bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in lupus-prone NZBW/F1 mice (119.12)
Authors: Zhu Fu-Gang , Jiang Weiwen , Dong Yu , Kandimalla Ekambar , La Monica Nicola , Agrawal Sudhir 
Published: January 2023

Abstract
Several studies have implicated Toll-like receptors (TLRs) 7, 8 and 9 in the development and progression of lupus. We have developed IMO-8400, a synthetic DNA-based antagonist that has shown potent inhibition of TLR7-, TLR8-, and TLR9-mediated immune responses in cell-based assays and in non-human primates. To assess the therapeutic potency of IMO-8400, we have tested this compound in lupus-prone NZBW/F1 mice. Mice were injected subcutaneously with IMO-8400 at 1.9, 3.8 or 7.5 mg/kg once a week or 7.5 mg/kg once every two weeks from the age of week 21 to 33, and sacrificed at week 34. NZBW/F1 mice treated with IMO-8400 at the weekly dose of 3.8 or 7.5 mg/kg or 7.5 mg/kg every two weeks showed a significant reduction in urine protein and blood urea nitrogen levels in compression to that of untreated mice. Additionally, anti-DNA, anti-RNP and anti-SM IgG levels were also lower in treated mice than untreated controls. No treatment-related side-effects were observed. Histological examination of kidney sections revealed improvement in nephritis (reduced glomerular sclerosis and decreased interstitial inflammation), accompanied by decreased glomerular deposits of IgG immune complex in mice treated with IMO-8400. These results indicate that IMO-8400 suppressed autoimmune antibody production and improved renal function by inhibiting immune responses in lupus-prone NZBW/F1 mice. Thus, IMO-8400 has the potential for the treatment of lupus and other autoimmune diseases.
Neuroprotective effects of bee venom by suppression of neuroinflammatory responses in mouse model of Parkinson’s disease: role of CD4+CD25+Foxp3+ regulatory T cells. (119.2)
Authors: Chung Eun Sook , Kim Himchan , Bae Hyunsu 
Published: January 2023

Abstract
In the present study, we examined whether bee venom (BV) promotes the survival of nigrostriatal dopaminergic (DA) neurons in the MPTP-induced Parkinson’s disease (PD) mice model. Treatment of BV prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. This nueroprotection afforded by bee venom was associated with the suppression of microglia and inhibition of recruitment of CD4+ T cells. Additionally, CD4+CD25+Foxp3+ Treg cells were significantly increased in vivo and in vitro after treatment of BV. Therefore, we carefully propose that neuroprotection of BV might be associated with its anti-inflammatory properties and could be employed as novel therapeutic agents for PD and other disorders associated with neuroinflammation.
Lymphotoxin reduces commensal diversity to enable diet induced obesity (120.2)
Authors: Upadhyay Vaibhav , Fu Yang-Xin 
Published: January 2023

Abstract
Commensal microbes exist in a state of symbiosis with host immunity and are essential for weight gain in diet induced obesity (DIO). Lymphotoxin α (LTα), a key molecule in mucosal defense, has been linked to obesity. We report that mice lacking LTα, LTβ, and LTβ-receptor (LTβR) resist DIO. The microbial communities of LTβR+/- mice and LTβR-/- mice differed on normal chow (NCD) and after high fat diet (HFD). The microbial community of LTβR+/- mice was less diverse after HFD, a hallmark of the “obese microbiome” in humans. On the contrary, LTβR-/- animals maintained similarly diverse communities to their NCD counterparts while on HFD. A specific microbe, Segmented Filamentous Bacteria (SFB), was cleared after HFD in LTβR+/- but not LTβR-/- mice and served as a marker of diversity loss. Transplantation of cecal contents from LTβR-/- animals conferred less weight gain than that of LTβR+/- mice to WT germ free mice, demonstrating a causal relationship between differing microbiota and weight gain. Housing LTβR-/- mice with their LTβR+/- siblings rescued weight gain, demonstrating horizontal transmissibility of the obese phenotype. HFD induced IL-23, an SFB associated cytokine, within the colon, but this induction was absent in LTβR-/- mice. Mice deficient in IL-23 (p19-/-) and the downstream cytokine IL-22 (RORγt-/-) also resisted DIO. Our data suggests that HFD induced inflammation reduces commensal diversity to enable weight gain, which may underlie the pathogenesis of obesity.
γ/δ T cells contribute to inflammation following long term low dose O3 exposure. (120.32)
Authors: Mathews Joel , Shore Stephanie 
Published: January 2023

