bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response Gene to Complement -32 exerts proinflammatory and profibrotic effects in immune complex mediated glomerulonephritis
Authors: Rus Violeta , Tatomir Alexandru , Nguyen Vinh , Talpos-Caia Ana , Papadimitriou John , Atamas Sergei , Luzina Irina , Sung Sun-Sang J , Badea Tudor , Rus Horea 
Published: January 2023

Abstract
Response Gene to Complement (RGC)-32 is a cell cycle regulator induced by complement activation, growth factors and cytokines. RGC-32 mediates TGF-β dependent profibrotic pathways, while in immune cells promotes the differentiation of Th17 cells in vitro and in vivo. RGC-32 expression is increased in tubules and glomerular infiltrating cells in kidney biopsies of patients with lupus nephritis. We used the nephrotoxic nephritis (NTN) mouse model to assess whether RGC-32 plays a local role in immune complex mediated glomerulonephritis (GN).
NTN was induced in WT and RGC-32−/− mice. Proteinuria, blood urea nitrogen and kidney histopathology were determined to assess kidney function and damage, IgG and C3 deposition. Single cell suspension of kidneys and spleens were analyzed by flow cytometry. Expression of IL-17A, collagen I, III and IV was determined by RT-PCR.
RGC-32−/− mice exhibit attenuated renal damage as shown by decreased proteinuria and glomerular scores, as well as decreased frequency of infiltrating PMN and decreased mRNA expression for IL-17A, collagen I, III and IV compared to WT mice. RGC-32 deficiency did not interfere with the induction of NTN as mouse anti-sheep IgG titers, percentage of splenic germinal center B cells, plasma cells, effector CD4+ T cells, Tregs, IL-17A, IFNg secreting cells and kidney deposition of autologous antibodies did not differ between RGC-32−/− and WT mice. These results suggest that RGC-32 contributes to the pathogenesis of immune complex mediated GN by promoting proinflammatory and profibrotic pathways. These data support further efforts to examine the mechanisms by which RGC-32 modulates these pathways and suggest that RGC-32 is a potential novel therapeutic target in the treatment of LN.
Targeting T cell activation and lupus autoimmune phenotypes with a novel glucose transporter inhibitor
Authors: Li Wei , Qu Ganlin , Choi Seung-Chul , Cornaby Caleb , Titov Anton , Teng Xiangyu , Wang Haiting , Morel Laurence 
Published: January 2023

Abstract
CD4+ T cells have numerous features of over-activated cellular metabolism in lupus patients and mouse models of the disease, including a higher glycolysis. We have previously shown that treatment of lupus-prone mice with 2-deoxy-D-glucose, which inhibits the first step of glycolysis, was sufficient to prevent autoimmune activation. Because 2DG has potential off-target effects, we sought to directly inhibit glycolysis by blocking glucose transporters. Here, we show that CG-5, a novel glucose transporter inhibitor, ameliorated lupus-like symptoms in a spontaneous lupus-prone mouse model, B6.NZM2410.Sle1.Sle2.Sle3 (Triple-congenic, TC), and in a chronic graft-versus-host-disease (cGVHD) model of induced lupus. Moreover, CG-5 treatment reduced lupus phenotypes including the expansion of germinal center B cells, as well as the production of autoantibodies in both TC mice and cGVHD models. In vitro, CG-5 blocked glycolysis in CD4+ T cells, and limited the expansion of CD4+ T cells induced by alloreactive stimulation. CG-5 also modulated CD4+ T cell polarization by inhibiting Th1 and Th17 differentiation and promoting regulatory T (Treg) induction. Finally, CG-5 blocked glycolysis in human T cells. Overall, our data suggest that blocking glucose uptake with a small molecule inhibitor ameliorates the symptoms of lupus, at least partially due to its inhibition of glycolysis in CD4+ T cells.
Supported by grants from the NIH (RO1 AI128901) and the Lupus Research Alliance (LRA-TIL 416522) to LM, and by an Experimental Pathology Innovative Grant from the Department of Pathology, Immunology and Laboratory Medicine, University of Florida to WL.
Human gingival tissue-derived MSC suppress osteoclastogenesis and bone erosion via CD39-adnosine signal pathway in autoimmune arthritis
Authors: Zheng Song Guo , Luo Yang , Wang Julie 
Published: January 2023

Abstract
Bone destruction is one of many severe complications that occurs in patients with rheumatoid arthritis (RA) and current therapies are unable to cure this manifestation. This study aims to determine whether GMSC can directly inhibit osteoclast formation and eventually attenuate osteoclastogenesis and bone erosion in inflammatory milieu. GMSC were co-cultured with osteoclast precursors that had been pretreated with or without the inhibitors of CD39 inhibitor, CD73 inhibitor or adenosine receptors and osteoclast formation were evaluated in vitro. 2×106 GMSC were transferred to CIA mouse and pathology scores, frequency of osteoclasts, and bone erosion in joints were assessed in vivo. We demonstrated that GMSC but not fibroblasts, markedly suppressed human or mice osteoclastogenesis in vitro. GMSC treatment also resulted in a dramatically decreased level of NF-κB p65/p50 in osteoclasts in vitro. Infusion of GMSC to CIA significantly attenuated the severity of arthritis, pathology scores, frequency of osteoclasts, particularly bone erosion, as well as a decreased expression of RANKL in synovial tissues in vivo. Blockade of CD73-CD39-adenosine receptors has significantly abrogated the suppressive ability of GMSC in vitro and therapeutic effect of GMSC on bone erosion during CIA. Thus, GMSC inhibit osteoclast formation in vitro and in vivo partially via CD73-CD39-adenosine signals. Manipulation of GMSC may have a therapeutic implication on rheumatoid arthritis and other bone erosion related diseases.
Inhibition of dendritic cells and Th17 cells by a flavonoid compound attenuates clinical severities in a murine collagen-induced arthritis model
Authors: Yen Hung-Rong , Pai Fu-Tzu , Lu Cheng-You 
Published: January 2023

