bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo blocking CD80 promotes Th17 polarization and amplifies autoimmune arthritis severity in mice infected with Mycoplasma arthritidis (43.15)
Authors: Mu Hong 
Published: January 2023

Abstract
Mycoplasma arthritidis, an agent that causes acute and chronic autoimmune arthritis and septic shock in rodents. Previously we demonstrated that the severity of septic shock induced in mice injected with M. arthritidis is associated with the up-regulation of co-stimulatory molecule CD80 on APCs and blockade of CD80 specifically enhances the severity of arthritis. In the present study, we report that anti-CD80 resulted in increased number of Th17 T cells and level of IL-23 expression by macrophages resulting in the increased expression and production of IL-17 and augmented Th17-associated transcriptional factors RORgt and Stat3 by CD4+ T cells. Also in arthritis susceptible mouse strain, injection of anti-TLR4 mAb significantly suppresses IL-23 response and IL-17 by CD4+ T cells and alleviate the arthritis. The inhibition of Th17 response by anti-TLR4 treatment is partially associated with the suppression of CD80 function. In addition, to elucidate the role of MAM, the superantigen secreted by M. arthritidis in Th17 polarization, mice injected with MAM-mutant M. arthritidis strains showed impaired IL-17 production, remarkably lower IL-23 and improved arthritis symptoms. Thus the contribution of MAM appears to be important for IL-17 contribution in the disease pathogenesis and is clearly involved in modulating pathways of immune responses leading to different disease outcomes and phenotypes in M. arthritidis-induced autoinflammatory disease.
Deficiency in interleukin 10 reverses the susceptibility phenotype of CBA/J mice during infection with Mycobacterium tuberculosis. (43.23)
Authors: Turner Joanne , Cyktor Joshua , Carruthers Bridget , Kominsky Rachel , Stromberg Paul , Beamer Gillian 
Published: January 2023

Abstract
Interleukin 10 is a known correlate of susceptibility to tuberculosis (TB) in man and similarly, elevated levels of IL-10 (either natural or induced) in mice can accelerate TB disease progression. The CBA/J mouse strain is a model that naturally produces abundant IL-10 and is also highly susceptible to infection with Mycobacterium tuberculosis (M.tb). We have generated CBA/J mice deficient in IL-10 (IL-10 KO) to determine the mechanisms of influence of IL-10 on TB disease progression in this highly susceptible mouse strain. In contrast to IL-10 KO on resistant mouse strain backgrounds where the lack of IL-10 has little impact on TB outcome, the CBA/J IL-10 KO was fully capable of limiting M.tb growth within the lung and spleen for an extended period of time, with over 2 Log fewer M.tb colony forming units (CFU), compared to CBA/J wild type. This reduction in bacterial growth correlated with a highly significant extension in survival, relative to CBA/J wild type mice. The ability to control M.tb infection was associated with an early detection of IFN-gamma within the lung and the detection of IFN-gamma producing antigen specific T cells throughout infection. Of particular significance was the finding that CBA/J IL-10 mice developed mature granulomas (encircled by collagen) with necrotic centers containing M.tb bacillus of variable acid-fast staining.
Identification of Plasmodium berghei novel liver stage CD8 T cell epitopes by caged MHC class I tetramer technology (43.30)
Authors: Pichugin Alexander , Ehrler Lindsey , Sehrawat Sharvan , Funk Theresa , Speake Cate , Duffy Patrick , Ploegh Hidde , Krzych Urszula 
Published: January 2023

Abstract
Studies conducted in mice and humans have shown that IFN-γ+ CD8 T cell are the key effectors against liver-stage (LS) malaria; however, owing to complexities associated with the development of Plasmodia parasites, specificities of CD8 T cell effectors have been difficult to establish. Direct detection of Ag-specific CD8 T cells in high-throughput manner became possible with the development of caged MHC-tetramer technology, based on conditional photo-cleavable MHC class I ligands that can be displaced during UV induced exchange with a peptide of interest. On the basis of previously identified P. falciparum (Pf) genes expressed exclusively during LS infection, we identified P. berghei (Pb) orthologues of Pf genes and validated their expression by qRT-PCR in Pb infected C57Bl/6 mice. Several Pb LS antigens, administered as DNA vaccines, significantly reduced LS parasite burden in mice infected with Pb sporozoites. Using sequences of the 28 novel Pb LS genes we screened ~400 peptides by the caged MHC class I tetramer approach. Our preliminary results demonstrate that 2 H-2Kb- and 1 H-2Db-restricted Pb peptides that correspond to protective Pb LS Ags form MHC class I tetramers that specifically bound to CD8 T cells from mice immunized with radiation-attenuated Pb sporozoites. Identification of these epitopes is crucial towards resolving the role of antigen-specific CD8 T cell responses and establishing these responses as correlates of protection to Plasmodia infection.
CCL19-Cre transgenics: targeting lymph node fibroblastic reticular cells in vivo (44.14)
Authors: Ludewig Burkhard , Chai Qian , Onder Lucas , Scandella Elke , Sparwasser Tim , Luther Sanjiv , Thiel Volker , Rülicke Thomas , Hehlgans Thomas 
Published: January 2023

