bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro exposure to the common water contaminant Atrazine inhibits CD4+ T cell proliferation and increases the frequency of FoxP3+ cells (168.5)
Authors: Wetzel Scott , Thueson Lindsay 
Published: January 2023

Abstract
Atrazine (ATR) is the second-most widely applied herbicide used in the United States. The US EPA has reported that ATR and its primary metabolite are the most common ground water contaminant in the US. While the majority of the US population routinely ingests ATR, much remains to be learned about its biological activity. Atrazine is a potent phosphodiesterase inhibitor and is classified as an estrogen-disrupting compound that has been linked to reproductive abnormalities and cancer development. Previous studies have also implicated the immune system as a target of ATR toxicity. In this study we examined the impact of ATR on antigen-driven, in vitro activation, phenotype and expansion of primary murine TCR transgenic CD4+ T cells. In the presence of ATR there were minimal changes T cell activation marker expression, although kinetics of CD69 and CD25 up-regulation and down-modulation of the TCR were slightly delayed. However, ATR treatment resulted in a significant inhibition of T cell proliferation and effector cytokine production. Rather than rescuing the T cell proliferation defect, addition of exogenous IL-2 resulted in a more pronounced proliferation defect in the ATR-treated cultures. We subsequently observed that the frequency of Foxp3+ T cells significantly was increased in the ATR-treated cultures by day 4. Studies are underway to determine mechanism of the ATR-mediated inhibition of T cell proliferation along with the increase in FoxP3+ T cell frequency.
Role of donor liver steatosis on immune responses to Hepatitis C, self antigens and allograft fibrosis following human liver transplantation (169.11)
Authors: Subramanian Vijay , Seetharam Anil , Tiriveedhi Venkataswarup , Angaswamy Nataraju , Anderson Christopher , Shenoy Surendra , Crippin Jeffrey , Chapman William , Mohanakumar Thalachallour 
Published: January 2023

Abstract
Hepatitis C virus (HCV) recurrence following liver transplantation (OLT) is associated with increased allograft fibrosis. Severe donor graft steatosis results in poor early post-operative outcomes but steatosis resolves within 3 weeks. Goal of this study is to characterize the role of donor liver steatosis on HCV immunity, fibrosis and outcome post OLT. Methods: HCV OLT recipients were enrolled at 1 year. Based on donor steatosis, grafts were divided into: Group 1-No steatosis (0-5% steatosis, n=18), Group 2 - Mild (5-33% steatosis, n=15), Group 3 - moderate (&gt;33% steatosis, n=10). Mononuclear cells were stimulated with HCV antigens, and IL-17 and IL-10 cells were enumerated by ELISpot. Serum antibodies (abs) to Collagen (Col) 3 were measured by ELISA. Results: Patient demographics were similar in all groups. Group 3 OLT had a higher incidence of fibrosis (Batts Ludwig grades 3 or 4) when compared to groups 2 and 1 (93%, 34%, 15%, p&lt;0.05). Group 3 demonstrated higher HCV specific IL17 (10±2.1, 12.2±5.2, 23±3.3 spots per million cells (spm) p&lt;0.05) and IL10 secreting cells (107±23.1, 259.6±30.5, 402.3±37.3 spm, p&lt;0.05). Groups 2 and 3 also had higher abs to Col 3 (11±1.1, 13±1.7, 17±1.5 µg/ml, p=0.05). Patient survival at 2 years was 100%, 95% and 84% among the three groups. Conclusion: Donor graft steatosis significantly influenced immune responses to HCV following OLT leading to increased IL17 and IL10 as well as increased incidence of autoimmunity and poorer outcome.
Recipient CD73-generated adenosine plays a preventive role in graft-versus-host disease by regulating allogeneic T cell activation (169.16)
Authors: Thompson Linda , Tsukamoto Hiroki 
Published: January 2023

