bluuebunny/crossref_metadata_2025_split huggingface dataset:
TCR signaling strength dependent regulation of T cell proliferation, survival and Th differentiation by TGF-βR3 (betaglycn)
Authors: Raman Chander , Ren Clark , Boas Stephanie , Sestero Christine M. , Chellappan Rajeshwari , Kesterson Robert A , De Sarno Patrizia , Soldevila Gloria 
Published: January 2023

Abstract
TGF-β receptor 3 (TGFβ-R3) or betaglycan, promotes high-affinity binding of TGF-β (1, 2 and 3) to TGFβ-R1 and TGFβ-R2. Additionally, it is also a receptor for bone morphogenic proteins (BMPs) and inhibins. Although TGFβ-R3 is widely expressed on cells of both the innate and adaptive immune system, embryonic lethality of Tgfbr3 knock-outs has been a limitation to obtain a mechanistic understanding of its function in immune response. We therefore developed a Tgfbr3f/fmouse and bred with the CD4Cre mouse. Remarkably, thymic inactivation of TGFβ-R3 had no significant effect on T cell development nor did the mice develop spontaneous autoimmunity. This led us infer that TGFβ-R3 is unlikely to have a necessary function in enhancing TGF-β signaling from TGFβ-R1/R2. To interrogate the function of TGFβ-R3 in mature T cells, we generated OT2.Tgfbr3f/f.dLckCre mice and control littermates. We observed that TGFβR-R3 deficient T cells exhibited greater early proliferation than controls, however, their ability to persist was compromised. This effect of TGFβ-R3 was more pronounced with increasing concentrations of OVA323–339 peptide. The differentiation of TGFβ-R3 deficient to Th1 cells under polarizing conditions was significantly reduced in proportion and absolute numbers compared to Tgfbr3f/f T cells and this correlated with lower Tbet expression. Encephalitogenic Th1 cells generated from Tgfbr3f/f.dLckCre mice induced significantly less severe EAE in naïve mice than that from Tgfbr3f/f littermates. Overall or data reveal a novel role for TGFβR3 in promoting of Th1 differentiation and regulation of regulation T-cell activation and survival.
A novel, intergenic enhancer contributes to Il2 gene expression via chromosomal looping.
Authors: Thomas Rajan M , Mehra Parul , Johnson Matthew , Grant Struan , Wells Andrew 
Published: January 2023

Abstract
IL-2 is a key immunoregulatory cytokine with pleotropic effects on many immune cell types. Its expression is highly regulated in T cells through multiple signaling pathways, chromatin remodeling, DNA methylation, and cooperative transcription factor binding. Recently, we identified an evolutionarily conserved intergenic enhancer 83 kb upstream of the Il2 gene that augments transcription from the Il2 promoter and upstream regulatory region (URR) by &gt;50-fold in recombinant reporter assays. Upon TCR/CD28 co-stimulation of primary CD4+ T cells, a long-range chromosomal loop is established between the −83 kb CNS and the endogenous Il2 promoter, and both regions become epigenetically marked by histone acetylation and methylation. To determine the relative contribution of the URR vs. this new distal element to inducible transcription of the Il2 gene, we deleted the URR or the −83 kb CNS in mice using CRISPR/CAS genome editing. Deletion of the URR (~500 bp beyond the TATA element) completely abolished the Il2 transcription by CD4+ T cells, while a ~500 bp deletion of the −83 kb CNS resulted in a 2- to 4-fold decrease in IL-2 production. Young mice deficient for the −83 kb enhancer exhibited no major defects in lymphoid development, however, mutant CD4+ T cells showed reduced proliferative capacity in vitro. Furthermore, TGFB-induced iTreg differentiation from mutant conventional CD4+ precursors was strongly impaired, but could be fully restored by addition of exogenous IL-2. These results show that induction of Il2 depends upon cooperation between the promoter-URR and at least one intergenic enhancer, and suggest mechanisms by which graded expression of Il2 might be achieved through ‘modular’ recruitment of distinct enhancer elements.
Inhibition of heme oxygenase-1 activity suppresses Mycobacterium tuberculosis infection in vivo by a mechanism dependent on T lymphocytes and IFN-γ production
Authors: Costa Diego L , Namasivayam Sivaranjani , Amaral Eduardo P , Arora Kriti , Mittereder Lara R , Maiga Mamoudou , Boshoff Helena I , Goulding Celia W , Andrade Bruno B , Sher Alan 
Published: January 2023