Abstract
The paracortex of lymph nodes (LNs) harbors a sponge-like scaffold of stromal cells known as fibroblastic reticular cells (FRCs). A major function of FRCs is to build and enwrap the conduit system of collagen fibers that directs interstitial fluids from the afferent lymph through the T-cell zone to HEVs. Furthermore, FRCs regulate T-cell migration and survival by producing the chemokines CCL19 and CCL21. To gain further knowledge on the biology of FRCs and possibly other stromal cell subsets, we have generated a bacterial artificial chromosome (BAC)-transgenic mouse model that utilizes the CCL19 promoter to direct the Cre-recombinase to LN stromal cells. Crossing of CCL19-Cre mice to the R26-EYFP reporter revealed that transgene expression in LNs was almost exclusively confined to podoplanin+CD31- cells. Likewise, transgene activity in spleens and Peyer’s patches of CCL19-Cre mice was largely restricted to FRC-like cells, i.e. stromal cells within the T cell zone and the T-B border. Selective ablation of the lymphotoxin-beta receptor on CCL19-Cre-positive cells resulted in profound changes in the development and organization of secondary lymphoid organs. Taken together, stromal CCL19-Cre expression is well-suited (i) to characterize the development of LN FRCs in vivo, (ii) to molecularly dissect the contribution of stromal cells to lymphoid organogenesis, and (iii) to address the function of LN FRCs in the generation of innate and adaptive immune responses.
Interleukin-22 Ameliorates Cerulein-Induced Pancreatitis in Mice by In-hibiting the Autophagic Pathway (44.15)
Authors: Park Ogyi , Feng Dechun , Radaeva Svetlana , Wang Hua , Yin Shi , Kong Xiaoni , Zheng Mingquan , Zakhari Sam , Kolls Jay , Gao Bin 
Published: January 2023

Abstract
Pancreatitis occurs when digestive enzymes are activated in the pancreas. Severe pancreatitis has a 10-30% mortality rate. No specific treatments for pancreatitis exist now. Here, we discovered that interleukin-22 (IL-22) may have therapeutic potential in treating acute and chronic pancreatitis. Wild-type and IL-22 knockout mice were equally susceptible to ceru-lein-induced acute and chronic pancreatitis, whereas liver-specific IL-22 transgenic mice were completely resistant to cerulein-induced elevation of serum digestive enzymes, pancreatic necrosis and apoptosis, and inflammatory cell infiltration. Treatment of wild-type mice with recombinant IL-22 or adenovirus IL-22 markedly attenuated the severity of cerulein-induced acute and chronic pancreatitis. Mechanistically, we show that the protective effect of IL-22 on pancreatitis was mediated via the induction of Bcl-2 and Bcl-XL, which bind to Beclin-1 and subsequently inhibit autophagosome formation to ameliorate pancreatitis. In conclusion, IL-22 ameliorates cerulein-induced pancreatitis by inhibiting the autophagic pathway. IL-22 could be a promising therapeutic drug to treat pancreatitis.
Interleukin-22 promotes liver progenitor cell proliferation in mice and patients with in viral hepatitis (44.16)
Authors: Feng Dechun , Kong Xiaoni , Weng Honglei , Park Ogyi , Wang Hua , Dooley Steve , Gershwin Eric , Gao Bin 
Published: January 2023