Abstract
Graft-versus-host disease (GvHD) is a systemic disease in which donor T cells attack the allogeneic recipient. Here we investigated the role of CD73 in GvHD induced by transplantation of BALB/c bone marrow and spleen cells into lethally irradiated C57BL/6 recipients. CD73 is an enzyme that generates extracellular adenosine, a nucleoside with anti-inflammatory and immunosuppressive activity mediated by adenosine receptors. Survival curves showed more severe GvHD in CD73-/- → CD73-/- transplants than in CD73+/+ → CD73+/+ transplants and serum IFNγ and IL-6 were higher in CD73-/- recipient mice. CD4+ and CD8+ T cells from CD73-/- donors proliferated more in vivo than those from CD73+/+ donors as assessed by CFSE dye dilution and cell numbers in spleens. However, irradiation-induced activation of dendritic cells as assessed by CD86 up regulation was similar in CD73+/+ and CD73-/- mice. In vivo anti-C57BL/6 CTL activity was higher in CD73-/- transplant recipients than in CD73+/+ recipients. Additional CD73-/- → CD73+/+ and CD73+/+ → CD73-/- transplants revealed that more severe GvHD is caused primarily by a lack of CD73 in recipients. The adenosine receptor antagonist caffeine exacerbated GvHD in CD73+/+ recipients, consistent with the idea that the protective effect of CD73 depends upon its adenosine-generating activity. In conclusion, recipient CD73 plays a primary preventive role in GvHD by regulating allogeneic donor T cell activation in an adenosine-dependent manner.
Chemokine independent transendothelial migration of effector and memory T cells to vascularized allografts (169.2)
Authors: Walch Jeffrey , Oberbarnscheidt Martin , Li Qi , Hoffman Rosie , Camirand Geoffrey , Williams Amanda , Lakkis Fadi 
Published: January 2023

Abstract
Memory T cells play a central role in the rejection of transplanted organs. The migration of memory T cells to allografts is thought to depend on chemokine stimulation of G-protein coupled receptor (GPCR) signaling. This paradigm was revisited by testing whether B6 (H-2b) effector or memory T cells generated against BALB/c (H-2d) alloantigens can migrate to and reject BALB/c cardiac allografts despite treatment with pertussis toxin (PTx), which blocks GPCR signaling. Flow cytometry analysis revealed no significant difference between the number and proliferation of PTx treated and non-treated effector or memory T cells recovered from cardiac allografts at 1, 3 and 6 days after i.v. transfer. There was no significant difference in the survival of cardiac allografts in recipients of either PTx treated or non-treated memory T cells. Neither naive nor natural memory T cells harvested from unimmunized mice migrated in significant numbers to cardiac allografts. To our knowledge these are the first results indicating that effector and memory T cells migrate to allografts independent of chemokine stimulated GPCR signaling, which is central to the traditional model of leukocyte migration. These findings suggest that targeting chemokine receptors may prove an unsuccessful therapy to prevent T cell mediated transplant rejection and that alternate mechanisms exist for the migration of T cells into non-lymphoid tissues.
Inflammasome-derived IL-1β regulates the production of GM-CSF by CD4+ T cells and γδ T cells (171.24)
Authors: Lukens John , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Recent findings have demonstrated an indispensable role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). However the signaling pathways and cell populations that regulate GM-CSF production in vivo remain to be elucidated. Our work demonstrates that IL-1 signaling centrally regulates GM-CSF production during EAE. IL-1R1 is required to induce GM-CSF production following polyclonal T cell stimulation under both TH17 (i.e. IL-23) and TH1 (i.e. IL-12) stimulatory conditions. Furthermore, we demonstrate that γδ T cells are also potent producers of GM-CSF during the inflammatory response and that their secretion of GM-CSF is similarly dependent on IL-1 signaling. Interestingly, we find that the expression of GM-CSF by myelin-reactive T cells during EAE is not restricted to discrete TH1 and TH17 cell lineages. Rather GM-CSF can be co-expressed with both IFNγ and IL-17. Inflammasome-derived IL-1β was identified to be an upstream amplifier of GM-CSF producing T cells during the priming phase of EAE. Finally, we show a central role for MYD88 in the control of GM-CSF production by both CD4+ T cells and γδ T cells. These findings highlight the importance of inflammasome-derived IL-1β and the IL-1R1/MYD88 signaling axis in the regulation of GM-CSF production.
The adaptor protein CIKS/Act1 is essential for imiquimod-induced psoriasis. (171.25)
Authors: Ha Hye-Lin , Wang Hongshan , Siebenlis Ulrich 
Published: January 2023

