD4 TILs that proliferated when combined with TIL-Bs alone, which indicates stimulation with endogenous tumor antigens. There were antigen-associated responders that required autologous tumor lysate to elicit a CD4 TIL response, and there were patient CD4 TILs that did not respond to antigen presentation. Exhausted B cells have been described in chronic infection i.e. HIV, and thus, to parallel our studies to a model of chronic infection, we analyzed activated and exhausted TIL-Bs with our antigen presentation assay. If TIL-Bs were activated (HLADR+CD69+CD27+CD21+), the resultant CD4 TILs were T helper (anti-tumor) CD4 T cells and if the TIL-Bs were exhausted (HLADR+CD69+CD27−CD21−), the resultant CD4 TILs were T regulatory cells (pro-tumor). These data suggest that TIL-Bs influence CD4 TILs in NSCLC patient tumors.
In conclusion, determining if TIL-Bs are activated or exhausted in NSCLC patients will determine the extent of their anti-tumor function in human cancer. Ultimately, results from this study will dictate how to target TIL-Bs in future immunotherapies.
Characterization of bovine γδ T cells phenotype during post-natal development and following Mycobacterium bovis vaccination or virulent infection
Authors: Guerra-Maupome Mariana , Larsen Michelle H. , Palmer Mitchell V. , Waters Ray , McGill Jodi L 
Published: January 2023

Abstract
Bovine tuberculosis caused by Mycobacterium bovis is a globally significant veterinary health problem. γδ T cells participate in the immune control of mycobacterial infections. Data in human and non-human primates suggest that mycobacterial infection regulates memory/effector phenotype and adaptive immune functions of mycobacterium-responsive γδ T cells. To date, the impact of age or M. bovis infection on bovine γδ T cells memory/effector phenotype remains unknown. In this study, we addressed the age-dependent changes of circulating γδ T cells, analyzed functional and phenotypic differences in memory and activation marker expression, and evaluated functional responses of M. bovis-specific γδ T cells following M. bovis Bacille Calmette-Guerin (BCG) vaccination or virulent M. bovis infection. As expected, aerosol vaccination and virulent infection induced robust mucosal and systemic M. bovis-specific γδ T cell proliferative responses. Analysis of peripheral blood γδ T cells indicated phenotypic differences based on the expression of CD27 and CD45R that could suggest distinct functional properties. Recall responses after in vitro stimulation with mycobacterial antigens showed that expression of CD27 is critical for the expansion of peripheral IFN-γ-producing γδ T-cells and suggest that the CD27+ subset may compose the mycobacterium-responsive γδ T cell compartment in calves responding to M. bovis vaccination or infection. The ability of γδ T cells to mount a robust response during mycobacterial infections supports the notion that vaccine-elicited γδ T cell immunity might prove beneficial. Therefore, defining correlates of protection based on this population can accelerate the development of novel vaccines against TB.
Protective role of conventional dendritic cells in experimental model of sepsis
Authors: Gargaro Marco , Briseno Carlos , Vivek Durai , Scalisi Giulia , Theisen Derek J , Bagadia Prachi , Turco Antonella , Anderson David A , Murphy Theresa L , Murphy Kenneth M , Fallarino Francesca 
Published: January 2023

Abstract
Sepsis is a serious medical condition caused by an overwhelming immune response to infection and is a major challenge in the intensive care unit, where it’s one of the leading causes of death. Dendritic cells (DCs), acting as sentinels, constantly sense and respond to environmental stimuli. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Recently, we demonstrated that activation of Aryl Hydrocarbon receptor (AhR), by tryptophan metabolites in DCs, represents a protective mechanism in an experimental animal model of Lipopolysaccharide (LPS)-induced septic shock. Based on these results we examined the role of DCs subsets in sepsis. To determine whether DCs are required for protection against LPS sterile septic shock we used Zbtb46DTR mouse model. We found that Zbtb46DTR chimeras treated with diphtheria toxin are unable to survive after sub-lethal LPS challenge compared to wild-type mice reconstituted with wild-type bone marrow. In addition, naive mice intravenously transferred with LPS-treated DCs survived to a lethal LPS challenge. Notably, we found that mice lacking of CD24+ DCs are extremely susceptible to LPS. Moreover, LPS selectively induces indoleamine-2,3-dioxygenase 1 (IDO1) in bone marrow-derived CD24+. Our data demonstrate for the first time that DCs and specifically CD24+ DCs, play a critical role in sepsis protection.
Dnase1L3 trafficking in inflammasome activation
Authors: Abbott Kennady N , Shi Guilan , Keyel Peter A 
Published: January 2023