Abstract
γ/δ T cells are involved in the responses to acute high dose ozone (O3) exposure (2 ppm for 3 hrs)( Matsubara, S et al, AJRCMB, 2009). However, elevated atmospheric O3 tends to persist not for hours, but for several days. The factors that determine pulmonary responses to short-duration, high-dose O3 exposure are different from those involved in responses to longer, lower-dose exposures and it is not know what role γ/δ T cells have in these longer term exposures. Consequently, we exposed mice deficient in γ/δ T cells (TCRδ-/-) and WT mice to O3 (0.3 ppm for 48 hrs). Bronchoalveolar lavage (BAL) was performed and the lungs were collected, digested, and analyzed by FACS. O3 caused an increase in numbers of γ/δ T cells, macrophages, and neutrophils in the lung tissue and/or BAL fluid. BAL and lung tissue neutrophils and macrophages were reduced in TCRδ-/- versus WT mice. BAL fluid IP-10, IL-6, MCP-1, LIF and KC were lower in TCRδ-/- versus WT mice. These chemokines are chemoattractive for macrophages and/or neutrophils and most can be produced by lung γ/δ T cells. In contrast, we found no difference in O3 induced lung damage between the WT and TCRδ-/- mice, as assessed by BAL protein or scores of terminal bronchiolar lesions on histological sections. Our data indicate that γ/δ T cells are involved in the initiation of inflammation following O3 exposure, potentially through the secretion of chemokines that recruit macrophages and neutrophils.
Skin-derived γδ T cells as a source of IL-17 in the lymph nodes and a possible initiator in contact hypersensitivity (121.22)
Authors: Nakamizo Satoshi , Egawa Gyohei , Miyachi Yoshiki , Kabashima Kenji 
Published: January 2023

Abstract
In the murine skin, there exist two subsets of γδ T cells, Vγ5+ dendritic epidermal T cells (DETCs) and Vγ4+ dermal γδ T cells. It remains unclarified about the role of skin γδ T cells in contact hypersensitivity and their homeostasis. Initially, to evaluate the mobility of cutaneous γδ T cells, we used kaede-transgenic mice which express photoconvertible fluorescence protein “kaede”. By exposing the skin to violet light, cutaneous cells changes its fluorescence from green to red. Using this labeling system, we demonstrated that γδ T cells migrated from the skin to draining lymph nodes (DLNs) even in the steady state and such transmigration was enhanced after hapten-application. Skin-derived γδ T cells were mainly Vγ4+ cells, suggesting that they were dermal origin. In addition, this subset produced a higher amount of IL-17 than either LN-resident γδ T cells or αβ T cells migrating from the skin. In addition, we found that γδ T cells assisted αβ T cells proliferation and production of IFN-γ and IL-17 in vitro. These data suggest that the main source of IL-17 in the DLN is γδ T cells from the dermis, and this population may play an important role to establish contact hypersensitivity response through modulating αβ T cell functions.
H1R signaling in antigen presenting cells is dispensable for eliciting pathogenic T cells in experimental allergic encephalomyelitis (123.14)
Authors: Saligrama Naresha , Noubade Rajkumar , Case Laure , Poynter Matthew , Teuscher Cory 
Published: January 2023

