bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral electrophilic nitro-fatty acids inhibit cutaneous immune responses
Authors: Wang Peng , Killeen Meaghan , Mathers Alicia R. 
Published: January 2023

Abstract
Allergic contact dermatitis (ACD) is a common inflammatory skin disease affecting as many as 15–20% of the population. ACD results from a delayed-type hypersensitivity reaction occurring in the skin upon re-exposure to the offending hapten and mediated by the activation of hapten-specific T cells. An increasing body of literature demonstrates that electrophilic nitro-fatty acids (NO2-FAs) exert potent anti-inflammatory actions by modulating metabolic and inflammatory pathways. Therefore, we evaluated the potential regulatory effects of NO2-FAs on ACD by a well-established model of contact hypersensitivity in mice utilizing 2,4-dinitrofluorobenzene (DNFB) as the hapten. Contrary to our hypothesis, topical pretreatment of nitro-oleic acid (OA-NO2) prior to DNFB application potentiated ACD. Given that ACD is mediated by adaptive immunity, topical administration of OA-NO2 may have an adverse effect on keratinocytes thereby limiting OA-NO2’s potential to systemically suppress the adaptive immune response. Therefore, we next compared the effect of oral OA-NO2 on ACD. In contrast to topical administration, oral OA-NO2 dose-dependently suppressed ACD. Moreover, oral OA-NO2 downregulated the production of cutaneous inflammatory cytokines. Interestingly, in vitro experiments demonstrate that OA-NO2 leads to a dose-dependent inhibition of keratinocyte proliferation and expression of IL-1β, TNF-α, and IL-6. Overall, these data emphasize the complexity of the cutaneous microenvironment. A better understanding of the immunoregulatory effects of NO2-FAs in the skin microenvironment will contribute to therapeutics and to our understanding of the pathophysiology of inflammatory skin diseases, such as ACD and psoriasis.
The effect of the common food additive tBHQ in OVA-elicited food allergy
Authors: Jin Yining , Bursley Jenna , Dover Heather , Gangur Venugopal , Rockwell Cheryl Elizabeth 
Published: January 2023

Abstract
Immune-mediated adverse reactions to food allergens are rising at an alarming rate on a global scale for reasons that are not completely understood. Although many factors such as microbiota, diet, obesity, and environmental chemical exposure have been proposed to contribute to this marked increase, the identification of specific causative factors has remained elusive. Here we tested the hypothesis that a common food additive, tert-butylhydroquinone (tBHQ), at concentrations relevant to human exposure, exacerbates allergic response in ovalbumin (OVA) sensitized mice. Female Balb/c mice (4 weeks old) were maintained on control diet or diet with 0.001% tBHQ for the duration of these studies. The mice were exposed to OVA once per week for 4 weeks during the sensitization phase. Sensitization to OVA was assessed by the rise in OVA-specific IgE and IgG1. Upon oral challenge, mice were monitored for hypothermia shock response (HSR) and mast cell protease (mMCP)-1 response. Although sensitization with OVA elicited a robust OVA-specific IgE antibody response in both the control and tBHQ diet groups, IgE levels were markedly higher in the mice on the tBHQ diet as compared to control diet. Likewise, in response to OVA challenge, a more marked decrease in body temperature was observed in the mice on the tBHQ diet. Furthermore, the mMCP-1 response to OVA challenge was 3-fold greater in the mice on the tBHQ diet as compared to control diet. Taken together, we report low concentrations of the food additive tBHQ promote OVA sensitization and exacerbate anaphylactic response to OVA challenge in a mouse model of food allergy.
Development of a novel mouse model to study tick-borne onset of red meat allergy
Authors: Chandrasekhar Jessica , Cox Kelly , Loo William , Tung Ken , Erickson Loren 
Published: January 2023

Abstract
Bites from Amblyomma americanum, also known as the lone star tick, cause a life-threatening food allergy that induces IgE-mediated allergic reactions in affected individuals after eating dietary ‘red’ meat such as beef, pork, and lamb. Currently, there is no treatment to prevent or cure red meat allergy. Thus, establishing how lone star ticks cause red meat allergy is important for protecting individuals against this allergy. Our lab has successfully developed a novel mouse model of hypersensitivity to tick exposure to better understand how bites from the lone star tick sensitize the host to produce and maintain allergic IgE. Using this model, we identified increased T follicular helper cell and germinal center B cell responses and elevated serum titers of tick-specific IgE and IgG1 in mice exposed to lone star ticks subcutaneously. Furthermore, these mice generate a hypersensitivity response after oral challenge with red meat, as measured by basophil activation. Finally, we found that both the formation of inflammatory skin lesions at the site of tick exposure and the production of IgE were dependent on CD4+ helper T cells. These findings suggest that contained within the tick are factors that markedly influence priming of CD4+ T cells leading to the production of allergic IgE. Based on these data, we propose that manipulation of the factors within lone star ticks that drive CD4+ helper T cell activity could be used locally in the skin at the tick bite site to prevent the onset of meat allergy and systemically to stop an allergic reaction from progressing to a state of severe hypersensitivity.
Arid5a orchestrates IL-17-mediated inflammation through post-transcriptional control of mRNA
Authors: Amatya Nilesh , Cruz J. Agustin , Aggor Felix , Garg Abhishek , Berman Andrea J. , Atasoy Ulus , Gaffen Sarah L. 
Published: January 2023