Abstract
Infection with M. tuberculosis (Mtb) induces the upregulation of heme oxygenase-1 (HO-1), a powerful antioxidant enzyme that catalyzes the degradation of heme into iron, biliverdin and carbon monoxide. We observed that administration of tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 activity inhibitor, to Mtb-infected mice resulted in pulmonary bacterial load reduction. Moreover, adjunct administration of SnPPIX to Mtb-infected mice receiving antibiotic treatment improved and accelerated pathogen clearance. Interestingly, both the induction of HO-1 expression in lungs of Mtb-infected mice and the efficacy of in vivo SnPPIX-mediated bacterial burden reduction were dependent on the presence of host TCR-α+ lymphocytes as well as IFN-γ suggesting a role for the immune response in the activity of the drug. Further investigation revealed that in the lungs of these immunodeficient mice the numbers of parenchymal CD11b+ myeloid cells staining positive for HO-1 were substantially reduced. SnPPIX treatment of Mtb-infected mouse bone marrow derived macrophages also resulted in diminished bacterial loads in vitro and this effect was reverted by iron supplementation and enhanced by iron chelation. Based on these observations we propose that HO-1 inhibition promotes control of Mtb by limiting the availability of nutrient iron and that the host Th1 response regulates this effect by controlling the recruitment to the lungs of a subset of myeloid cells that is both capable of HO-1 expression and permissive to bacterial infection. This work was supported by the intramural research program of the NIAID.
Non-apoptotic signaling through Fas activates Akt and promotes T cell differentiation through Caspase-8
Authors: Yi Fei , Ouyang Claudia , Yamamoto Tori , Cruz Anthony , Chan Francis K , Frazzette Nick , Thomas Stacy , Restifo Nicholas P , Siegel Richard M. 
Published: January 2023

Abstract
The TNF receptor Fas (CD95, TNFRSF6) is known for inducing apoptosis in primary cells via binding with Fas ligand (FasL) and activation of caspase-8 through the adapter protein FADD. In addition, recent research showed that the apoptotic signaling requires palmitoylation of Fas near its transmembrane region to localize on the lipid rafts. Fas palmitoylation-defective mutant is unable to induce apoptosis in primary cells but continues to enhance T cell differentiation into effector memory cells (CD44hiCD62Llo), indicating that Fas can also trigger non-apoptotic signaling in primary T cells. Fas non-apoptotic signaling has unexpected roles in modulating T cell tumor immunotherapy and autoimmunity (Klebanoff et al. 2016; Cruz et al. 2016). We have investigated the signaling pathways underlying non-apoptotic Fas signaling in T cells. Co-stimulation with oligomerized Fas Ligand activates Akt and ribosomal S6 protein phosphorylation, and Fas induced T cell differentiation is blocked by Akt or mTOR inhibitors. Further studies showed that T cells from RIP3−/− and Caspase-8−/− double deficient mice, but not mice deficient in RIP3, were refractory to Fas-induced differentiation, indicating that Caspase 8 is essential for Fas non-apoptotic signaling. Similar results were obtained with FADD. Our findings suggest that in addition to apoptotic functions, Fas also promotes non-apoptotic signaling via Caspase-8 and induces T cell differentiation by activating the Akt pathway. These results reveal a common role for Caspase-8 in non-apoptotic and apoptotic functions of Fas, with potentially different caspase-8 substrates mediating these diverse functions of a single receptor.
Chronic mTOR activity impaires lysosome maturation in lupus
Authors: Monteith Andrew J , Vincent Heather , Kang Sunah , Li Patrick , Claiborne Tauris , Moorman Nathaniel , Vilen Barbara 
Published: January 2023