Abstract
The histamine H1 receptor (Hrh1/H1R) was identified as a shared autoimmune disease (SAID) gene in experimental allergic encephalomyelitis (EAE) and autoimmune orchitis, the principal AI models of multiple sclerosis (MS) and idiopathic male infertility, respectively. As a SAID gene, Hrh1/H1R can exert effects in multiple cell types including endothelial cells, T cells, and antigen presenting cells at critical check points during both the induction and effector phases of disease. In this regard, we showed that selective re-expression of H1R by endothelial cells in Hrh1-KO (H1RKO) mice significantly reduced disease severity whereas H1R expression by H1RKO T cells complemented EAE severity and cytokine responses. Given that the H1R has been reported to influence innate immune cell maturation, differentiation, chemotaxis, and cytokine production, which in turn influences CD4+ T cell effector responses, we selectively re-expressed H1R in CD11b+ myeloid cells of H1RKO mice to test the hypothesis that H1R signaling in these cells contributes to EAE susceptibility and/or T cell effector responses. We demonstrate that transgenic re-expression of H1R by H1RKO-CD11b+ cells neither complements EAE susceptibility nor T cell cytokine responses. These results further highlight the cell-specific effects that an AID gene can play in the pathogenesis of complex diseases such as EAE and MS, and the need for cell-specific targeting in optimizing therapeutic interventions based on such genes.
Type I IFN promotes IL-10 production from Th17 cells to suppress autoimmune inflammation (123.17)
Authors: Guo Beichu , Zhang Lixia 
Published: January 2023

Abstract
Recent studies reveal a considerable degree of heterogeneity and flexibility in T-cell lineage differentiation, particularly in the development of Th17 cells. However, how the immune system regulates the plasticity of CD4 T cells in vivo during pathogen infection or autoimmunity is poorly defined. In this study, we investigated the direct effects of type I IFN (IFNα/β) on Th17 cell differentiation and plasticity. In this study, we demonstrate that the plasticity of Th17 cells could be influenced by IFNα/β. Our data show that IFNβ treatment of T cells cultured under Th17 polarizing conditions resulted in reduced production of IL-17, but increased production of IL-10. Furthermore, type I IFN induced IL-10 production by antigen specific T cells derived from immunized mice. We also found that IFNβ treatment leads to shift from Th17 phenotype to Th1 phenotypes with upregulation of IFN-gamma in antigen-specific T cells in vivo. IFN-treated Th17 cells were able to inhibit EAE in vivo via adaptive transfer models. Together, our current findings demonstrate the direct effects of type I IFN on Th17 cells and reveal that Th cell plasticity is influenced by type I IFN during immune response.
B cell depletion - a double-edged sword (123.18)
Authors: Tai Ningwen , Wen Li 
Published: January 2023

Abstract
B cell depletion therapy has been proved beneficial in multiple T cell mediated autoimmune diseases, but the underlying mechanisms remain largely unknown. To investigate the immediate effect of B cell depletion on T cells in T1D, we used hCD20/NOD mouse model to determine the effect of short-term B cell depletion on the phenotype and function of effector T cells. B cells were depleted by a single dose injection of anti-hCD20 (2H7) in 7-8 week old mice. Mouse IgG was used as control. As expected, B cells in blood and secondary lymphoid organs were significantly reduced at day 3 and remained low until day 21. Surprisingly, splenic CD4+ and CD8+ T cells were also significantly reduced after B cell depletion. Several T cell subsets were dramatically reduced after B cell depletion, which included CD4-CD8-TCRβ+, B220+CD4+, CD40+CD4+ and CD45RB+CD4+ T cells. B cell depletion also induced ICOS expression in CD4+ T cells at day 3 and 7. Both CD4+ and CD8+ T cells expressed more TNF-α in 2H7-treated mice. T cell function post B cell depletion was tested in vivo using adoptive transfer approach. Either purified splenic T cells or FACS sorted CD40+CD4+ T cells from 2H7-treated mice (day 7) induced accelerated diabetes in NOD.scid or NOD Rag- mice compared with the same cells from control mice. Our results suggest that B cell depletion acts as a double-edged sword, which could enhance the function of T cell effectors to be pathogenically aggressive shortly after B cell depletion.
Lupus prone DBA/2 (DBA) CD4 T cells exhibit greater B cell help, poorer help for CD8 cytotoxic T lymphocytes (CTL) and induce more severe renal disease compared to B10.D2 CD4 T cells in parent-into F1 (P→F1) mice. (123.27)
Authors: Via Charles , Puliaiev Maksym , Soloviova Kateryna 
Published: January 2023

