bluuebunny/crossref_metadata_2025_split huggingface dataset:
The murine Pbx1-d lupus susceptibility allele accelerates mesenchymal stem cell differentiation and impairs their immunosuppressive function (BA4P.143)
Authors: Morel Laurence , Lu Shun , Zeumer Leilani , Sorensen Heather , Riva Alberto , Croker Byron , Wallet Shannon 
Published: January 2023

Abstract
Pbx1-d is a dominant negative splice isoform of the gene Pbx1 that corresponds to the NZM2410 lupus susceptibility locus Sle1a1. Pbx1 is required to maintain stem cell self-renewal, including that of mesenchymal stem cells (MSCs). MSCs have immunosuppressive functions that require stem cell maintenance. We tested the hypothesis that the expression of Pbx1-d favors MSC differentiation and impairs their immunosuppressive functions. We demonstrate that Sle1a1 MSCs express high levels of Pbx1-d as compared to congenic C57BL/6 (B6) MSCs. Sle1a1 MSCs grew faster and differentiated significantly more rapidly into osteoblasts than B6 MSCs. This corresponded to a significant decrease in the expression of genes associated with stemness and an increase in the expression of genes associated with differentiation. In addition, Sle1a1 MSCs express a gene expression profile associated with an enhanced innate immunity and inflammation. Suppression of Ig production from TLR-activated B6 B cells and IL-2 secretion from activated B6 CD4+ T cells was significantly impaired is Sle1a1 MSCs as compared to B6 MSCs. B6.Sle1a1 MSCs showed intermediate activity in suppressing lupus immunophenotypes in three different mouse models. Together these data suggest that the expression of the lupus susceptibility allele Pbx1-d isoform impairs MSC functions, which may contribute to lupus pathogenesis both through a defective immunosuppression and the promotion of a pro-inflammatory environment.
B7-H1 regulates autoimmunity in αCTLA-4, bm12 transfer and pristane-induced models through distinct sexually dimorphic and non-dimorphic effects (BA4P.128)
Authors: Gupta Harshita , Clark Curtis , Lin Pei , Pandeswara Srilakshmi , Hurez Vincent , Curiel Tyler 
Published: January 2023

Abstract
Females have more autoimmunity through poorly understood mechanisms. Regulatory T cells (Tregs) defend against autoimmunity. We show that B7-H1 signals dampen estrogen (E2)-driven Treg mTOR activation through estrogen receptor-β, maintaining Treg function in E2. B7-H1-/- female mice (but not males or WT of either sex) developed αCTLA-4-induced autoimmunity, rescued by E2 removal or B7-H1+/+ dendritic cell (DC) transfer. Monocytes or B or T cells also gave protective B7-H1 signals to restore Treg function in E2. B7-H1-mediated E2 protection was during Treg differentiation and was not via CD80, PD-1 or Treg B7-H1. E2 also reduced male B7-H1-/- Treg function in vitro and in vivo. Sex-matched B7-H1-/-bm12 splenocyte transfer (minor MHC mismatch) caused lupus symptoms (albuminuria, alopecia) earlier in B7-H1-/- females than B7-H1-/- males or WT. B7-H1-/- males also sickened faster than WT males, showing sex-independent B7-H1 effects. Transfer of B7-H1+/+bm12 splenocytes into B7-H1-/- mice did not induce rapid symptoms, suggesting rescue by B7-H1 signals in bm12 cells. In pristane-induced lupus, B7-H1-/- females had earlier proteinuria than WT females. Plasmacytoid DC or granulocytes from female B7-H1-/- produced more IFN-α in vitro with pristane+TLR7 agonist than WT females. Thus, B7-H1 regulates autoimmunity through diverse sexually-dimorphic and non-dimorphic mechanisms. Defining B7-H1 effects in autoimmunity will help understand female predilection and immunopathogenesis.
Impact of weight loss on obese adipose tissue immune cell function (CAM1P.154)
Authors: Zamarron Brian , Mergian Taleen , Martinez-Santibanez Gabriel , Lumeng Carey 
Published: January 2023