Abstract
The proliferation of liver progenitor cells (LPCs), which have bipotential capabilities to differentiate into hepatocytes and biliary epithelial cells, is often observed in the inflammatory region of chronic liver diseases; however, how inflammation promotes LPC proliferation remains obscure. We examined the role of IL-22 on LPC proliferation on human viral hepatitis patients and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding mice model. We found that interleukin-22 (IL-22), a survival factor for hepatocytes, is highly elevated and correlates with the grade of inflammation and LPC proliferation in patients with viral hepatitis. In a murine model of LPC proliferation induced by feeding DDC diet, overexpression of IL-22 in the liver via the generation of liver-specific IL-22 transgenic (IL-22TG) mice or injection of IL-22 adenovirus markedly increases LPC proliferation. STAT3, the major downstream signal of IL-22, is highly activated in the LPCs from DDC-fed IL-22TG mice. An additional deletion of hepatocyte-specific STAT3 in IL-22TG mice diminishes LPC proliferation. In vitro IL-22 treatment activates STAT3 and increases cell proliferation of isolated EpCAM+CD45-LPCs from DDC-fed mice and BMOL cells (a mouse LPC line), both of which are detected expression of IL-22R1. Conclusion: inflammatory cell-derived IL-22 promotes LPC proliferation via an STAT3-dependent manner, and IL-22 is a key link between inflammation and LPC proliferation in viral hepatitis.
Interaction of vimentin and phosphorylated mitogen-activated protein kinases in FcϵRI and CC chemokine receptor 1 engaged mast cells (44.18)
Authors: Kuo Chuan-Hui , Toda Masako , Borman Satty , Richardson Ricardo , Inoko Akihito , Inagaki Masaki , Schneider Klaus , Ono Santa 
Published: January 2023

Abstract
Accumulating evidence points to cross-talk between FcϵRI and CC chemokine receptor (CCR)-mediated signaling pathways in mast cells. Here, we propose that vimentin, a protein composing type III intermediate filament, participates in such cross-talk for CCL2/ monocyte chemotactic protein 1 production in mast cells. Co-stimulation via FcϵRI, with IgE/antigen, and CCR1, with recombinant CCL3/macrophage inflammatory protein-1α increased expression of phosphorylated, disassembled and soluble vimentin in rat basophilic leukemia (RBL)-2H3 cells expressing human CCR1 (RBL-CCR1 cells), a model of mucosal type mast cells. Furthermore, the co-stimulation enhanced production of CCL2 and phosphorylation of mitogen-activated protein (MAP) kinases. Treating the cells with p38 MAP kinase inhibitor SB203580, but not with MAP kinase kinase (MEK) inhibitor PD98058, reduced CCL2 production, suggesting that p38 MAP kinase, but not extracellular-signal-regulated kinase 1/2 (ERK1/2), plays a critical role in the chemokine production. Immunoprecipitation analysis showed association of vimentin with phosphorylated ERK1/2 and p38 MAP kinases in the co-simulated cells. Preventing formation of the soluble vimentin by aggregating vimentin filaments using beta,beta'-iminodipropionitrile reduced the association of vimentin with phospholylated MAP kinases, and CCL2 production in the cells. Taken together, soluble vimentin could need optimal CCL2 production in mast cells.
The Effect of Cytokine Biasing During CD8 T Cell Priming on Subsequent Memory Development (44.22)
Authors: Marshall Brett , Klonowski Kimberly 
Published: January 2023

Abstract
Following encounter with cognate antigen in the context of an APC, CD8 T cells undergo rapid expansion, contraction, and a select few will differentiate into memory T cells poised for rapid response upon subsequent antigen exposure. While several studies have described the phenotype of precursor memory T cells and the signals responsible for their survival and entry into the memory pool, it is becoming clear that the priming environments for each infection model are distinct and may influence memory development. Our studies address the physiological relevance of individual and combinations of common gamma chain cytokines, which may differentially be present during CD8 T cell priming and contribute to the subsequent development of specific subsets of memory T cells. Our studies use an in vitro model system in which CD8 T cells are primed with dendritic cells in the presence of IL-2, IL-7, and IL-15, as well as thymic stromal lymphopoietin (TSLP). These studies test the effects of various combinations of cytokine stimuli during T cell priming on the development of KLRG1-CD127+ memory precursors, as well as their further differentiation into CCR7+CD62Lhi central or CCR7-CD62Llo effector memory subsets following adoptive transfer into recipient animals. Together, our studies will help identify cytokine milieus best capable of driving development of specific subsets of CD8 memory, which may have implications for optimal immunity to distinct pathogens.
Effect of antimicrobial proteins/alarmins on DNA mediated activation of pDC and inflammation. (45.11)
Authors: Tewary Poonam , de la Rosa Gonzalo , Sharma Neeraj , Rodriguez Luis , Shirota Hidekatzu , Steinhagen Folkert , Klinman Dennis , Yang De , Oppenheim Joost 
Published: January 2023