Abstract
Multiple genetic and environmental factors activate lymphocytes and myeloid cells to promote systemic lupus erythematosus (SLE). This complexity has made it difficult to define underlying mechanisms. We previously demonstrated that hematopoietic cells from lupus-prone mice accumulate nuclear antigens on their cell surface due to an inability to mature the lysosome. On myeloid cells, the accumulation of nuclear antigens reflects IgG-immune complexes (IgG-ICs) bound to FcγRs. Further, lupus-prone mice lacking FcγRI fail to develop myeloid and lymphoid-associated pathologies suggesting a critical role for FcγRI in SLE. How FcγRI signaling influences lysosomal maturation is unclear. Herein, we show that lysosome acidification, a key step in the maturation process, relies on the strict regulation of mTORC2, activation of caspase-1, and cleavage of Rab39a. In macrophages from MRL/lpr mice, we find that chronic mTORC2 activation disrupts lysosomal maturation by inducing constitutive phosphorylation of cofilin. This prevents the association of cofilin with phagosomes containing IgG-ICs. As a result, inflammasome-independent activation of caspase-1 in proximity to the phagosome does not occur. Consequently, Rab39a remains intact on the phagosomal membrane, and the lysosome does not acidity. These findings reveal unique roles for mTORC2, cofilin, and pyroptototic caspases critical to an unappreciated signaling pathway promoting lysosome acidification. Further, this signaling cascade becomes disrupted in SLE, preventing the lysosome-mediated degradation of apoptotic debris upstream of multiple lupus-associated pathologies.
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces tolerance by altering the gut microbiome
Authors: Neamah Wurood Hantoosh , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
The compound 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) belongs to the polychlorinated dibenzodioxins (PCDDs) and is known to act as an immunosuppressant for humoral and cell-mediated responses. In the current study, we investigated TCDD-mediated mechanisms related immunosuppression. Gut microbiota serves an important role in immune function and development of disease, and it has been shown that changes in host microbiota is not only a marker of disease, but also actively contributes to disease pathogenesis. We, therefore, investigated how 3 days of TCDD exposure in mice could alter the gut microbiome compared to control groups. We performed 16S rRNA sequencing on bacterial DNA isolated from fecal samples from the experimental groups. We found separate clustering of the bacterial composition in TCDD versus the vehicle treated groups based on principal coordinate analysis. Interestingly, we found that TCDD-treated mice showed significant decrease in Sutterella, a bacterium belonging to Proteobacteria phylum, Betaproteobacteria class, Burkholderiales order and Alcaligenaceae family. Moreover, Sutterella is present normally in gut flora and elevated in some inflammatory disorders. Collectively, our data suggests that TCDD induces tolerance by inducing dysbiosis in gut microbiome that leads to impairment of proinflammatory bacteria.
Complexes assembled from myelin self-antigen and a toll-like receptor antagonist promote tolerance
Authors: Hess Krystina L , Jewell Christopher M 
Published: January 2023

Abstract
Myelin, a matrix that insulates the axons of neurons, is attacked by the immune system in multiple sclerosis (MS), leading to neurodegeneration. MS treatments are currently limited because they are non-curative and broadly-acting immunosuppressants that can leave patients immunocompromised. Recent reports show co-delivery of myelin peptides (MOG) along with regulatory signals can promote tolerance to myelin rather than cause inflammation. New studies reveal inflammatory toll-like receptors (TLRs) play a significant role in driving disease in both humans and mice. Further, several reports demonstrate that regular treatment with TLR9 antagonist, GpG, attenuates disease in mouse models of MS. We hypothesized that GpG DNA and cationic MOG peptide would electrostatically self-assemble into complexes, allowing co-delivery, increased cargo protection, and enhanced uptake by immune cells. These complexes might redirect the response against myelin through suppression of inflammatory TLR9 signaling during myelin presentation. Importantly, polyplexes significantly reduced inflammatory TLR9 signaling in a reporter cell line. Primary dendritic cells (DCs) internalized MOG-GpG complexes, resulting in a reduction of activation and decreased proliferation of myelin-reactive T cells. In a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), complex injection reduced disease severity more than 2-fold and incidence by 30%. This data demonstrates the ability of GpG to condense self-antigens while remaining an active immunomodulator. This work also suggests a new carrier-free platform for co-delivery of antigens and immune signals that still provides the more attractive features of biomaterials.
Effect of cannabidiol (CBD) on CD4+ cells under differential immunological activation state.
Authors: Dhital Saphala , Kaplan Barbara L. F. 
Published: January 2023