Abstract
Transfer of parental B6 T cells into B6D2F1 (B6→F1) mice results in acute graft-vs- host disease (GVHD) due to donor CD8 CTL that eliminate host cells. Donor CD8 CTL fail to mature in the opposite parental transfer (DBA→F1) resulting in chronic lupus-like GVHD and severe renal disease. To determine whether CTL failure and subsequent lupus like disease in DBA→F1 mice is an intrinsic CD8 defect or extrinsic due to poor CD4 help, female CD4 and CD8 T cells were purified from DBA or C57/Bl background, MHC identical (H-2d) B10.D2 donor T cells and transferred in all 4 possible combinations into female F1 mice. Transfer of B10.D2 CD4 +B10.D2 CD8 (D2+D2→F1) mice and DBA+DBA→F1 mice (positive controls) exhibited the expected acute and chronic GVHD phenotype respectively at 2 weeks. For mixed subsets, D2+ DBA→F1 exhibited a 2 week phenotype not significantly different from control acute GVHD indicating that normal (D2) CD4 help could correct a DBA CD8 CTL defect seen as absent KRLG-1 upregulation. By contrast, DBA+D2→F1 mice exhibited an intermediate phenotype significantly different from either control group indicating that normal D2 CD8 CTL maturation was significantly impaired with DBA CD4 help. Long term, only DBA+DBA→F1 and DBA+D2→F1 mice exhibited lupus autoantibodies or renal disease. Thus, DBA CD4 T cells are the primary determinant of clinical lupus in this model by virtue of greater help for autoreactive B cells and poorer help for down regulatory CD8 CTL.
Membrane-bound Fas ligand accelerates autoimmune disease in an induced murine model of systemic lupus erythematosus (123.3)
Authors: Bossaller Lukas , Rathinam Vijay , Schmidt-Lauber Christian , Moody Krishna , Bonegio Ramon , Fitzgerald Katherine , Latz Eicke , Marshak-Rothstein Ann 
Published: January 2023

Abstract
Lpr and gld, are loss of function mutations in the Fas death receptor and its ligand, respectively. However, in addition to its pro-apoptotic activity, FasL can also trigger the production of pro-inflammatory cytokines. The lpr and gld mutations normally result in a lymphoproliferative syndrome and exacerbate clinical disease in SLE autoimmune-prone strains of mice. Unexpectedly, the lpr and gld mutations were reported to attenuate disease progression in mice injected with pristane, an agent known to induce SLE. FasL is a transmembrane protein with a matrix metalloproteinase (MMP) cleavage site in the ectodomain. MMP cleavage inactivates membrane-bound FasL (mFasL) and releases a soluble form, sFasL, reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage, we have eliminated the cleavage site through targeted mutation, to produce the ΔCS line. ΔCS mice express more mFasL and fail to make sFasL. Pristane-injected ΔCS mice exhibit a markedly exacerbated disease profile associated with a striking change in ANA specificity, increased proteinuria and kidney pathology, a massive increase in spleen size due to infiltrating granulocytes and macrophages, a bias toward a Th2 response, and a trend towards increased numbers of Th17 T cells, compared to control mice. These results demonstrate that cleavage plays an important role in limiting the pro-inflammatory activity of FasL in the context of pristane-induced autoimmunity.
B7-H4 Ig treatment during relapsing-remitting EAE increases the number an function of regulatory T cells (123.37)
Authors: Podojil Joseph , Miller Steve 
Published: January 2023