Abstract
Plasmacytoid dendritic cells (pDCs) commonly known as IFN-α producing cells, detect microbial nucleic acids via endosomal Toll-like receptor (TLR)-7 and TLR-9. Antimicrobial peptides (AMPs) like LL37, derived from neutrophil granules and keratinocytes enhance the production of IFN-α by pDCs by forming complexes with self nucleic acids by converting them into a potent trigger of pDC activation (Lande K. et al. Nature 449-564, 2007). This report led us to study the effect of other antimicrobial proteins stored in neutrophils or produced by keratinocytes during inflammation. In this study we present opposing effects of two antimicrobial alarmins; Human Beta Defensin 3 (HBD3) and Lactoferrin (LF), on IFN alpha production by pDCs. HBD3, an epithelial cell product and a host defense molecule, acts as a potent activator of pDCs by promoting DNA induced IFN alpha production by pDC and subsequent activation of bystander myeloid cells. Hence HBD3 may be important contributor to ongoing inflammation and can exacerbate inflammation in autoimmune pathologies like psoriasis. On the other hand LF inhibited DNA induced IFN alpha production by preventing uptake of both self and CpG DNA indicating that it acts as a scavenger molecule for DNA motifs, potentially reducing the undesirable effects of high levels of IFN-α. We therefore propose that a delicate balance between different AMPs present at inflammatory sites determines the outcome of IFN-mediated pDC activation.
Visualization of the splenic iNKT cell effector program reveals cross-talk with dendritic cells at the marginal zone (45.13)
Authors: Leadbetter Elizabeth , King Irah , Tighe Michael , Veerapen Natacha , Besra Gurdyal , Mohrs Markus 
Published: January 2023

Abstract
Invariant Natural Killer T (iNKT) cells are an innate, CD1d-restricted T cell lineage that rapidly secretes cytokines such as interleukin (IL)-4 and interferon gamma upon activation. iNKT cells potentiate adaptive T cell immunity, in part, by activating or “licensing” dendritic cells (DCs). However, the choreography of DC licensing within secondary lymphoid organs remains unclear. Using a combination of gene reporter mice and mCD1d-specific tetramer staining in situ, we localize the endogenous splenic iNKT cell population and characterize their migration pattern and site of canonical cytokine production in response to cognate lipid antigen encounter. We show that iNKT cells are distributed throughout the spleen of naive mice, but upon activation with αGalCer or pathogen-derived lipids rapidly accumulate in the bridging channels and marginal zone where they secrete IL-4. Early iNKT cell cytokine production and migration depends on the presence of marginal zone DCs. iNKT activation acts reciprocally to upregulate CCR7 and relocalize marginal zone DCs to the splenic T cell zone, another means by which iNKTs may “license” DC-mediated adaptive immunity. Studies of iNKT migration and DC licensing during live bacterial infection are currently underway to further understand how iNKT cells exert their anti-microbial effects in vivo.
A fast and simple method for the isolation of untouched human gamma-delta T cells from PBMC (45.7)
Authors: Tabatabaei-Zavareh Nooshin , Le Fevre Tim , Thomas Terry , Fairhurst Maureen 
Published: January 2023

Abstract
T cells expressing the γδT cell receptor (γδTCR) comprise a minor subset of human circulating T cells (1-10%). γδT cells are distinct from αβT cells in that they exhibit limited combinatorial diversity of the TCR and recognize non-peptide antigens independent of HLA molecules. γδT cells exert innate effector functions including rapid release of cytokines and killing of target cells. Adaptive immune responses such as memory functions have also been attributed to γδT cells. Typically, elaborate purification protocols such as FACS-based cell sorting or expansion in culture are needed to obtain enough γδT cells for subsequent studies. Here, we describe a negative selection method to isolate untouched γδT cells from fresh or previously frozen peripheral blood mononuclear cells (PBMC). This method uses immunomagnetic, column-free cell separation technology (EasySepTM). Briefly, bispecific antibody complexes are used to cross-link non-γδT cells to dextran-coated magnetic particles. The unwanted cells are then removed using an EasySepTM magnet. Starting with 3±0.9% γδTCR+ T cells in PBMC, purities of 90±2% (n=7) are achieved. The isolated γδT cells produce IFN-γ when activated with non-peptide antigens. γδT cells have potential therapeutic applications in cancer and infectious diseases. This rapid method for the isolation of γδT cells will assist in the study of γδT cell biology and the development of γδT cell-based immunotherapies.
B16 melanoma inhibits cellular response to Interleukin-12 via multiple mechanisms including paracrine action of Wnt-inducible Signaling Protein-1 (46.10)
Authors: Klinke David , Kulkarni Yogesh , Chambers Emily , McGray A. J. Robert , Ware Jason , Bramson Jonathan 
Published: January 2023