Abstract
Obesity induces inflammation in adipose tissue involving the recruitment and activation of macrophages, CD8+ and CD4+ T cells. These cells play a critical role in the development of insulin resistance seen with obesity. Weight loss can improve insulin resistance and health, but little is known concerning the effects of weight loss on immune activity in adipose tissue. Diet switch from a 60% high-fat diet to 13% normal-fat diet was used to induce weight loss in diet-induced obese C57Bl/6 mice. Adipose tissue fibrosis and macrophage accumulation was evaluated by histology. Leukocyte populations were analyzed by flow, including sorting and cytokine expression comparisons of adipose tissue macrophages before and after weight loss. Weight loss improved glucose tolerance and reduced serum insulin. However extensive adipose fibrosis developed after diet switch and was associated with macrophage accumulation. Analysis of macrophages after weight loss showed they retained a pro-inflammatory gene expression profile and had high surface marker expression of T cell co-stimulatory markers, similar to macrophages found in obese adipose tissue. These adipose macrophages were comprised of both old and newly recruited cells that continued to be activated after weight loss. The continued inflammatory activation of leukocytes after weight loss may help explain the variation seen in metabolic improvements and long-term weight management of patients in response to weight loss interventions.
Grem1 is a key regulator of synovial hyperplasia in rheumatoid arthritis. (CAM1P.162)
Authors: Han Eun-Jin , Choi Sussanna , hwang daehee , you sungyong , Kim Wan-uk 
Published: January 2023

Abstract
Fibroblast like synoviocyte plays critical roles is the major cell in the inflammatory processes of Rheumatoid arthritis. We attempted to identify a key regulator that can drive aggressive phenotypes of RA FLS. For this, we performed an integrative transcriptome data analysis using three datasets from independent RA studies, a panel of normal tissues, and NCI60 cancer cell line panel. Through the analysis, we identified Gremlin (GREM1), which is robustly up-regulated in RA and predominantly expressed in FLS. GREM1 is identified as bone morphogenetic proteins antagonist and is known to bind BMPs. To investigate potential roles of GREM1 in RA, we first examined the level of GREM1 expression in synovial tissues, synovial fluid (SF) and FLS from RA. Immunohistochemistry and ELISA revealed up-regulation of GREM1 protein in RA compared to OA. Proinflammatory cytokines also induced the expression of GREM1 in RA FLS and their expressions were significantly correlated with GREM1 expression in RA SF. We next investigated cellular functions of GREM1 using RA FLS. GREM1 deficieny by siRNA elicited significant suppression of FLS proliferation, migration and invasion. In contrast, stimulation with rhGREM1 to RA FLS increased cell survival and invasion. Furthermore, we found that GREM1 activates AKT1 and MAPK signaling cascade, as well as antagonizes BMP2. This study demonstrated that GREM1 is a key regulator responsible for synovial hyperplasia and FLS migration.
Proinflammatory role of tissue-resident fibroblastic reticular cells (CAM1P.146)
Authors: Klementowicz Joanna , Tang Qizhi 
Published: January 2023

Abstract
Fibroblastic reticular cells (FRC) play an important role in maintaining immune homeostasis and orchestrating immune responses by producing chemokines and cytokines that promote immune cell migration, organization, function, and survival in secondary lymphoid organs. However, little is known about their function in the development and maintenance of inflammation in the tissue. Here we show that FRC-like cells can be found in inflamed islets of Langerhans in type 1 diabetes-prone NOD mice. No FRC are found in non-inflamed islets and crucially their number increases with severity of islet infiltration. Islet FRC share many characteristics of lymph node FRC, including CCL19 and IL-7 expression. However, in contrast to lymph node FRC, islet FRC are a major source of IFNγ-induced CXCL9 in inflamed islets, indicating their more proinflammatory phenotype. In addition, co-culture of islet FRC with activated T cells results in increased expression of proinflammatory molecules including granzymes, perforin, and IFNγ by T cells. Finally, LTβR-Ig treatment leads to dramatic reduction of islet FRC, which is associated with a significant loss of CD4 and CD8 T cells among islet infiltrates as early as 3 days after treatment. These data indicates FRC-like cells in inflamed tissue actively contribute to the local inflammatory responses and may act as a viable therapeutic target for the treatment of type 1 diabetes.
Unprocessed IL-36a co-operates with IL-1 in psoriasiform skin inflammation (CAM1P.148)
Authors: Jensen Liselotte , Milora Katelynn , Fu Hangfei 
Published: January 2023