Abstract
Interleukin-17A (IL-17) is a proinflammatory cytokine essential for clearance of microbial pathogens, but conversely drives immunopathology in autoimmune settings. Surprisingly, very little is known about IL-17 receptor-mediated signaling pathway. Although IL-17 is consistently found to be a modest activator of gene transcription in experimental settings, its biological impact in vivo is profound. In addition to de novo transcription, IL-17 also upregulates inflammatory gene expression by stabilizing their transcripts. mRNA stabilization is a central, but still poorly understood facet of IL-17 signaling. Here, we report an RNA binding protein Arid5a (AT-rich interactive domain-containing protein 5A) as a novel mediator of IL-17-induced stabilization of inflammatory mRNAs. IL-17 stimulation upregulated Arid5a expression, whereupon Arid5a was rapidly recruited to TRAF2. Arid5a stabilized multiple IL-17-induced cytokine mRNA transcripts, including Il6, Cxcl1 and Cxcl5, by binding to their 3′ untranslated regions (UTR). In some cases, Arid5a counteracted mRNA degradation mediated by the endoribonuclease MCPIP1 (Regnase-1). Additionally, Arid5a enhanced IL-17-induced expression of the transcription factors IκBz (Nfkbiz) and C/EBPβ (Cebpb), which could then transactivate IL-17-dependent promoters. Arid5a bound to Nfkbiz or Cebpb transcripts, but surprisingly did not detectably affect total Nfkbiz or Cebpb mRNA levels. Rather, Arid5a facilitated translation of IkBz and C/EBPb. Thus, Arid5a orchestrates a feed-forward amplification loop within the IL-17 pathway, revealing a new function for Arid5a in controlling translation and demonstrating a role in controlling downstream IL-17 signaling.
Type II Cytokines Guide Early Thymic Progenitor Lineage Choice and Influence Negative Selection of Myelin-Reactive T cells
Authors: Cattin-Roy Alexis N. , Barik Subhasis , Miller Mindy M. , Ukah Tobechukwu Kenneth , Zaghouani Habib 
Published: January 2023

Abstract
IL-4 and IL-13 are considered anti-inflammatory cytokines and have been effective in sustaining peripheral T cell tolerance and modulation of experimental allergic encephalomyelitis (EAE), an animal model for human multiple sclerosis. Herein, evidence is presented suggesting that both IL-4 and IL-13 contribute to central tolerance of myelin-reactive T cells and restrain the development of EAE. Indeed, IL-4 and IL-13 signaling through their IL-4Rα/IL-13Rα1 heteroreceptor (HR) activates STAT6 transcription factor to inhibit the potential of early thymic progenitors (ETPs) to mature to T cells. In parallel, the cytokines trigger phosphorylation of STAT1 which promote ETPs to give rise to myeloid cells most of which belong to the CD11c+CD8α+ dendritic cell (DC) subset which reside in the thymus. These ETP-derived thymic resident DCs are able to function as antigen presenting cells (APCs) and are proven effective in supporting central tolerance of myelin-reactive T cells in vivo leading to resistance against the development of EAE. Since IL-4 and IL-13 are usually induced in response to parasitic infection or exposure to allergen, the findings are interpreted to mean that these cytokines provide a link between environmental triggers and central tolerance, a concept that bodes well with theories of the hygiene hypothesis and the discrepancies in autoimmune diseases incidence among undeveloped and western countries
MIR205HG is a Long Noncoding RNA with Distinct Functions in the Thymus versus the Anterior Pituitary
Authors: van Oers Nicolai S. , Du Qiumei , Dozmorov Igor , Raj Prithvi , Molina Erika , de la Morena M. Teresa , Mendell Joshua T. , Cleaver Ondine 
Published: January 2023