Abstract
We previously reported that cannabidiol (CBD), one of the Cannabis sativa-derived cannabinoids, induced functional CD4+CD25+FOXP3+ Tregs in response to low level stimulation of PMA/Io. CBD increased CD25+FOXP3+ cells in CD4+, CD4+CD25+, and CD4+CD25− T cells, as well as in CD4+ T cells derived from FOXP3-GFP mice. T cell stimulation conditions were suboptimal PMA/Io (4 nM/0.05 μM, S/o) and ultrasuboptimal PMA/Io (1 nM/0.0125 μM, Us/o). We also observed that CBD + Us/o increased IL-2, IL-10 and TGF-β1 immunomodulatory cytokines. Here, we measured the effect of CBD + Us/o or S/o on CD4+ cells. Splenocytes were treated with CBD (1–10 μM) for 30 min plus S/o or Us/o activation and cultured for 1 day or 5 days. Immunofluorescence staining showed that CBD + Us/o treatment increased the percentage of CD4+ cells while CBD + S/o treatment decreased the percentage of CD4+cells. CD4+CD25+ expression by Us/o or S/o activation alone was also measured. CD25 expression in response to Us/o activation was lower than that by S/o activation in CD4+ cells. This study will provide important information on the effect of CBD on CD4 cells under differential immunological activation state by PMA/Io.
Bee venom phospholipase A2 (bvPLA2) protects against LPS-induced abortion
Authors: Bae Hyunsu , Baek Hyunjung , Shin Dasom , Hwang Deok-Sang 
Published: January 2023

Abstract
Implantation of the fertilized egg into maternal uterus depends on the fine balance between inflammatory and anti-inflammatory processes that prepare the uterus for this important event. Regulatory T cells (Tregs) are a key regulator for the protection of allogenic fetus against rejection by maternal immune system. In the present study, we carried out to investigate the protective effects of bvPLA2 on LPS-induced abortion mice model. LPS was injected intraperitoneally to induce spontaneous abortion at day 9.5 of pregnancy and the mice were administered bvPLA2. The results clearly revealed that bvPLA2 can prevent the fetal loss accompanied by growth restriction in remaining viable fetus. When the LPS-induced abortion mice were treated with bvPLA2, Treg cells were significantly increased compared to the no pregnant, WT and LPS group. After LPS injection, Th1 type cells (CD4+IFN-γ+) were markedly increased compared to the WT group mice, while bvPLA2 treatment showed no significant differences in CD4+IFN-γ+cell populations. These findings suggest that bvPLA2 has protective effects in LPS-induced abortion mice model by regulating Treg populations. Further studies are necessary in order to define the detailed mechanisms underlie Treg function by bvPLA2 treatment during in LPS-induced model of abortion.
Acknowledgement: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No.NRF-2015R1C1A1A02037172)
Characterization of merocytic dendritic cells homeostasis
Authors: Audiger Cindy , Chabot-Roy Geneviève , Lesage Sylvie 
Published: January 2023

Abstract
In contrast to conventional dendritic cells (cDC), when merocytic DC (mcDC) present antigens (Ag) derived from apoptotic bodies, T cell anergy is reversed rather than induced. Although helpful to tumor clearance, reversing T cell anergy is detrimental in autoimmunity. Interestingly, mcDC are present in higher proportion in type 1 diabetes (T1D)-prone NOD mice than in B6 mice. Still, little is known about the immunological properties of mcDC that define them as a DC subset. Phenotypic characterization of mcDC revealed that they express the cDC-restricted transcription factor, Zbtb46. Moreover, we found that mcDC are potent inducers of mixed lymphocyte reactions, a key trait defining them as cDC. Investigation of other transcription factors associated with specific cDC functions, such as Irf4 and Irf8, reveal that mcDC are heterogeneous, with phenotypic and functional characteristics more closely resembling CD8α cDC. Comparative gene profiles by principal component analysis revealed that mcDC clustered more closley to CD8α cDC than other DC subsets. Still, mcDC are distinct from CD8α cDC, as mcDC are present in Batf3-deficient mice. Together, these data demonstrate that mcDC are a cDC subset with unique ability to break antigen specific tolerance. Understanding the homeostatic regulation of this new cDC subset will permit to develop new therapies for diseases, such as autoimmunity or cancer where they can be either pathogenic or beneficial.
Role of group 2 innate lymphoid cells (ILC2) in SHARPIN-deficient mice
Authors: HogenEsch Harm , Elesela Srikanth , Chien Syu-Jhe , Silva Kathleen , Kennedy Vicki , Sundberg John P. 
Published: January 2023