Abstract
Psoriasis has been linked to overzealous IL-1 and IL-36 signaling; however, whether these cytokines have redundant, interrelated or independent functions have not been examined. It is also unknown if the IL-36 cytokines undergo processing in vivo. Here, we examined IL-36 expression, functional involvement and interaction with IL-1/IL-1R1 signaling in a mouse model of drug induced psoriasiform skin inflammation. Normal skin did not express detectable levels of IL-36a, IL-36b, or IL-36g protein. All 3 cytokine mRNAs were up-regulated during inflammation; however, only IL-36a secretion could be detected in explant skin cultures. Significantly less (25%, p&lt;0.01) was released from IL-1R1 deficient skin. This demonstrates that IL-1 regulates IL-36a expression in vivo. Interestingly, the released IL-36a was not processed. Using knockout (KO) mice for each individual IL-36 cytokine, we found that IL-36a, but not IL-36b and IL-36g, significantly contributed to pathology. Specifically, we observed thinner epidermis and decreased dermal inflammation in IL-36a KO mice compared to wild type. Treated IL-36a/IL-1R1 double KO mice exhibited even thinner epidermal and dermal thickness. Neutrophil recruitment to the epidermis was impaired in the IL-36a KO mice, but could be rescued with application of the chemokine CXCL1. In summary, we conclude that IL-1 dispatches unprocessed IL-36a, which in turn boosts the pro-inflammatory activity of IL-1 signaling during psoriasis-like skin inflammation.
Integrin αvβ8-mediated TGFβ activation by effector regulatory T cells is essential for suppression of T cell-mediated inflammation (CAM1P.150)
Authors: Travis Mark , Kelly Aoife , Smedley Catherine , Bauché David , Campbell Simon , Marie Julien , Worthington John 
Published: January 2023

Abstract
Foxp3+ regulatory T-cells (Tregs) play a pivotal role in suppressing self-harmful T-cell responses to prevent inflammatory disease. An important cytokine in the development and function of Tregs is TGFβ, a latent cytokine that must be activated to function. Compelling evidence suggests that T-cells need to respond to TGFβ in order for Treg-mediated suppression to occur. Yet, how TGFβ is regulated to promote this suppression is poorly understood. We now show that both mouse and human Tregs have high expression of the TGFβ-activating integrin αvβ8, which enables these cells to activate high levels of latent TGFβ. However, deletion of integrin αvβ8 expression from Tregs resulted in no overt phenotype at rest, indicating that the integrin plays little role in controlling immunity during homeostasis. Strikingly, we find that integrin αvβ8 expression and function is highly upregulated on an activated/effector Treg subset marked by KLRG1, and that Tregs lacking expression of integrin αvβ8 were unable to function as suppressive cells during models of colitis and delayed type hypersensitivity in vivo. Thus, we have uncovered an essential mechanism by which effector Tregs suppress T-cells during inflammation, highlighting a key role for Treg-mediated activation of latent TGFβ in suppression of self-harmful T-cell responses. Our work therefore highlights a novel pathway that could be therapeutically targeted to treat inflammatory disease.
IL-1 family members induce pro-inflammatory cytokine release in costimulated T cells outside of TCR stimulation (CCR3P.209)
Authors: Tsurutani Naomi , St. Rose Marie-Clare , Mittal Payal , Adler Adam , Vella Anthony 
Published: January 2023

Abstract
Toll-like receptor stimulation induces production of pro-inflammatory cytokines such as IL-1 or IL-12 that act as a 3rd signal in programming antigen-specific effector T cell differentiation. Signal 3, however, can stimulate already differentiated effector T cells to release cytokines such as IFN-g or IL-4. The identity of signal 3 mediators is important to better understand how signal 3 can drive T cell function in the absence of an obvious TCR ligand, which could occur during infection or cancer. We discovered that IL-36 play this role when T cells were co-stimulated with TNF super family members and had differentiated into effectors. By RT-PCR it was found that IL-2 induced IL-36 receptor gene expression and that IL-36 stimulation, in the absence T cell receptor stimulation, released prodigious levels of IFN-g. To understand how signal 3 responses were related to cellular function we used an RNA-POL ChIP-seq approach and found that optimally costimulated T cells were more prone to possess a higher metabolic state. Measurement of glycolysis in these T cells confirmed that they were actively able to consume glucose, but as this activity diminished so did the capacity to respond to IL-36. Thus, the data suggest that T cells can use an “innate” response pathway such as the IL-36R pathway but only when they are undergoing a strong glycolytic response. Therefore, cytokine therapy for effector T cells is possible as long as they are in the correct metabolic state.
The TORC1-activated proteins, p70S6K and GRB10, regulate IL-4 signaling and M2 macrophage polarization by modulating phosphorylation of insulin receptor substrate-2 (CCR3P.214)
Authors: Heller Nicola , Fang Xi , McCormick Sarah , Gowda Nagaraj , Thompson Joshua , Lamworth Jessie , Warren Kristi 
Published: January 2023