Abstract
Psoriasis is a relapsing skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory immune cells. The IL-23/IL-17 cytokines axis is thought to play an important role in the pathogenesis of psoriasis. The TLR7/8 ligand Imiquimod (IMQ) can induce/exacerbate psoriasis in patients and it induces a psoriasis-like condition in mice. In addition to IL-17A and IL-17F, which are produced primarily by Th17 and innate T cells, IL-17C has very recently been implicated in IMQ-induced psoriasis as well. To determine by what mechanisms IL-17 cytokines critically contribute to IMQ-induced psoriasis, we have begun to investigate a mouse model in which signaling by all IL-17 cytokines is abrogated due to the loss of the obligate adaptor protein CIKS/Act1. Importantly, the gene for this adaptor protein has also recently been identified as a strong susceptibility locus in psoriasis. Here we show that IMQ applications induced many markers of psoriasis in wild-type mice, but failed to do so in CIKS-deficient mice. These data demonstrate that signaling by IL-17 cytokines via the adaptor protein CIKS is essential for IMQ-induced psoriasis and thus the CIKS pathway may provide targets for therapeutic intervention in psoriasis. We will report on the progress in understanding the functions of IL-17 cytokines in development of psoriasis.
IL-23 inhibits autoimmunity by facilitating clearance of apoptotic bodies in the marginal zone (171.26)
Authors: Li Hao , Hsu Hui-Chen , Li Jun , Yang PingAr , Wu Qi , Cua Daniel , Oukka Mohamed , Mountz John 
Published: January 2023

Abstract
IL-23 helps expansion of Th17 cells which are important in the pathogenesis of spontaneous autoimmune disease in BXD2 mice. In this study, we surprisingly found that IL-23p19-deficient BXD2 mice (BXD2-Il23-/-) exhibit accelerated development of spontaneous germinal centers (GCs) and production of pathogenic autoantibodies, compared with wild-type BXD2 mice. Expression of IL-23 by adenovirus in BXD2-Il23-/- mice reversed these phenotypes. IL-23R was mainly expressed by marginal zone macrophages (MZMs) in the spleen of mice, as indicated by the GFP-IL-23R reporter. In BXD2-Il23-/-, however, there was an age-related loss of both MZMs and CD21hiIgMhi marginal zone (MZ) B cells. MZMs are a small subset of specialized splenic macrophages essential for clearance of apoptotic cells entering to the spleen from circulation to prevent generation of immunogenic autoantigens. MZM specific depletion by clondronate liposome severely accelerated BXD2 autoimmune disease progression. Absence of IL-23 correlates with downregulated expression of BAFF by MZMs which is essential for the differentiation of MZ B cells. Our results suggest a unique mechanism for IL-23 to limit autoimmunity in that IL-23 supports the cross-talk between MZM and MZ B cells. In this model, IL-23 acts on MZM to upregulate BAFF to promote the survival of MZ B cells, and MZ B cells help to maintain the survival of MZM. Loss of MZM is associated with defective clearance of apoptotic cells and acceleration of autoimmunity.
Defective Lysosomal Degradation of Immune Complexes in Lupus-Prone Mice (171.30)
Authors: Monteith Andrew , Kang Sun ah , Jacobson Ken , Costello M. , Moorman Nat , Vilen Barbara 
Published: January 2023

Abstract
The production of autoantibody and subsequent tissue deposition of immune complexes (ICs) contributes to the end-organ disease associated with systemic lupus erythematosus. What role ICs play in the autoimmune disease process remains unclear. In this study we found that low levels of ICs were displayed on dendritic cells (DCs), macrophages (MFs) and B cells from C57BL/6 (B6) mice via Fc receptors (FcRs). In contrast, cells from lupus-prone (MRL/lpr) mice had a 30-50-fold increase in surface-bound ICs. MRL/lpr MFs internalized ICs at a rate comparable to B6 however, they failed to degrade the ICs and consequently recycled them back to the cell surface within 48 hours. The recycling defect was not due to the failure of endosomes to properly mature, as cryoelectron microscopy showed equal numbers of ICs in secondary lysosomes. Rather, it appeared that a defect occurred in the ability of MFs to properly acidify lysosomes. Ratiometric imaging revealed that vesicles found in B6 MFs consistently acidified to a pH of 4, while those within MRL/lpr MFs failed to attain a pH lower than 5. These findings suggest that the recycling of ICs to the surface of MRL/lpr MFs results from defects within the endocytic pathway that prevent degradation of internalized cargo. Studies are underway to define the molecular events preventing acidification, and to assess whether the accumulated ICs activate autoreactive B cells, or promote excessive cytokine secretion by DCs and MFs from lupus-prone mice.
An IL15-dependent novel immune cell subset with multiple functionalities affecting the onset and severity of autoimmune disease (171.36)
Authors: Voynova Elisaveta , Bolland Silvia 
Published: January 2023