Abstract
Pediatric-onset systemic lupus erythematosus (SLE) and the related autoimmune disease hypocomplementemic urticarial vasculitis syndrome (HUVS) are linked to deficiencies in the endonuclease Dnase1L3. Dnase1L3 prevents SLE by digesting apoptotic chromatin extracellularly, but the mechanism by which Dnase1L3 prevents HUVS is unknown. Two autoimmune murine strains, MRL and NZB/W F1, bear the activity-reducing T89I mutation in Dnase1L3. Previous data suggest that this mutation alters Dnase1L3 trafficking. Altered trafficking could allow Dnase1L3 to function intracellularly to regulate inflammation. We previously showed that Dnase1L3 is required for inflammasome activation by facilitating ASC nuclear export, though how Dnase1L3 reaches the nucleus is unknown. Here, we tested the hypothesis that Dnase1L3 trafficking regulates inflammasome activation. We showed that IL-1β secretion was reduced in the presence of T89I. We tested if other activity-reducing mutations alter Dnase1L3 trafficking. We transfected HeLa cells with Dnase1L3 containing point mutations in the signal sequence, C-terminus, and catalytic residues and determined the subcellular localization of Dnase1L3. We also determined their endonuclease activity relative to wild type Dnase1L3. Trafficking studies could establish a physiological intracellular function for Dnase1L3. The relationship between the mutations and localization could explain the mechanism of Dnase1L3 involvement in inflammasome activation. Mutational analysis could serve as a tool to evaluate the structure of Dnase1L3 necessary for inflammasome activation and IL-1β secretion, revealing the function of Dnase1L3 in the pathogenesis of autoimmune diseases like SLE and HUVS.
Hydroxychloroquine Improves Atherosclerosis in SLE
Authors: Niu Haitao , Liu Tianxing , Zhang Shuyang 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) patients suffer from earlier premature and severer presentation of coronary artery disease (CAD). By using lupus combining atherosclerosis murine model, we proved that onset of SLE aggravates atherosclerosis. Lupus atheroma were characterized by inflammatory cell infiltration, such as dendritic cells and macrophages. Moreover, excessive immunoglobulin G deposition was also observed in lupus atheroma. Hydroxychloroquine (HCQ) prevented atherosclerosis progression mainly by reversing immune status abnormality caused by SLE. HCQ administration reduced aortic macrophage number and dendritic cell number in lupus mice. HCQ treatment also significantly suppressed IgG deposition. These findings strongly suggest that anti-inflammatory therapies and HCQ provides a new possible strategy for treating SLE patients suffered from atherosclerosis.
Novel functions CD11c+ IgM+ memory B cells suggested from transcriptome analysis
Authors: Levack Russell C , Papillion Amber M , Dishaw Lisa , Winslow Gary 
Published: January 2023

Abstract
Our laboratory has identified a distinct subset of CD11c+ T-bet+ IgM memory B cells during ehrlichial infection in mice. These cells are likely closely related to phenotypically similar B cells that have been described in a range of other conditions, including hepatitis, AIDs, malaria, SLE, and age-related autoimmunity. In order to identify novel functions of CD11c+ T-bet+ IgM memory B cells, we performed RNAseq analysis. The cells were purified from infected mice on day 30 post-infection, and were compared to CD11c-negative CD19+ B cells isolated from the same mice. The CD11c+ B cells exhibited a distinct transcriptomic profile, compared to the CD11c-negative B cells, as over 900 genes were differentially regulated. Differentially-expressed genes included those encoding for integrins, Fc receptors, transcription factors, complement and receptors involved in innate immunity. Differentially-expressed complement-related genes included those encoding for the C1q complex, properdin, and complement factor B, which were all upregulated. Other genes that were upregulated included those encoding the adenosine receptor Adora2a, Bcl-6, which encodes a transcription factor required for GC B cells and the B cell inhibitory FcR, Fcgr2b. These data open new avenues of exploration of CD11c+ T-bet+ B cell function, and will lead to a better understanding of the role of these novel B cells in human health and disease.
Comprehensive analysis of serum and innate immune cells revealed age-related alternations
Authors: Metcalf Talibah U , Wilkinson Peter , Wertheimer Anne , Nikolich-Zugich Janko , Haddad Elias 
Published: January 2023