Abstract
The abundance of M2 macrophages in the airways of both human asthmatics and mouse models correlates with disease severity. M2 macrophage differentiation is induced by IL-4 and IL-13. The cytosolic adaptor, IRS-2, is tyrosine phosphorylated (pY-IRS-2) following engagement of the type I IL-4 receptor and it mediates M2 gene expression. Therefore, the goal of this study was to determine negative regulators of IRS-2 activity. We found an inverse relationship between tyrosine and serine phosphorylation of IRS-2. IRS-2 was highly serine phosphorylated (pS-IRS-2) in unstimulated cells and pS-IRS-2 levels decreased as pY-IRS-2 increased following IL-4 stimulation. Inhibiting serine phosphatase activity caused a dramatic increase in IRS-2 serine phosphorylation and IL-4-induced M2 gene expression was ablated. By using phospho-serine kinase arrays and inhibitors of serine/threonine kinases, we showed that TORC1 and p70S6K inhibition but not TORC2, JNK or GSK3β inhibition, resulted in prolonged pY-IRS-2. p70S6K inhibition also augmented expression of the hallmark human M2 macrophage genes, CD200R, CCL22, and TGM2. Lastly, we showed interaction between IL-4Rα, γC, IRS-2 and the TORC1-activated protein GRB10. Using siRNAs to GRB10, we enhanced pY-IRS-2, prolonged IL-4 receptor expression and increased M2 gene expression in human monocytes after IL-4 stimulation. These data highlight p70S6K and GRB10, downstream of TORC1, as key negative regulators of IL-4 signaling in human monocytes.
An alternatively spliced IL-15 isoform modulates cell activation via inducing differential IL-15 receptor-dependent signaling pathways (CCR3P.203)
Authors: Ku ChiaChi , Chang Yi-Hsuan , Lee Tsung-Lin , Chien Yun , Lin Yu-Jei , Kung John 
Published: January 2023

Abstract
IL-15 is a pleiotropic cytokine mediating proliferation and survival of memory CD8+ T cells, natural killer (NK) and NKT cells as well as enhancing cytokine production. Deregulated and excessive expression of IL-15 has been implicated in promoting pathophysiologic state for human inflammatory diseases and malignant transformation. In a routine phenotype-driven screen, we identified a point mutation in exon 7 of the IL-15 gene in Pedigree 191 of N-ethyl-N-nitrosourea (ENU) mutagenized mice which expressed a depressed level of CD44 in CD8+ T cells (called DM for deficiency in memory) and resulted in an increased expression of alternatively spliced IL-15 isoform (IL-15ΔE7). Mechanical stimulation of DM skin reduced keratinocyte activation. Ectopic expression of IL-15ΔE7 in WT skin profoundly blocked neutrophil infiltration to inflamed skin induced by abrasion, sodium dodecyl sulfate or immiquimod treatment, suggesting a regulatory role of IL-15∆E7 in mediating proinflammatory response in skin. While treating T cells with recombinant soluble IL-15∆E7 protein activated a transient but delayed activation of MAPK/p38, IL-15∆E7 failed to activate phosphorylation of STAT5 and its downstream target bcl-2 expression. The capacity of IL-15ΔE7 in inducing differential signaling has pointed IL-15ΔE7 as a potential therapeutic agent for treating inflammatory disorders.
Immune-related trends in bio-medical literature (CCR3P.208)
Authors: Geifman Nophar , Bhattacharya Sanchita , Butte Atul 
Published: January 2023

Abstract
Bio-medical knowledge, including immunology-related knowledge, evolves and changes over time. Examining such changes, along with other immune-related patterns and trends may reflect changes in the field and may assist in detecting new and un-addressed areas of research. We have recently developed a cytokine-centered knowledgebase focusing on the role of cytokines in diagnostics and therapeutics and their association with immune cell types and a variety of different diseases. As a part of its initial development, the knowledgebase was extensively populated with information extracted from relevant biomedical literature. Here, we present interesting cytokine-, cell- and disease-related trends found in the literature (and captured in our knowledgebase). For example, the association of Rheumatoid Arthritis (RA) with tumor necrosis factor alpha (TNFa) has increased over time; on the other hand, at the same time, there was a dramatic decrease in the number of publications linking RA with Interleukin 1 indicating a shift in the focus of RA-cytokine related research. Such changes over time in immune-related topics as well as the association of cytokines and diseases across different tissue types, age groups and ethnic groups demonstrates the usefulness of the knowledgebase in capturing immune-related patterns and focusing at possibly useful avenues of research.
TSLP plays roles that are distinct from IL7 in normal human B cell development (HEM1P.227)
Authors: Payne Kimberly , Milford Terry-Ann , Francis Olivia , Baez Ineavely , Coats Jacqueline , Dovat Sinisa , Morris Chistopher , Su Ruiijun 
Published: January 2023