Abstract
The present studies evaluate the potential therapeutic efficacy of B7-H4-Ig treatment in PLP139-151-induced relapsing-remitting EAE (R-EAE). The present data show that B7-H4 Ig inhibits CD4+ T cell proliferation and differentiation in the presence of various CD4+ effector T cell lineage-promoting conditions in vitro. We then go on to show that B7-H4 Ig treatment both directly and indirectly decreases effector CD4+ T cell activity by increasing regulatory T cell function and number. We also tested the ability of B7-H4 Ig treatment to reduce the severity of both PLP139-151-induced R-EAE in SJL mice and MOG35-55-induced C-EAE in C57BL/6 mice. Our results show that if B7-H4 Ig treatment is initiated on Day 0 of R-EAE, the primary disease relapse is inhibited as determined by mean clinical score and DTH responses to the spread epitope PLP178-191. Likewise, if B7-H4 Ig treatment is initiated during ongoing disease (~Day 20 post disease induction) in both R-EAE and C-EAE, disease severity and epitope spreading are decreased. Furthermore, this decrease in disease severity correlates with a decrease in the number of activated CD4+ T cells (CD4+CD44+) within the CNS and spleen, and a concurrent increase in number and functional suppressive capacity of regulatory T cells within the spleen (CD4+CD25+FoxP3+). Therefore, based on our in vitro and in vivo data, B7-H4 Ig demonstrates potential promise as a therapeutic in relapsing MS.
Role of the PD-1 pathway in regulating islet-reactive CD4 T cells during autoimmune diabetes (123.39)
Authors: Pauken Kristen , Fife Brian 
Published: January 2023

Abstract
Engagement of the inhibitory receptor PD-1 with its ligand PD-L1 is critical for preventing Type 1 diabetes in non-obese diabetic (NOD) mice. The mechanism by which PD-1 signaling limits self-reactive CD4 T cells is not well understood. To investigate this we transferred a low number of self-reactive BDC2.5 T cell receptor transgenic CD4+ T cells into prediabetic NOD mice. These cells became activated due to the presence of endogenous antigen. Following activation we administered anti-PD-L1 antibody to block PD-1 signaling and determined the affect on the BDC2.5 cells. PD-1 blockade resulted in an increase in BDC2.5 T cells in the spleen, pancreatic lymph node, and pancreas. This increase correlated with an increase in proliferation in the secondary lymphoid organs measured by CFSE dye dilution. However, it is unclear whether the increase in the pancreas was due to increased proliferation or enhanced recruitment. To investigate the requirement for PD-1 and/or PD-L1 on effector CD4+ T cells, we utilized genetically deficient BDC2.5 T cells. We determined that PD-1 on the BDC2.5 T cell was required to suppress proliferation and recruitment to the pancreas, whereas PD-L1 on the BDC2.5 T cell was dispensable. These data suggest that PD-1 is required on the autoreactive CD4+ T cells and under normal conditions will suppress proliferation in the secondary lymphoid organs and limit recruitment to the pancreas in a cell intrinsic manner.
IL-17-induced Rgs16 expression is essential for follicular T helper cell localization in the germinal centers of autoimmune BXD2 mice (123.44)
Authors: Ding Yanna , Hsu Hui-Chen , Druey Kirk , Wu Qi , Li Jun , Yang PingAr , Zajac Allan , Mountz John 
Published: January 2023