Abstract
Interferon-producing killer dendritic cells (IKDC) are a recently discovered innate cell subset that shares morphological and functional characteristics of NK and DC cells. The aim of this study is to investigate the role of IKDCs in terms of initiating autoimmune disease. We found that these cells are expanded in mice with multiple copies of the TLR7 gene and that the number of these cells correlates with disease activity. Expansion of this population is due to their cell intrinsic sensitivity to TLR7 stimulation. IKDCs are dependent of IL15, produce high levels of IFN type I and type II after stimulation with a TLR7 agonist, are capable of MHC class II antigen presentation, and can cross-present antigen to CD8 cells. Adoptive transfer of IKDC to wild type mice causes activation of naïve T cells, expansion of inflammatory monocyte populations and IFN-dependent CD8 activation. IKDC adoptive transfer also induces elevated inflammatory cytokine and IgG levels in the serum. We found that IFN type I and CD40/CD40L interactions are essential for the inflammatory effect of these cells. Taken together these results uncover a potential role for this cell populaiton in the development of autoimmune pathologies.
Sec61 is essential for antigen cross-presentation and the development of lupus nephritis (171.4)
Authors: Tsumiyama Ken , Shiozawa Shunichi 
Published: January 2023

Abstract
Objective: We repeatedly immunized mice normally not prone to autoimmune diseases with the same antigen to show that repeated immunization reproducibly led to the development of SLE, where full-matured CTL generated via antigen cross-presentation caused lupus nephritis. Here we clarify the molecular mechanism of antigen cross-presentation in relation to SLE. Methods: Bone marrow-derived dendritic cell (BMDC) from BALB/c mice was cultured with fluorescent-labeled OVA. Early endosome antigen 1 (EEA1), calnexin and Sec61 were detected using immunofluorescent staining. For in vivo study, BALB/c mice were repeatedly immunized with OVA to evoke SLE. Exotoxin A was co-immunized with OVA to inhibit Sec61. Proteinuria and IFNγ-producing CD8+ T cell were measured. Results: Upon culture of BMDC, OVA was co-localized with the endosomal marker EEA1, and subsequently separated from EEA1. OVA was never co-localized with the endoplasmic reticulum (ER) marker calnexin. Instead, OVA was co-localized with a translocon, Sec61, indicating that OVA was exported directly from endosome to cytoplasm via Sec61. Generation of both CTL and lupus nephritis was abrogated by in vivo treatment with exotoxin A, an inhibitor of Sec61. Thus, export of antigen from endosome to cytoplasm via Sec61 is essential for antigen cross-presentation. Conclusion: Direct export of antigen from endosome to cytoplasm via Sec61 is essential both for antigen cross-presentation and induction of lupus nephritis.
B1a cell expansion and autoimmunity promoted by cyclin-dependent kinase inhibitor Cdkn2c deficiency in a mouse model of lupus (171.41)
Authors: Potula Hari hara , Xu Zhiwei , Zeumer Leilani , Morel Laurence 
Published: January 2023

Abstract
By using a combination of genetic mapping and candidate gene analysis, we previously identified Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18INK4c (p18), as the top candidate gene for the lupus susceptibility locus Slec2c1 in the NZM2410 mouse. P18 is expressed at about 4 time lower levels in B6.Sle2c1 than in B6 B cells, leading to an increased cell cycle activity. Here, we showed that p18 deficiency results in a large expansion of the B1a cell compartment in the peritoneal cavity (Pc), which is the Slec2c1 primary phenotype. This was further confirmed by an increased production of polyreactive IgM (another feature of Sle2c1 phenotype) in the serum of B6.p18-/- similar to B6.Sle2c1 mice. Furthermore, B6.p18-/- mice produced anti-nuclear autoAbs and dsDNA IgG, which are serological markers strongly associated with lupus. We further showed p18 deficiency results in a significantly increased homeostatic expansion of Pc B1a cells but not B1b or B2 cells in B6.Rag mice. Finally, Cyclin D2 deficiency abrogates Sle2c1-induced B1a cell expansion, with the number of Pc B1a cells similar between B6.Sle2c1.D2-/- and B6 mice. This demonstrates a causal relationship between defective p18 gene expression, B1a cell expansion and development of murine SLE. These results provide concrete evidence that p18 plays a critical role in B1a cell self-renewal, and its impaired expression leads to accumulation of B1a cells, leading to autoimmunity either directly or indirectly.
Metabolomic analysis of macrophage activation and relevance of the cross-talk between energetic metabolism and polarized gene expression (172.12)
Authors: Bosca Lisardo , Través Paqui , Pimentel-Santillana María , de Atauri Pedro , Marin Silvia , Cascante Marta 
Published: January 2023