Abstract
Age-related alterations in immunity have been linked to increased incidence of infections and decreased responses to vaccines in the aging population. These immune dysfunctions, termed immunosenescence, have been linked to the intricate interactions between the innate and adaptive immune responses. The impact of aging on innate immunity remains an open question. We performed a comprehensive analysis of serum and peripheral blood mononuclear cells (PMBCs) isolated from healthy non-frail adults (≤ 40 years) and old individuals (≥ 65 years). The basal level of circulating inflammatory cytokines and chemokines were measured, as well as transcriptome data was analyzed for both ex vivo and agonist stimulated DCs and monocyte subsets. We observed that sorted DC (BDCA-1, -2, and -3) and monocyte (CD14+CD16−,CD14dimCD16+, and CD14+CD16+) subsets were primarily distinct and have unique transcriptional profiles. Under ex vivo conditions, innate subsets did not reveal significant age-related alternations; however, agonist stimulated-monocytes from adults and old subjects did show differences at the transcriptional and functional levels. After stimulation of TLR4 (LPS), TLR7/8 (CLO97), and RIGI (5′-pppRNA), we observed higher production of interferons, CCL8, CCL20, and IL1B in monocytes isolated from adults compared to old individuals. Pathway analysis revealed that innate agonists induced functional pathways in monocytes isolated from both adults and old subjects. Overall, our data reveals a wide range of potential age-associated alternations in pattern recognition receptors (PRRs) signaling and have implications for strategies to enhance the immune response in the context of infection or immunization.
The IL-33/ST2 axis is crucial in type 2 airway responses induced by the Staphylococcus aureus protease SplD
Authors: Krysko Olga , Teufelberger Andrea , Nordengrün Maria Maria , Maes Tania , Bröker Barbara , Bachert Claus 
Published: January 2023

Abstract

Background
Chronic airway inflammatory diseases such as chronic rhinosinusitis with nasal polyps and asthma showed increased nasal Staphylococcus aureus (S. aureus) colonization. Serine protease like protein D (SplD) and other closely related proteases secreted by S. aureus have recently been identified as inducers of allergic asthma in humans and mice but their mechanism of action is largely unknown

Objective
We investigated the role of recombinant SplD in driving Th2-biased responses and IgE formation in a murine model of allergic asthma.

Methods
Allergic asthma was induced in C57BL/6 J wild type mice, TLR4−/− mice and Rag2 Rag2−/− mice by repeated intratracheal applications of SplD. Inflammatory parameters in the airways were assessed by flow cytometry, ELISA, Luminex and immunofluorescence. Serum SplD-specific IgE levels were analysed by ELISA.

Results
We observed that repeated intratracheal exposure to SplD led to IL-33 and eotaxin production, eosinophilia, bronchial hyperreactivity and goblet cell hyperplasia in the airways. Blocking the IL-33 activity using a sST2 receptor significantly decreased the numbers of eosinophils, CD4+ T cells, and IL-5 and IL-13 production by lymph node cells but had no effect on IgE production. SplD-induced airway inflammation and IgE production were largely dependent on the presence of the functional adaptive immune system and independent of TLR4 signalling.

Conclusion
The S. aureus-derived protein SplD is a potent allergen of S. aureus and induces a Th2-biased inflammatory response in the airways in an IL-33-dependent, but TRL4-independent manner. sST2 could be an efficient strategy to interfere with SplD-induced Th2 inflammation, but does not prevent the allergic sensitization.
Pathogenic conversion of RORγt+/Foxp3+ double positive regulatory T cells involves β-catenin up-regulation
Authors: Quandt Jasmin , Haghi Leila , Emmanuel Akinola Olumide , Gounari Fotini 
Published: January 2023

