bluuebunny/crossref_metadata_2025_split huggingface dataset:
Curdlan induces Th17 polarization via Jagged1 activation in human dendritic cells (47.12)
Authors: Matsushita Sho , Hashimoto Kumiko , Takagi Rie , Higashi Takehiro 
Published: January 2023

Abstract
Th17-inducing activity is carried by certain polysaccharides such as ƒÀ-glucan derived from Candia albicans. Our previous studies have shown that Th1- and Th2-inducing activities can be qualitatively evaluated by the expression patterns of Notch ligand isoforms, using human monocyte-derived dendritic cells (DCs) and some leukemic cell lines. Thus, the Th1- and Th2-inducing activities correlate with the upregulation of Delta4 and Delta1 mRNA, respectively. However, the association of Th17-inducing activities with Notch ligand expression patterns has been unclear. The present study shows that curdlan, one of ƒÀ-glucans, has the ability to induce DC-mediated Th17 differentiation, by using a mixed lymphocyte reaction (MLR) between human monocyte-derived DCs and allogeneic naïve CD4+ T cells. It is also interesting to note that Jagged1 mRNA in DCs is up-regulated by curdlan. Furthermore, polyclonal anti-Jagged1 antibody inhibited such DC-mediated Th17 differentiation. These findings suggest that curdlan induces human DC-mediated Th17 polarization via Jagged1 activation in DCs.
A method for enrichment and detection of viable human and mouse IL-17-secreting T cells (47.16)
Authors: Assenmacher Mario , Niemoeller Michaela , Foerster Anna , Zyntek Claudia , Winkels Monika , Schmitz Jürgen , Richter Anne 
Published: January 2023

Abstract
IL-17 plays a key role to defend infections, but also in chronic inflammatory disorders. We developed tools for the enrichment and detection of IL-17-producing cells.
After T cell activation IL-17 was detected on the surface of IL-17-producing cells after first labeling the cells with a bispecific CD45-IL-17 antibody affinity matrix. Cells were again cultured for 45 min to allow IL-17 secretion. Secreted IL-17 was specifically caught onto the affinity matrix of IL-17-producing cells. Subsequently IL-17-secreting cells were fluorescently stained with a second IL-17 antibody or additionally labeled with magnetic beads.
Stimulation of mouse spleen cells with PMA/ionomycin showed a maximal IL-17 secretion after 4 h in &lt;0.5% of CD4 and CD8 T cells, but in around 20% g/d T cells and 7% NKT cells. In contrast in human PBMC the IL-17 secretion was mainly restricted to CD4 T cells, with a maximum of 0.1-1% of them producing IL-17 after 4 h activation with the artificial superantigen CytoStim. Magnetic enrichment yields in IL-17+ cell populations with a purity of &gt;90%. Nearly all of the enriched IL-17+ CD4 T cells co-expressed CD154, confirming the specificity of the detection and enrichment method.
The IL-17 secretion assays allow detection of IL-17-secreting cells and provides highly enriched populations of viable IL-17-producing cells to investigate its function and the role of IL-17 in host defense and disease development.
Different by Destruction: Unequal Inheritance of the Transcription Factor T-bet as a Mechanism to Diversify Daughter T Cell Fates (47.29)
Authors: Chang John T , Kim Jiyeon , Kinjyo Ichiko , Yin Catherine , Berg Leslie , Jordan Martha , Koretzky Gary , Reiner Steven L. 
Published: January 2023

Abstract
We have previously suggested that asymmetric cell division might represent a mechanism to ensure that appropriate diversity of cell fate arises from the descendants of a single lymphocyte during an immune response. We now show that the fate-determining transcription factor T-bet is asymmetrically inherited by dividing CD4+ and CD8+ T cells recruited into an immune response. T-bet is induced in interphase T cells within hours of activation. During mitosis, T-bet undergoes proteasome-dependent degradation. Mitotic destruction is mediated by T cell receptor-induced tyrosine phosphorylation of T-bet. Unequal inheritance of T-bet is associated with asymmetric segregation of the proteasomal degradative machinery during mitosis and cytokinesis. Mutations of T-bet at the critical tyrosine and those disabling the T cell receptor-associated kinase, ITK, both result in symmetric inheritance of T-bet without affecting asymmetry of the proteasome. These results suggest that two experimentally distinct mechanisms promote the unequal inheritance of T-bet by initial daughter T cells: one signal that targets T-bet for mitotic destruction and another signal that renders inequality in the inheritance of the cellular machinery that destroys T-bet. These findings offer a new framework for understanding how signaling to a single T lymphocyte can result in unequal fate determination of its daughter cells.
Notch ligand-Dll4 regulated T cell activation and IL17 production (47.30)
Authors: Mukherjee Sumanta , Schaller Matthew A. , Lukacs Nicholas W. 
Published: January 2023