Abstract
MicroRNAs (miRNAs) are processed from primary RNA transcripts (pri-miRNAs) encoded in host genes. Several miRNAs including miR-205 are present within long noncoding RNAs (lncRNAs). MiR-205 is an epithelial-specific miRNA that supports thymopoiesis by positively regulating Forkhead Box N1 (Foxn1) expression. We assessed whether the host gene for miR-205, MIR205HG, has independent functions as a lncRNA. The more severe stress-induced thymic atrophy reported in miR-205-deficient mice is also evident in MIR205HG knockout lines. However, MIR205HG knockouts have a small stature phenotype. A new set of miR-205KI mice did not have this phenotype. The smaller mouse size of the MIR205HG null animals is partly a consequence of reduced levels of endocrine hormones produced by the anterior pituitary. In addition, the MIR205HG null animals had abnormal development of the lacrimal and harderian glands that produce eye secretions. Transcriptome analyses revealed that MIR205HG regulates gene expression in the anterior pituitary unlike miR-205. In contrast, transcripts regulated by miR-205 and MIR205HG in the epithelial cells of the skin and thymus overlap significantly. These data indicate that MIR205HG has a specific function as a lncRNA in the anterior pituitary in addition to its primary role as the host gene for miR-205 in thymic epithelial cells.
The role CTCF and transcription in sculpting the TCRβ repertoire
Authors: Nganga Vincent K. , Majumder kinjal , Mishra Bikash , Kyle Katherine E. , Oltz Eugene M. 
Published: January 2023

Abstract
Primary Tcrb diversification is preceded by distinct changes in chromatin conformation and transcription during the early stages of T-cell development. However, the mechanisms by which these changes occur and how they shape the repertoire remain unclear. We have shown that distal and proximal Trbv segments are distinctly regulated. For instance, a CTCF binding site, known as 5′ PC, mediates long-range interactions that bring distal Trbvs into spatial proximity with the DβJβ segments. The 5′PC and several other CTCF sites in the 3′ end of the locus are oriented in a manner that we predict to facilitate specific contact, and thus recombination, between groups of Trbv segments the DβJβ segments. To specifically test this, we individually deleted key CTCF sites from the mouse Tcrb locus and sequenced Trbv gene usage in DN thymocytes. We find that loss of the 5′ PC results in a repertoire skewed against distal Trbv segments but favors proximal Trbv usage. Deletion of another CTCF site at the 3′ end of the locus, near the DβJβ clusters, does not significantly alter Trbv repertoire, presumably due to functional redundancy with another set of DβJβ-flanking CTCF sites. To test how transcriptional state affects the Trbv repertoire, we deleted an area spanning the Trbv12-2 and Trbv13-2 segments, which displays the highest levels of transcriptional and chromatin activation. We find that Trbv12/13 deletion enhances the usage of neighboring Trbv genes in the primary repertoire. Collectively, these data show that specific CTCF sites and regional transcription, at least in part, shape Tcrb repertoire.
A critical epithelial survival axis regulated by MCL-1 maintains thymic function
Authors: Jain Reema , Sheridan Julie M. , Policheni Antonia , Heinlein Melanie , Gandolfo Luke C. , Dewson Grant , Smyth Gordon K. , Sansom Stephen N. , Fu Nai Yang , Visvader Jane E. , Mintern Justine D. , Tan Iris , Holländer Georg , Strasser Andreas , Gray Daniel H.D. 
Published: January 2023

Abstract
T cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function. Age-related thymic involution is recognised as a potentially fatal brake on immune recovery following haematopoietic stem/progenitor cell transplantation and cancer treatments. To uncover new strategies to restore thymic function, we determined the molecular mechanisms that control life and death decisions in TEC. We recently published that while TEC-specific deletion of pro-survival proteins BCL-2 and BCL-XL did not cause gross abnormalities, MCL-1 deficiency impacted on TEC as early as E15.5, resulting in early thymic atrophy, T cell lymphopenia, with near complete loss of thymic tissue by 2 months of age. MCL-1 was continually required for the survival of medullary TEC, including autoimmune regulator (AIRE) expressing TECs and the maintenance of overall thymic architecture. A screen of TEC trophic factors in organ cultures showed that epidermal growth factor upregulated MCL-1 via the MAPK/ERK kinase activity, providing a molecular mechanism for the support of TEC survival. However, these findings do not imply that the intrinsic pathway of apoptosis necessarily controls TEC death during homeostasis. Therefore, we removed essential effectors of this pathway, BAX and BAK, specifically in TECs and found that there was a specific increase in a medullary TEC subset leading to an overall increase in TEC numbers both in young and old mice. This signalling axis governing TEC survival, death and thymic function represent a compelling strategy for protecting the thymus during blood cancer treatment to prevent immunodeficiency, without counterproductive survival of haematopoietic lineages.
A requirement for Lysine-specific histone demethylase 1A (Lsd1) for T cell development
Authors: Stamos Daniel , Li Liqi , Rosenfeld Michael , Love Paul E. 
Published: January 2023