Abstract
The role of TSLP in human B cell development is largely unknown and its function in context of IL7 is unstudied. We found that TSLP can replace IL7 in providing a signal essential for in vitro production and proliferation of human CD19+ Pax-5+ B cell progenitors. To study the role of TSLP in human B cell development, in the context of IL7 stimulation, we developed a novel xenograft model. Mouse IL7 is active on human cells, however, this is not the case for TSLP. We took advantage of this to develop a xenograft model system comprised of mice that provide human TSLP (+T mice) and control mice that do not (-T mice). Using this model we found that TSLP increases proliferation and upregulates Mcl-1 in CD34+CD19-IL7Ra progenitors resulting in a 3-4 fold expansion of the CD34+ pro-B cell compartment in +T as compared to -T mice. This expansion is maintained during subsequent stages of B cell development, partially due to increased protection from apoptosis that occurs independently of Bcl-2 family pro-survival proteins. While TSLP stimulates in vitro proliferation of pro-B cells, in vivo proliferation of B lineage precursors was similar in +T and -T mice suggesting redundancy with IL7. B cell subsets in normal pediatric bone marrow samples show progenitor ratios and Mcl-1 expression that mirrors that in +T xenograft mice. These data provide evidence that TSLP function in human B cell development includes both unique activities as well as activities redundant to those of IL7.
Bmi1 maintains the self-replenishing ability of B-1a cells in postnatal mice. (HEM1P.230)
Authors: Yoshimoto Momoko , Kobayashi Michihiro , Gao Rui , Yoder Mervin , Liu Yan 
Published: January 2023

Abstract
B-1a cells are innate immune cells that reside in the peritoneal cavity. We have recently reported that some B-1 cells originate from hemogenic endothelial cells in the early mouse embryo, and are independent of HSC-derived hematopoiesis. B-1a cells are also considered to possess self-replenishing capacity. The mechanisms that permit B-1a cells to undergo self-replenishment in vivo independent of HSCs remain unclear. Bmi1 is a polycomb group protein that is known to be critical for self-renewal of adult BM HSCs. In Bmi1-/- postnatal BM, the number of HSCs was markedly reduced and long-term reconstituting ability was lost. We hypothesized that Bmi1 is also critical for B-1a cell self-replenishment ability. Bmi1 mRNA expression was higher in B-1a cells than other lymphoid subsets in adult wild type mice. In Bmi1-/- mice, absolute cell numbers in the spleen, BM, and peritoneal cavity were decreased but the percentage of each mature lymphoid population was not altered except for B-1a cells. The percentage of peritoneal B-1a cells was 4-7 fold less than wild type. Bmi1-/- B-1a cells displayed impaired self-replenishing ability upon transplantation into the peritoneal cavity of recipient mice. Ink4a-Arf is one of the known target genes of Bmi1, and its expression is increased in Bmi1-/- HSCs and B-1a cells. The percentage and numbers of B-1a cells were restored in Ink4a-/-Arf-/-Bmi1-/- mice. These data suggest that Bmi1 maintains the self-replenishing ability of B-1a cells.
STAT5 antagonism of B cell superenhancer networks initiates progenitor B cell leukemia and predicts patient survival (HEM1P.222)
Authors: Farrar Michael , Katerndahl Casey , Heltemes Harris Lynn , Willette Mark , Henzler christine , Yang Rendong , Silverstein Kevin , Frietze Seth , Schjerven Hilde , Ramsey Laura , Hubbard Gregory , Muschen Markus , Kornblau Steven 
Published: January 2023

Abstract
B cell Acute Lymphoblastic Leukemia (B-ALL) arises from the transformation of progenitor B cells. The transcription factor STAT5 is required for transformation but how STAT5 mediates this effect is unclear. Previous studies suggested that STAT5 only acts to promote survival of progenitor B cells. However, other roles for STAT5 in B cell development and B-ALL have not been explored. Here we show that STAT5 activation drives leukemia in cooperation with defects in a linear signaling pathway emanating from the pre-BCR, including Blnk, Btk, Prkcb, Nfkb1, and Ikzf1. Using microarray analysis and ChIP-Seq we demonstrate that STAT5 disrupts the function of superenhancer binding transcription factor networks that normally promote B cell development. STAT5 versus NFkB or IKAROS binding to these enhancers largely had opposing effects on target gene expression. The antagonism between STAT5 and IKAROS or NFκB has direct clinical relevance as the balance between these transcription factors affects patient outcome; patients with high ratios of active STAT5 to NFκB or IKAROS had more aggressive disease characterized by shorter remission and decreased survival. Thus, our studies illustrate how modest perturbations in two opposing transcriptional programs can have dramatic consequences for B cell development and transformation and how the degree of antagonism between these transcriptional programs ultimately predicts patient outcome to therapy.