Abstract
The activation and differentiation of T cells are dependent upon numerous initiating events that are influenced by the immune environment, nature of the antigen, as well as the activation state of APCs. The study evaluated how activation by a specific notch ligand, delta-like 4 (DLL4), expressed by dendritic cells relates to the development of specific aspects of T cell differentiation. In particular, our data have indicated that DLL4 is inducible by pathogen-associated signals through TLR activation but not by early response inflammatory cytokines, IL-1 and IL-18 that also activate cells via MyD88 adapter molecules. To investigate the ability of Dll4 to activate T cells, our observations from in vitro specific cultures with ovalbumin peptide specific TCR transgenic cells (DO11.10) confirmed earlier reports that Dll4 inhibits Th2 cytokine production but further indicated that it also influences the generation of IL-17 producing T cells. However additional skewing conditions were necessary to drive IL17 production. In the absence of notch signals IL17 production was significantly inhibited. We also identified that both RORγt and IL17 are direct transcriptional notch targets that further enhance the differentiation of Th17 cell populations. Thus, the regulation of T cell differentiation may depend upon the efficient activation of T cells by specific notch ligand stimulation by novel activation pathways.
Acknowledgement: This work was supported by the NIH RO1-AI073876 grant to Nicholas W. Lukacs.
Mammalian target of rapamycin complex 2 regulates helper T cell differentiation and function (47.31)
Authors: Lee Keunwook , Gudapati Prathyusha , Magnuson Mark , Killeen Nigel , Boothby Mark 
Published: January 2023

Abstract
Mammalian target of rapamycin (mTOR) is involved in cellular processes such as survival and proliferation. Regulation of the original rapamycin-sensitive complex, mTORC1, in signaling downstream from Akt is well defined. However, physiological roles in lymphoid cells of an alternative mTOR complex, mTORC2, are unknown. Using conditional deletion of rictor, an essential subunit of mTORC2, we recently uncovered a rate-limiting role of mTORC2 in T cell development and Akt activation. We now show that mTORC2 regulates helper T cell development and function by a pathway that is either Akt-dependent or largely independent of Akt, depending on the direction of differentiation. Specifically deleting rictor late in T cell ontogeny impaired T cell help to Ab class switching for both Th1- and Th2-regulated isotypes. mTORC2 relayed signaling of helper T cell help differentiation into both Th1 and Th2 effector cells, and proliferation distinct from pro-survival effects. Strikingly, a constitutive active Akt was sufficient to restore normal Th1, but not Th2 differentiation. Overall, our data indicate that mTORC2 plays fundamental roles in cellular differentiation while orchestrating differential signaling relays.
AhR-dependent changes in gene transcription induced by TCDD during naive CD4+ T-cell differentiation (47.5)
Authors: Rohlman Diana C , Pham Duy , Steppan Linda B , Kerkvliet Nancy I 
Published: January 2023

Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ligand for the AhR and a potent immunosuppressant in vivo, inhibiting Th1, Th2 and Th17 T-cell dependent responses. The AhR is an orphan receptor that functions as a ligand-activated transcription factor upon dimerization with AhR nuclear translocator (ARNT). In this study, AhR-dependent changes in expression of genes associated with T-cell differentiation or containing AhR-ARNT binding sequences were examined. Purified CD4+ T-cells were stimulated under Th0 or Th1 conditions for 24, 36 or 48 hours in the presence of TCDD or vehicle. RNA was isolated for real time PCR. Treatment with TCDD significantly increased the expression of AhR-regulated genes Cyp1a1 and Cyp1b1 under both Th0 and Th1 conditions, in AhR+/+ but not AhR-/- T-cells. Expression of the AhR gene itself was not altered. Under Th0 conditions, expression of Tbet, IL-10, CTLA-4 and IFNy was decreased, while expression of CD69, IL-12rb2, Gata3 and Nfe2l2 was increased. Under Th1 conditions TCDD-treated cells responded with increased expression of IFNy, IL-12rb2 and Tbet, but decreased Stat4. These results support the hypothesis that AhR activation by TCDD influences early CD4+ T-cell differentiation. (Supported by NIEHS Training Grant #T32ES007060)
The tyrosine kinase MerTK negatively regulates the function of murine natural killer T cells (47.7)
Authors: Flores Rafael R. , Wang Bo , Tisch Roland 
Published: January 2023