Abstract
Interleukin-12 (IL12) enhances anti-tumor immunity when delivered locally within the tumor microenvironment. However, immunoregulatory elements within the tumor microenvironment are thought to dampen the effect of IL12 as an adjuvant. The objective of this study was to identify biochemical mechanisms of tumor-immune cell cross-talk that locally suppress the action of IL12. A high content in vitro assay was developed to quantify tumor-mediated suppression of the action of IL12 using a T helper type 1 cell line. Following an induction period, the melanoma cell model, B16F0, inhibited the cellular response to IL12 in vitro. This paracrine effect was not explained by induction of apoptosis or creation of a cytokine sink, despite both mechanisms at work within the co-culture assay. Secreted protein, acidic and rich in cysteine (SPARC); exosomes; and Wnt-inducible signaling protein-1 (WISP-1) were identified using a proteomics workflow and confirmed to be enriched in B16F0-conditioned media. Neutralization of WISP-1 recovered and recombinant WISP-1 dose-dependently inhibited the activity of Signal Transducer of Activated Tyrosine 4 (STAT4), a key transcription factor within the IL12 pathway, within the in vitro co-culture assay. Moreover, WISP-1 was expressed in vivo following intradermal challenge with B16F10 cells and exhibited an inverse dependence on tumor size.
Identification of HER-2/neu peptide p373-382 as a naturally processed immunodominant HLA-A2 binding epitope (46.11)
Authors: Henle Andrea , Erskine Courtney , Benson Linda , Knutson Keith 
Published: January 2023

Abstract
HER2 is a prime target for cancer therapeutics due to its high overexpression in tumors. Advanced clinical trials, in breast and prostate cancer, investigating the use of the HLA-A2-binding HER2 peptide p369-377 (E75) as a vaccine are ongoing. In the present study, we investigated the proteasomal processing of p369-377 and other epitopes from HER2. We did not detect processing of p369-377 by either the proteasome or immunoproteasome in vitro, suggesting that tumor cells do not naturally process this epitope from HER2 for presentation on HLA-A2. However, other HER2 peptides were found to be consistently processed by the proteasome and immunoproteasome. One newly identified processed peptide, HER2 p373-382, was found to bind HLA-A2 stronger than p369-377, despite algorithms that predicted p369-377 as a stronger binder. Cytotoxic T lymphocytes (CTL) specific for p373-382 recognized target cells pulsed with either p373-382 or p369-377. CTL specific for p373-382 also lysed HER2+HLA-A2+ human breast cancer cells more efficiently than p369-377-specific CTL. These results suggest that cancer cells are naturally processing and presenting p373-382. Furthermore, our results suggest that T cells generated against p369-377 in previous studies may have been cross-reacting with p373-382. Thus, the newly identified p373-382 peptide may be a more appropriate candidate for vaccines with this new evidence that it is processed and presented by HLA-A2 for recognition by HER2-specific CTL.
A CD28 based bi-directional molecular bridge that support plasma cell survival in the bone marrow. (46.16)
Authors: Nair Jayakumar , Murray Megan , Koorella Chandana , Rozanski Cheryl , Carlson Louise , Shaughnessy John , Bergsagel P. , Boise Lawrence , Lee Kelvin 
Published: January 2023

Abstract
Dendritic cells (DC) are essential for the long term survival of plasma cells (PC) in the bone marrow and for the maintenance of persistent antibody titers. But the molecular basis for these interactions is not very clear. Both normal and malignant PC (like myeloma) express the T-cell co-stimulatory molecule CD28. Our data show that CD28 expressed on PC play a major role in CD80/CD86 (B7) mediated DC induction of growth factors such as IL-6 and immunosuppressive enzyme indoleamine 2,3 dioxygenase (IDO) as well as in antibody or DC mediated protection of PC in vitro. While IL-6 protected PC in vitro, IDO induced the formation of regulatory T cells in culture. Use of myeloma drug lenalidomide to inhibit DC-B7 expression or anti-CD28(Fab)2 fragments to block CD28-B7 interactions reduced DC ability to protect MM cells or produce IL-6/IDO. Moreover, just like in T-cell models, CD28 activation in malignant PC triggers similar molecular events such as tyrosine phosphorylation and association of p85. We believe that downstream of CD28, while PI3K/Akt governs survival, the Vav1/SLP76 pathway regulate PC proliferation and these form the molecular basis for a bi-directional molecular bridge between the PC and bone marrow microenvironment. Targeting this bridge could form the basis for future therapeutic strategies. Our data suggests a role for CD28-B7 in plasma cell survival by modulating the bone marrow microenvironment.