Abstract
Immune activation rapidly and substantially enhances metabolic outputs. Macrophage activation is followed by rapid changes in nutrient flux, which also seems to be necessary for immune activation, indicating that signals produced by immune cells might directly regulate their metabolism. Macrophages respond to a variety of extracellular stimuli developing patterns of gene expression that also encompass metabolic changes linked to the activation programs and that are not fully understood. Macrophages can be activated to two opposite end-points: M1-polarization accomplished by pro-inflammatory stimuli, and M2-polarization. The study of how energetic and redox metabolism of macrophages varies in accordance with recruitment and activation (M1, M2 or mixed combinations) and how these conditions are required for the specific functions of the macrophage (oxidative burst, phagocytosis, migration and infiltration, etc) are relevant to protect organ activity and to restrict the involvement of macrophages in chronic inflammation. We have studied the metabolic profile associated with relevant activation pathways using a [1,2-&lt;13&gt;C]glucose tracer-based metabolomic approach and bioinformatic tools to analyze changes in isotopomer distribution and changes in main energetic metabolites under M1/M2 conditions. Our data show the existence of specific metabolic signatures depending on the activation pattern elicited by the macrophages.
KIR mediated natural killer cell function modified by Tim3 expression level in early untreated HIV infection (172.18)
Authors: Brayton Bonnie , Crawford Timothy , Chew Glen , Ndhlovu Lishomwa , Barbour Jason 
Published: January 2023

Abstract
Tim-3 is a regulator of Natural Killer (NK) cell function. The polymorphic killer cell Ig-like receptor (KIR) expressed on NK cells is associated with HIV-1 progression rate. We examined Tim-3 expression level, NK cell function, and KIR genetics in 596 recently HIV-1 infected adults. We measured KIR genotype by SSO (One Lambda, Inc.) (n=596), and NK cell function (n=147) in an 11 color flow cytometry intra-cellular cytokine stain (ICS) assay, after stimulation with K562 cells, IL12/IL18, and HLA I transfectants. Tim-3 levels were lower on NK cells from KIR3DS1 gene carriers (all heterozygotes, hence KIR3DL1+ heterozygotes), [KIR3DS1+ Tim-3 median 84% (range 64-91%, N = 12) vs. KIR3DS1- median 91% (range 79-98%), p &lt; 0.05]. Upon stimulation Tim-3+ NK cell responses did not differ in responses (IFN-g or CD107a) by KIR3DS1 gene carriage (p = NS), suggesting that while KIR3DS1 gene carriage relates to lower total Tim-3 expression levels on NK cells, KIR3DS1 gene carriage is not a potent regulator of effector activities of the Tim-3 bearing NK subset. Variation in NK function of KIR3DS1+ persons may be attributable to mixed KIR3DL1/3DS1 carriers whose variable level of KIR3DL/S1 expression, and lower level of Tim-3 expression mitigates differences in NK function. Tim-3, a molecule that restrains but does not abrogate NK effector activity, may play a key role in regulating KIR mediated effector functions of NK cells.
p38 MAPK but not ERK is required for eosinophil migration and degranulation (172.29)
Authors: Shamri Revital , Young Kristen , Weller Peter 
Published: January 2023

Abstract
Eosinophil-associated RNases (EARs); the human eosinophil-derived neurotoxin and eosinophilic cationic protein and their murine orthologs, are stored in eosinophil cytoplasmic granules and secreted upon inflammation as part of innate immune responses. In eosinophil-associated diseases, such as hyper eosinophilic syndrome, allergy and asthma, EARs play crucial roles in disease pathology and can be used as biomarkers for disease severity. However, secretion mechanisms of EARs are not fully understood, especially in mouse eosinophils, the major animal model for eosinophil-associated diseases. Our study aimed to understand the mechanisms of eosinophil EAR secretion following chemokine stimulation. Both ERK and p38 MAPK activation were found to increase in mouse eosinophils in response to CCL11. CCR3-mediated EAR secretion was blocked by p38 inhibitor (SB202190), confirming previous data in human eosinophils. However, a specific inhibitor for ERK, a MEK1-derived peptide, did not inhibit CCR3-mediated secretion or migration. These results are in contrast to previous studies in human eosinophils and our studies in mouse eosinophils, showing ERK is crucial for CCR3-mediated EARs secretion and migration using PD98059, a less specific inhibitor of the ERK-activating enzyme, MEK. Collectively, these data suggest a signaling pathway for CCR3-mediated EAR secretion that includes: PI3K and p38 but not ERK. These findings are pertinent to host defense and eosinophil-associated diseases.