Abstract
NKT cells have multiple effector functions including the capacity to prevent the growth of tumors, and the ability to immunoregulate autoimmunity. The key events that regulate NKT cell activation and function remain ill-defined. Recently, NKT cells were shown to express the receptor tyrosine kinase (RTK) Mer (MerTK). MerTK belongs to the Tyro3 RTK family. These RTK mediate the clearance of apoptotic cells (AC) and regulate the activation of dendritic cells (DC) and macrophages. Recently, we demonstrated that DC lacking MerTK are resistant to the inhibitory effects of AC. In this study, we sought to determine the role for MerTK in regulating NKT cell activation and function. To address this issue C57BL/6 mice (B6) lacking MerTK expression (B6.mertkkd/kd) were employed. Our data demonstrates that unprimed B6.mertkkd/kd NKT cells exhibit a heightened level of activation in comparison to wild-type NKT cells, while long-term exposure to alpha-GalCer (αGC) activated both sets of NKT cells similarly. Previously primed B6.mertkkd/kd NKT cells secreted cytokines upon subsequent stimulation with αGC, whereas wild-type NKT cells failed to be activated and remained anergized. In addition, stimulation with αGC pulsed DC, IFNγ and IL-4 production was significantly increased in NKT cells prepared from B6.mertkkd/kd versus B6 mice. These results indicate that MerTK serves to down-regulate cytokine production by NKT cells.
Novel role of tissue transglutaminase (TG2) in chronic inflammatory diseases (48.12)
Authors: Cexus Olivier Nicolas Felix , Labrousse Delphine , Luciani Alessandro , Elliott Tim , Maiuri Luigi , Quaratino Sonia 
Published: January 2023

Abstract
Tissue transglutaminase (TG2) has a critical role in the pathogenesis of chronic inflammatory diseases. We have previously described the key role of TG2 in cystic fibrosis (CF), a genetic disease characterised by chronic lung infections and inflammation. In CF, mutation on the CFTR gene results in an increased TG2 expression and activity leading to functional sequestration of the anti-inflammatory PPARγ and increase of inflammation.
Here we tested whether in vivo inhibition of TG2 can reverse inflammation in chronic inflammatory diseases. To assess the importance of TG2, we injected cystamine, a potent TG2 inhibitor, in a transgenic mouse model of CF and in the TAZ10 transgenic mice that spontaneously develop autoimmune thyroiditis.
Intraperitoneal administration of cystamine had a significant impact on the lung epithelium in the CF model, where it decreased TG expression and activity. The treatment was also able to dampen all the classic inflammatory parameters as well as restoring normal cellular levels of functional PPARγ. Interestingly, cystamine injections could also block inflammation in the TAZ10 TCR transgenic mouse model, highlighting the pivotal role of TG2 in generating inflammation in two very different pathologies.
This work underlines the critical role of TG2 in inflammation and provides new opportunities to develop therapeutic strategies for sufferers of chronic inflammatory diseases.
A critical role of BTLA in peripheral T cell tolerance induction (48.18)
Authors: Liu Xikui , Alexiou Maria , Martin-Orozco Natalia , Chung Yeonseok , Nurieva Roza , Tian Qiang , Lu Sijie , Kollias George , Graf Daniel , Dong Chen 
Published: January 2023

Abstract
T cell activation and tolerance are delicately regulated by costimulatory molecules. Although B and T lymphocyte attenuator (BTLA) has been shown as a negative regulator for T cells activation, its role in peripheral T cell tolerance induction in vivo has not been addressed. In this study, we generated a novel strain of BTLA-deficient mice, and employed three different models to characterize the function of BTLA in controlling T cell tolerance. In an oral tolerance model, BTLA-deficient mice were found resistant to the induction of T cell tolerance to an oral antigen. Moreover, compared with wild-type OT-II cells, BTLA-/- OT-II cells were less susceptible to tolerance induction by high-dose Ova peptide administered intravenously. Finally, BTLA-/- OT-I cells caused autoimmune diabetes in RIP-mOVA recipient mice. Our results thus demonstrate an important role of BTLA in the induction of peripheral tolerance of both CD4+ and CD8+ T cells in vivo.
Distinct lineages of human T-cell clones, including Th17/Th1 cells, isolated at different stages of anti-factor VIII immune responses (48.26)
Authors: Ettinger Ruth A , James Eddie A , Liberman Joseph A , Kwok William W , Thompson Arthur R , Pratt Kathleen P 
Published: January 2023