Abstract
Lysine-specific demethylase 1A (Lsd1), also known as Kdm1a, is a part of the histone demethylase family of enzymes. Histone demethylases are key epigenetic regulatory proteins of the mammalian genome that participate in chromatin remodeling. It has been shown that Lsd1 mediates H3K4me2/me1 histone demethylation, and this event has been connected with gene repression in hematopoietic stem cells (HSC) and HSC maintenance. While Lsd1’s role in plasma cell differentiation and as a therapeutic target in cancer are well established, its role in T cell development has not been examined. To investigate Lsd1’s role in T cell development, we used the CD2i-Cre system to conditionally delete Lsd1 in immature double negative (DN) thymocytes. Here we show that deletion of Lsd1 causes a severe reduction in total thymocyte numbers attributable to a defect at the CD8+CD4−CD3lo intermediate single positive (ISP) stage. In addition, Lsd1 deficient T cells are reduced in number, exhibit a memory phenotype, and express low surface levels of T cell antigen receptor (TCR) as assessed by TCRβ and CD3 staining. Together, these findings identify an important role for Lsd1 in T cell maturation and indicate that regulation of H3K4 histone demethylation is essential at several critical stages of thymocyte development.
Lck activity regulates NKT subset development.
Authors: Alberola-Ila Jose , Berrett Hannah , Henry Sara 
Published: January 2023

Abstract
Invariant natural killer T cells (iNKT cells) are a conserved population that expresses a canonical TCR α rearrangement, Vα14-Jα18 in mice, and recognizes CD1d+glycolipid antigens. Different subsets of iNKT cells have been reported, including NKT1, NKT2 and NKT17 cells. We have shown that a small alteration in E protein activity during development of iNKT development results in a decrease in the development of NKT1s at the expense of NKT2 and NKT17 cells. E protein activity is regulated by the expression levels of Id proteins, which are induced downstream TCR signals during positive selection. Therefore, we hypothesized that changes in TCR signal strength may influence NKT subset differentiation. To test this we have used a gain-of-function, loss-of-function model, where signal strength is modified at the level of Lck by expression of a constitutive active (dLGF) or catalytically inactive (dLGKR) Lck mutant at low levels. Our results show that in dLGKR mice, which have less Id induction and increased E protein activity during positive selection, the percentage of NKT2 in the thymus is increased. In contrast, in dLGF(Balb/c) mice there is a dramatic shift from the NKT2 and NKT17 subsets in the thymus towards the NKT1 subset. These results suggest that TCR strength may bias NKT subset differentiation, but it is unclear what determines signal strength during NKT positive selection. Differential Vβ usage affects NKT TCR affinity for different ligands, and there is evidence that Vβ usage is biased (i. e. Vβ7 is overrepresented in NKT2). However, despite the major shift in subset representation in dLGF mice, there are only minor changes in the Vβ usage. Therefore, Vβ expression is unlikely to to be the only factor influencing TCR signal strength.
Vβ recombination signal sequences enforce TCRβ allelic exclusion
Authors: Wu Glendon S. , Yang-Iott Katherine , Bassing Craig 
Published: January 2023

Abstract
The assembly of antigen receptor (AgR) genes via RAG1/RAG2 (RAG) mediated recombination of variable (V), diversity (D), and joining (J) gene segments is essential for adaptive immunity. V(D)J recombination of Tcrb, Igh, and Igk loci is regulated such that functional AgR genes are assembled on and expressed from one allele (allelic exclusion) in most cells. It is assumed that allelic exclusion is achieved by mono-allelic initiation and feedback inhibition of the V-to-(D)J recombination step, and intrinsic features of recombination signal sequences (RSSs) have been proposed to mediate mono-allelic V-to-DJ recombination of Tcrb and Igh loci. To investigate the role of Vβ RSSs in enforcing allelic exclusion, we established and analyzed mice with the Trbv2 or Trbv31 RSS replaced by a RSS possessing greater recombination activity. Each of these RSS substitutions causes a profound increase in the development of T cells expressing either Trbv2+ or Trbv31+ TCRβ chains at the expense of cells expressing other TCRβ chains, reflecting that the RSSs flanking Vβ segments are major determinants of Vβ recombination frequency. Each RSS replacement also promotes a modest increase in the fraction of cells expressing Trbv2+ or Trbv31+ TCRβ chains along with another type of TCRβ chain. Strikingly, mice with Trbv2 and Trbv31 RSS replacements on opposite alleles have a 30-fold higher than normal level of bi-allelic Trbv2+ and Trbv31+ expression, demonstrating that the RSSs flanking Vβ segments enforce TCRβ allelic exclusion. Our data suggests that the infrequency of Vb recombination, as determined by weak Vβ RSSs, limits bi-allelic assembly of Tcrb genes within the time window before feedback inhibition permanently cements allelic exclusion.
Infantile-onset primary alveolar proteinosis with hypogammaglobulinemia caused by heterozygous mutations of 2′-5′-oligoadenylate synthase 1
Authors: Okano Tsubasa , Cho Kazutoshi , Kawamura Shunsuke , Onai Nobuyuki , Fujii Wataru , Kakuta Shigeru , Kanai-Azuma Masami , Ohteki Toshiaki , Imai Kohsuke , Kanegane Hirokazu , Otsu Makoto , Ariga Tadashi , Morio Tomohiro 
Published: January 2023