Abstract
The nature of regulatory T cells (Tregs) in cancer is ambivalent. In Colon Cancer (CC) patients and animal models of CC, we previously described a distinct subset of Tregs that suppresses anti-tumor effector T cell functions but simultaneously maintains inflammation. These Tregs co-express the Th17 lineage transcription factor RORγt along with Foxp3. Moreover, we causatively linked the pro-inflammatory skewing of T cells to Wnt/β-catenin-signaling. To elucidate how Wnt/β-catenin signaling orchestrates the induction of pathologic properties in Tregs we analyzed inflammatory bowel disease (IBD) patients. As IBD can progress to CC, this disease presents a unique platform to study the mechanisms underlying the emergence of RORγt+/Foxp3+Tregs. Indeed, in a sub-population of IBD patients we were able to detect RORγt+/Foxp3+Tregs, expressing high levels of β-catenin in the patients’ blood and tissue. To further establish that activated Wnt/β-catenin signaling is responsible for the pro-inflammatory skewing of Foxp3+ Tregs we over-expressed β-catenin Treg-specifically in a conditional Foxp3-Cre driven mouse model. Mice expressing constitutively active β-catenin in Tregs show striking X-linked immune pathology. Males die 4 weeks after birth of a severe scurfy-like phenotype. Although their Tregs are highly activated, they fail to suppress the proliferation of effector T cells. In heterozygous Foxp3-Cre mice, representing natural chimeras harboring wildtype and β-catenin over-expressing Tregs, the relative fitness of genetically altered Tregs is decreased. By further elucidating how Wnt/β-catenin signaling mediates the pathogenic conversion of Tregs, we hope to reveal novel targets for cancer immuno-therapy.
Transcriptomic analysis reveals the potential of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus to modulate immune system activation related to host-pathogen and damage associated signaling in infected porcine monocytes.
Authors: Miller Laura C , Fleming Damarius , Li Xiangdong , Bayles Darrell , Blecha Frank , Sang Yongming 
Published: January 2023

Abstract
One of the largest risks to the continued stability of the swine industry is by pathogens like porcine reproductive and respiratory syndrome virus (PRRSV) that can decimate production as it spreads among individuals. These infections can be low or highly pathogenic, and because it infects monocytic cells, PRRSV can undermine the innate immune response. This is especially true of the interferon stimulated inflammatory response. To shed light on the effect of PRRSV pathogenicity on activation status of the immune response, we polarized infected and control monocyte-derived cells (mDCs), applied transcriptomic analysis, and predicted protein-protein interactions as networks to elucidate the interconnected biological processes related to low and highly pathogenic PRRSV infection. Differentially expressed genes (DEGs) from each polarized/unpolarized and PRRSV infected/ uninfected comparison was used to predict networks and subsequent molecular functions affected by the viruses and mediators. The analysis uncovered previously uncharacterized evidence of the ability of PRRSV to effect M1 activation by altering expression of genes related to viral defense, the extra-cellular matrix (ECM), toll-like receptor (TLR) signaling, and damage induced inflammatory signaling. Genes showing variability in expression, as well as the most common predicted biological network from the comparisons, were related to cellular structure and inflammatory immune responses. These results supply additional insight into the interplay of PRRSV pathogenicity and immune system evasion by affecting multiple routes of host inflammatory signaling, as well as mDC polarization.
CD11c+ cells are required for lymphocyte trafficking into previously infiltrated pancreatic islets during type 1 diabetes.
Authors: Sandor Adam , Lindsay Robin S , Gebert Matthew J , Bradley Brenda J , Haskins Kathryn , Jacobelli Jordan , Friedman Rachel S 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is a largely T cell mediated autoimmune disease that destroys the beta cells of the pancreatic islets. Inhibition of cell trafficking to an active disease site has been an effective therapy for multiple autoimmune diseases, but the requirements of lymphocyte trafficking to the islets are not fully understood. We show that lymphocyte entry into previously infiltrated islets is dependent on the presence of CD11c+ cells in the islets. T cells and B cells transferred prior to CD11c+ cell depletion were able to enter the islets; whereas, short-term CD11c+ cell depletion rapidly prevented further entry. CD11c+ cells include cells that are highly efficient antigen presenters; however, we show entry of both activated or naïve T cells into previously infiltrated islets was not reliant on antigen. An alternative role for CD11c+ cells in lymphocyte entry into the islets is the production of chemokines and cytokines. These molecules can then either directly recruit lymphocytes through chemoattraction or increased adhesion to the vasculature. Initial experiments show that there are no changes in adhesion to the vasculature after CD11c depletion, suggesting that CD11c+ cells act through recruitment by chemokines following lymphocyte arrest on the vascular endothelium. CD11c+ cells in the islets express high levels of CXCL9, a chemoattractant for T and B lymphocytes. CXCR3, the receptor for CXCL9, is present on both T and B cells in the islets. We hypothesize that CD11c+ cells facilitate the process of extravasation into the islets through chemokine production. Targeting CD11c+ produced chemokine production may be useful therapeutically for the treatment of T1D by preventing T cell entry into remaining or transplanted islets.