Abstract
Approximately 25% of hemophilia A patients, who lack functional factor VIII (FVIII), develop neutralizing antibodies after receiving therapeutic infusions of FVIII. HLA-DRA-DRB1*0101-restricted T-cell clones that respond to FVIII2194-2213 were isolated from a hemophilia A subject (the proband) ~5 and 21 months following his development of a high-titer FVIII neutralizing antibody response, and from his brother who has not developed a clinically significant antibody response. Three clones obtained from the proband at 5 months were TH17/TH1-polarized and two were TH1/TH2-polarized. The 8 proband clones isolated at 21 months were TH2-polarized, indicating T-cell lineage changes over time. The 6 clones from the brother were TH1-polarized, indicating that B-cell tolerance to FVIII can be maintained even with circulating antigen-specific TH1-polarized cells. Several TCRBV-D-J junction sequences were identified suggesting differences in TCR interaction with the MHC class II-peptide complex. Current investigations are examining the response of clones to altered peptide ligands. This is the first evidence that TH17/TH1-polarized cells play a role in hemophilic immune responses to FVIII; it is also the first detailed characterization of antigen-specific TH17/TH1 clones isolated using standard culture conditions.
Research Support: Bayer Hemophilia Award, CSL Behring Hemophilia Research Award, NIH.
Alterations in both coagulation and fibrinolytic pathways mediate thrombosis in the skin during murine Graft-Versus-Host (GVH)-induced scleroderma (48.5)
Authors: Burwell Tim , Delaney Tracy , Chen Cindy , Connor Jane , Coyle Anthony J , Lemaire Raphael 
Published: January 2023

Abstract
Scleroderma is a systemic autoimmune disease characterized by fibrosis, inflammation and vasculopathy of the skin, kidney and lung. The vasculopathy features occlusion of small arteries due vasoconstriction, intimal proliferation and thrombosis. Thrombosis results from an imbalance between coagulation and fibrinolysis. Whether thrombosis in scleroderma is primarily due to alteration in fibrinolysis or coagulation remains unclear. In this study, we investigated thrombosis in a murine GVH model of human scleroderma exhibiting an occlusive vasculopathy. We looked at fibrinolysis and coagulation biomarkers in skin, kidney and lung using qPCR and IHC. GVH skin showed microthrombi in dermis blood vessels. This was associated with an increase in a number of key regulators of fibrinolysis (PAI-1, tPA and uPAR) and coagulation (Tissue Factor, Factor VII and X), suggesting that thrombosis in GVH skin is caused by alterations in both fibrinolysis and coagulation pathways. Unlike skin, kidney and lung did not show fibrinolysis and coagulation alterations, suggesting that vasoconstriction rather than thrombosis mediates the occlusive vasculopathy in these tissues, consistent with increased endothelin-1 levels in kidney VSMCs. In conclusion, our study suggests that the GVH mouse is a useful model to study the balance of fibrinolysis and coagulation leading to thrombosis in scleroderma vasculopathy in the skin.
Uptake of apoptotic dendritic cells by viable dendritic cells: a novel mechanism of inducing immune tolerance (48.7)
Authors: Kushwah Rahul , Wu Jing , Oliver Jordan R , Jiang George , Zhang Jinyi , Siminovitch Katherine A , Hu Jim 
Published: January 2023

Abstract
Dendritic cells (DCs) are professional antigen-presenting cells, which can be affected by the death of other cells in close proximity. Spontaneous DC apoptosis has been observed in patients with sepsis and breast cancer. Additionally defects in DC apoptosis have also been associated with development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses are unclear. Here we show that apoptotic DCs can mediate induction of immune tolerance by converting immature DCs into tolerogenic DCs. The uptake of apoptotic DCs by viable DCs prevents LPS-induced activation and T-cell proliferation, and also results in the upregulation of TGF-beta2 gene expression and TGF-beta1 secretion, which mediates differentiation of naïve T cells into regulatory T cells (Tregs). Additionally, delivery of apoptotic DCs prevents LPS-induced DC maturation and migration to lymph nodes in mice. Moreover, intranasal delivery of apoptotic DCs to LPS-inflamed lungs results in rapid resolution of inflammation along with production of TGF-beta1 and expansion of Tregs. Delivery of apoptotic DCs followed by immunization with ovalbumin (OVA) in Complete Freund's Adjuvant (CFA) resulted in generation of OVA-specific Tregs in wild-type mice and expansion of Tregs in T-cell receptor transgenic (OT-II) mice. Taken together, our findings identify apoptotic DCs as potent inducers of immunological tolerance.
The soluble CTLA-4 splice variant affects the function of CD4+CD25+ regulatory T cells (49.10)
Authors: Kissler Stephan , Fischer Kay , Zheng Peilin , Rainbow Dan , Wicker Linda 
Published: January 2023