Abstract
SHARPIN is a component of the linear ubiquitination assembly complex and a key regulator of NFkB and integrin signaling. SHARPIN-deficient mice develop a phenotype known as chronic proliferative dermatitis (cpdm), characterized by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. We recently reported that the cutaneous inflammation in SHARPIN-deficient mice (Sharpincpdm) develops independently of B and T lymphocytes. We therefore sought to determine the role of innate lymphoid cells (ILCs) in the dermatitis of Sharpincpdm mice. ILCs were identified as a discrete population of CD45+ Lin−CD90.2hi cells in the skin and draining lymph nodes (LN) of wild type (WT) and Sharpincpdm mice. The number of ILCs was markedly increased in Sharpincpdm mice. The majority of cells were group 2 ILC (ILC2) as indicated by labeling for GATA3, IL5, and IL13. The skin of Sharpincpdm mice had increased expression of Il33 and Tslp mRNA. To determine the role of IL33, double mutant mice were generated in which the receptor for IL33 (Il1lr1 also known as ST2) was deleted. Loss of IL33-signaling greatly reduced the number of ILCs and reduced the severity of the dermatitis. These experiments suggest that the dermatitis in Sharpincpdm mice is driven by IL33-dependent ILC2. Supported by the NIH (AR049288).
Intestinal barrier disruption inversely regulates liver inflammation via IL-10-producing macrophages
Authors: Taniki Nobuhito , Nakamoto Nobuhiro , Mikami Yohei , Kanai Takanori 
Published: January 2023

Abstract
The gut-liver axis is a clinical topic as a potential therapeutic target of liver diseases. The interaction between microbial products and immune responses in the liver is still unknown. In the current study, we have demonstrated IL-10-producing CD11b+ F4/80+ macrophages contribute to immune tolerance in the inflamed liver under diminished intestinal barrier function in murine tandem model of dextran sulfate sodium (DSS)-colitis and Concanavalin A (ConA)-hepatitis. DSS-ConA mice with increased intestinal permeability developed less liver injury compared with DW-ConA mice. Of note, the severity of colitis was inversely correlated with subsequently induced liver injury. In DSS-ConA livers, increased CD11b+ macrophages showed regulatory characteristics with IL-10 production in vitro. Pretreatment with α-IL-10 antibody partially exacerbated the suppressed liver injury by DSS-ConA in vivo. Furthermore, pretreatment with CD11b+ macrophages derived from DSS-ConA livers protected mice from the subsequent liver injury. Mechanistically, we observed the contribution of gut microbiota, as the immunological tolerance induced by DSS-ConA is partially ablated by gut sterilization. Pretreatment with the portal serum derived from DSS-ConA mice partially protected mice from the subsequent liver injury. These results suggest that altered gut microbiota and the metabolites that pass through the portal vein with disrupted intestinal barrier directly gave rise to immunological permissiveness against the excessive stimulation in the liver. This study clarified the contribution of the gut-liver axis in the maintenance of immune balance in the liver and highlighted the microbiota as a potential therapeutic target for liver diseases.
Pathogenesis of Hepatic Deposited IgG-induced Liver Inflammation in SLE
Authors: Deng Guo-Min , Fang Xiang , Guo Xuanxuan 
Published: January 2023

Abstract
Hepatic disorders are frequent in patients with systemic lupus erythematosus ( SLE), yet the etiology and pathogenesis of liver injury in SLE remain unclear. We used lupus-prone mice and established an animal model of intrahepatic deposited lupus IgG to investigate the pathogenesis of liver damage in SLE. We found that liver damage spontaneously developed in lupus-prone mice and that there were a large number of inflammatory cell infiltrates around the portal areas of the liver, apoptosis of hepatocytes, and IgG deposition in the liver. Liver inflammation developed in mice with intrahepatic injection of immune complexes (ICs) from SLE patients. We found that ICs stimulated Kupffer cells (KCs) to secrete TNF-α and mediated hepatic apoptosis. Moreover, IL-12 secreted by KCs induced the accumulation and activation of natural killer cells (NKs) in the liver. Further, IFN-γ produced by activated NKs directly mediated liver damage and also enhanced the TNF-α-mediated apoptotic pathway. The depletion of KCs and NKs abolished apoptosis induced by ICs in vivo, suggesting that KCs and NKs have a synergic effect on liver injury. Lupus IgG induced Syk activation, and inhibitor of sky suppressed skin inflammation triggered by lupus IgG. Taken together, our findings confirmed that the hepatic disease was mediated by SLE, which may provide insight into the cellular and molecular mechanisms of lupus hepatitis; further, our results may aid in future investigations of potential therapeutic strategies for the treatment and control of lupus-mediated injury in disease settings.