Abstract
Autoimmune BXD2 mice developed spontaneous germinal centers (GCs) and displayed increased number of CXCR5+ICOS+follicular T helper (Tfh) cells in the spleen. Although IL-21 but not IL-17 has been reported to be essential for the development of Tfh, there were significantly reduced PNA+Fas+GC B cells in the spleen of BXD2-Il21-/- and BXD2-Il17ra-/- mice. Interestingly, the frequency of Tfhs was 2.5-fold lower in BXD2-Il21-/- but 1.5-fold higher in BXD2-Il17ra-/- mice compared to wild type. Although increased, CXCR5+CD4 T cells were not specifically localized to the GCs in BXD2-Il17ra-/- spleens. Administration of AdIL-21 increased IL-17 levels in Tfhs and serum but had minimal effect on GC B cell frequencies in BXD2-Il17ra-/- spleens. In contrast, administration of AdIL-17 to BXD2-Il21-/- mice partially expanded GC B cells, suggesting that IL-17 acts downstream of IL-21 to facilitate the GC response. IL-21 stimulation of spleen CD4 T cells in vitro increased the frequency of Tfhs and upregulated expression of IL17R on Tfhs. IL-17 stimulated expression of Rgs16 and diminished CXCL13-mediated chemotaxis of CD4 T cells in vitro. Consistent with this, there were fewer GC CD4 T cells in BXD2-Rgs16-/- spleens in vivo. Our study suggests that IL-21 and IL-17 are required to promote the maximal autoreactive GC responses. IL-21 is important for Tfh development whereas IL-17 induced Rgs16 expression is required for Tfh localization in GCs to promote GC B-cell development.
The role of interleukin-21 in the pathogenesis of inflammatory bowel disease (123.45)
Authors: Poholek Catherine , Harrington Laurie 
Published: January 2023

Abstract
Th17 CD4 T cells are necessary for protection against pathogens but have also been cast as pathogenic in the context of many autoimmune diseases, including Inflammatory Bowel Disease (IBD). Th17 cells produce several inflammatory cytokines, including IL-17, IL-21, IL-22, and IL-26. Although these cytokines may act in concert to induce inflammation in colitis, IL-21 is a strong candidate for further scrutiny. IL-21 expression is increased in biopsies from patients with ulcerative colitis compared to healthy controls, and recent Genome Wide Association Studies have shown an association between the locus containing IL-2/IL-21 and IBD. We have shown that IL-21 signaling is required for the full induction of IBD in a murine model of disease. While others have shown in vitro that exogenous IL-21 acts to induce IL-17 production by CD4 T cells, our in vivo data suggests that IL-21 deficient cells are capable of producing IL-17A and IL-17F to a greater degree than IL-21 competent cells during IBD. In addition, our data disputes the previous finding that IL-21 suppresses the transcription factor Foxp3 as we have shown that IL-21 deficient T-regulatory cells express equal or less Foxp3 both in vitro and in vivo during IBD. Taken together, these data indicate that IL-21 plays a role in the induction of IBD that is separate from modulating the balance between effector and regulatory T cell responses. This work highlights a previously unrecognized role for IL-21 in the pathogenesis of IBD.
Optimizing conditions for the study of actively dividing T regulatory cells in flow cytometry (124.8)
Authors: Wilkinson Martha , Kwong Yu , Boyce Christopher , Elia Jeanne , Hingorani Ravi 
Published: January 2023

Abstract
The study of T regulatory (Treg) cells along with actively dividing cells can provide us with useful information in immunological studies since the cycling of Treg is different from the T effector cells. However, the buffer conditions may not always be compatible to combine FoxP3 staining with staining for dividing cells. We aimed to characterize the fixation and permeabilization buffers in the BD Biosciences catalog for the simultaneous staining of FoxP3 and Ki-67 in normal donors (both human and mouse). Six different buffer conditions were tested and experimental conditions optimized for detection of dividing Treg cells: BD Cytofix/Cytoperm™, BD Phosflow™ Perm I, BD Phosflow Perm II, BD Phosflow Perm III, BD Phosflow Perm IV, a new buffer system and ethanol. We have found that the new buffer system for fixation and permeabilization yields high quality data for FoxP3, Ki-67 and staining of surface markers. Other buffer systems also yield high quality data and can be used for the simultaneous detection of FoxP3 and Ki-67 with caveats that are discussed more in details within the poster.