Abstract
Type 1 diabetes is a polygenic autoimmune disorder. One of the genetic polymorphisms linked to type 1 diabetes, as well as to other autoimmune diseases, is located within the CTLA-4 gene. This polymorphism is associated with a change in splicing frequency, altering the ratio between full-length and soluble CTLA-4 (sCTLA-4) in human. The role and function of sCTLA-4 are as yet unknown. To investigate the sCTLA-4 isoform in a model organism, we generated nonobese diabetic (NOD) mice in which expression of sCTLA-4, but not full-length or ligand-independent CTLA-4, is constitutively reduced by RNAi. We find that loss of sCTLA-4 significantly reduces the potency of regulatory T cells, providing a possible explanation for the effect of the human CTLA-4 polymorphism on disease susceptibility. Our study demonstrates the utility of RNAi for the study of single splice variants in vivo, and supports a role for sCTLA-4 in regulatory T cell function.
A polymorphism within interleukin-21 receptor (IL21R) confers risk for systemic lupus erythematosus and is associated with malar rash in lupus patients (49.17)
Authors: Sawalha Amr , Webb R , Merrill J , Kelly J , Sestak A , Kaufman K , Langefeld C , Ziegler J , Kimberly R , Edberg J , Ramsey-Goldman R , Petri M , Reveille J , Alarcón G , Vilá L , Alarcón-Riquelme M , James J , Gilkeson G , Jacob C , Moser K , Gaffney P , Vyse T , Nath S , Lipsky P , Harley J 
Published: January 2023

Abstract
Interleukin (IL) 21 is a member of the type I cytokine superfamily that exerts a variety of effects on the immune system including B cell activation, plasma cell differentiation, and immunoglobulin production. The IL21 receptor (IL21R) is expressed on B cells, T cells, NK cells, and monocyte-derived dendritic cells. The expression of IL21R is reduced in B cells from lupus patients, while IL21 serum levels are increased in both lupus patients and some lupus-murine models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to lupus. Herein, we genotyped SNPs in the IL21R gene located on chromosome 16p11. We identify and confirm the association between rs3093301 and lupus in two independent European-derived and Hispanic cohorts (p=7.2X10-5). In addition, the presence of the homozygous risk genotype in rs3093301 (A/A) was associated with the development of malar rash in the European-derived female lupus patients (OR=2.83, 95% CI=1.56-5.13, p=0.00045).
Development of inflammatory arthritis in DR4 transgenic and wild type DBA/1J mice immunized with human fibrinogen (49.9)
Authors: Cordova Kristen N , Holers V. Michael 
Published: January 2023

Abstract
The human MHC allele DR4 is associated with susceptibility for rheumatoid arthritis (RA). Citrullinated proteins, derived from the conversion of peptidyl-arginine to peptidyl-citrulline, are present in the joints of RA patients, who also uniquely produce high levels of anti-citrullinated protein antibodies (ACPAs). ACPAs enhance damage in animal models of autoimmune arthritis. DR4 molecules have been shown to preferentially bind citrullinated peptides over arginine controls. Recently, the DR4 allele was shown to be essential to develop arthritis in C57Bl/6 mice immunized with human citrullinated fibrinogen, but these mice demonstrated delayed arthritis at relatively low incidence and severity as compared to other arthritis models.
To potentially obtain a more susceptible strain, we backcrossed the DR4 gene onto the DBA1/J strain. Following immunization with either human citrullinated or noncitrullinated fibrinogen, these mice developed inflammatory arthritis around day 24 regardless of whether they were DR4+ or DR4- littermates. Serum from both strains demonstrated ACPA generation as defined by reactivity to a citrullinated but not control peptide, as well as a splenic proliferative response to both citrullinated and noncitrullinated human, but not mouse, fibrinogen. The DR4 DBA/1J transgenic strain may provide a useful tool for the analysis of ACPA-related arthritis.
Grant U19 AI146374