Abstract
2′-5′-oligoadenylate synthase 1 (OAS1) is one of the interferon-stimulated genes (ISG) which plays a critical role in innate anti-viral immunity. Stimulated by viral double strand RNA (dsRNA), OAS1 produces 2′-5′ linked oligomer of adenylates (2′-5′A) and the produced 2′-5′A activates ribonuclease-L (RNase-L) which results in degradation of viral RNA and inhibition of viral replications.
We identified autosomal inherited OAS1 missense mutations in three Japanese pedigrees with infantile-onset primary alveolar proteinosis with hypogammaglobulinemia. Patients’ peripheral blood monocytes and CD11c+ myeloid dendritic cells (mDC) were progressively decreased; CD27+ memory B cells were lacking. The alveolar macrophages showed decreased phagocytosis activity; and the enlarged and foamy form was scarcely observed, which were typical in conventional pulmonary alveolar proteinosis (PAP). Their bone marrow monocyte progenitors were decreased and showed reduced colony forming potentials. One of the patients is currently alive without PAP after hematopoietic stem cell transplantation.
The recombinant mutant OAS1 protein had unaltered dsRNA binding activity. Patient-derived lymphoblastoid cell lines showed normal expression of OAS1 protein and mRNA, and unaltered function in OAS1 - RNase-L pathway. We generated model OAS1 knock-in mice by CRISPR/Cas9 based gene editing and analyzed immune-phenotypes. The mice show normal B and DC numbers and normal serum immunoglobulin levels so far. Detailed functional study on mutant OAS1 protein with the multi-Omics approach is currently underway.
Cell-intrinsic PD-L1 and PD-1 signal effects in bladder cancer
Authors: Zhang Deyi , Sun Xiujie , Gupta Harshita B. , Reyes Ryan M. , Svatek Robert S. , Curiel Tyler J. 
Published: January 2023

Abstract
PD-1/PD-L1 provides a mechanism of immune escape, the blockage of which has reinvigorated interest in the treatment of urothelial cancer. We recently reported on cell-intrinsic PD-L1 effects in melanoma and ovarian cancer, and considered that effects in bladder cancer cells could differ based on distinct mutational landscapes. Using CRISPER/Cas9 methodology, we knockout PD-L1 in the murine bladder cancer cell line MB49 and the human bladder caner cell line RT. We show here that cell-intrinsic MB49 and RT4 cells express PD-L1 and PD-1 that each mediate cell-intrinsic signals. PD-L1 knockout has little effect on cells proliferation in vitro, but significant difference could be found in tumor size when we used MB49 Ctrl or MB49 PD-L1KO cells to challenge C57B16 mice. αPD-L1 and αPD-1 antibodies reduced bladder cancer cell proliferation in vitro demonstrating direct signaling effects. Bladder cancer cell-intrinsic PD-L1 promoted mTORC1 and tumor initiating cell generation similar to melanoma and ovarian cancer cells. By contrast to melanoma and ovarian cancer cells, bladder cancer cell PD-L1 promoted autophagy and had little effect on in vivo immune-independent growth. Base one the functional role, PD-L1 knockout increased proliferation inhibition induced by Rapamycin in both mouse and human bladder cancer cells. Furthermore, we found intrinsic PD-L1 suppress cytokine production, including CXCL10. Corresponding with increased CXCL10 secretion, more CXCR3+ NK cells could be attracted by PD-L1KO cancer cells. Overall, our findings further illustrated the intrinsic role of PD-L1 in bladder cancer development and found PD-1 expression on human bladder cancer cells for the first time.