Abstract
Rheumatoid arthritis is a common autoimmune disease, which leads to severe disabilities and affecting approximately one percent of the worldwide population. It is manifested with significant infiltration of immune cells, synovial inflammation, bone erosion and progressive disability. Despite the use of conventional therapies and biological agents, there are still some unmet needs and concerns. We aimed to develop novel therapeutic agents for the treatment of rheumatoid arthritis. We first identified that flavonoid compound CD001 derived from plants possesses suppressive effects on the maturation of dendritic cells and reduced the production of cytokines by dendritic cells. CD001 inhibited the Th17 differentiation in a dose-dependent manner in vitro. CD001 also inhibited the IL-6 secretion by SW982 synovial cells stimulated by IL-17 in vitro. Furthermore, in a murine model of collagen-induced arthritis, administration of CD001 significantly ameliorated paw edema and clinical scores in a dose-dependent manner. IL-17, IL-22 and TNF-a production of CD4 T cells decreased after treatment with CD001, while the percentage of Tregs increased. Immunohistochemistry stains also showed that CD001 decreased IL-17+ cells in the joints. In summary, pharmacological approach to inhibit dendritic cells and Th17 cells may be a promising intervention to treat rheumatoid arthritis.
The potential role for berberine, an alkaloid dietary supplement, in mitigating the subclinical pathology and delaying onset of rheumatoid arthritis
Authors: Vita Alexandra Adorno , Pullen Nicholas A , Lyons David 
Published: January 2023

Abstract
Berberine (BBR), a dietary supplement, is primarily marketed for the alleviation of polycystic ovary syndrome, type II diabetes, and inflammatory bowel disorders, with evidence from successful clinical trials. However, evidence also suggests that BBR might alleviate symptoms of rheumatoid arthritis in vivo, and have a potential prophylactic role from in vitrostudies. We examined BBR’s prophylactic potential for delaying onset of collagen-induced arthritis (CIA) in DBA/1J mice. To induce arthritis, mice were injected with a collagen/CFA emulsion on day 0 and a booster injection of collagen/IFA on day 18. Mice were either treated with 1 mg/kg of BBR daily (CIA+BBR group) or a vehicle control (CIA+PBS) via IP injections from day 0 to day 28, were left untreated (CIA group), or were in a non-arthritic control group. Incidence of arthritis by day 28 in CIA+BBR mice was 40%, compared to 90% in the CIA and CIA+PBS groups. Populations of B cells and T cells from the spleens and draining lymph nodes were examined from random mice across treatment groups during the pre-clinical stage of arthritis (day 14), and from the remaining mice on day 28 when arthritic signs and symptoms were expected to be apparent. Expression of co-stimulatory molecules CD80, CD86, MHC Class II, and CD40 was quantified on CD19+ B cells, and CD40L and CD28 on CD4+/CD3+ T cells. The concentrations of collagen type II-specific IgG2a, IgG1, and total IgG was obtained via ELISA. Finally, leukocyte infiltration into synovial tissue was imaged via confocal microscopy and compared across treatment groups on day 14 and day 28. The results indicate that there may be a potential role for BBR as a prophylactic supplement, although further examination into mechanism of action must be elucidated.
Two morphological changes of cancer cells under natural killer cell killing
Authors: CHOI YEO JIN , Ahn Gi Beom , Kim Hyung Sook , Lee Hong Kyung , Kim Youngsoo , Hong Jin Tae , Han Sang- Bae 
Published: January 2023

Abstract
Natural killer (NK) cells use granule exocytosis to kill cancer cells, which involves perforin-mediated delivery of granzymes from NK cells to cancer cells. Once inside the cancer cells, granzyme B, a member of serine protease family, activates caspase-3, which activates the serine/threonine kinase Rho-associated coiled coil–containing protein kinase (ROCK) I, an effector of the small GTPase Rho. Activated ROCK I increases the phosphorylation of myosin regulatory light chain and thus stimulates actomyosin contraction, required for apoptotic membrane blebbing. Ultimately, cancer cells under NK cell attack show rounding, shrinkage, and membrane rupture, which are classical morphological changes observed at the onset of apoptosis. Although much has been learned about these morphological changes, a fundamental question of how melanoma cell death is induced by NK cells remains unanswered. Do all melanoma cell lines undergo the classical dying process? If not, is there another dying process? To address this simple issue, we examined the dying of B16 melanoma cell lines under NK cell attack by using time-lapse imaging. Upon contact with NK cells, B16-F10 cells rounded and most of them showed membrane rupture (98 min); however, B16 parent cells showed writhing and delayed membrane rupture (235 min). This morphological difference depended on the expression levels of myosin regulatory light chain 9 (MYL9) but not activating ligands (CD112, CD155, Rae-1, and MULT-1), SPI, FasL, or PD-L1. Taken together, our data show that melanoma cells show two distinct types of morphological changes upon contact with NK cells and suggest that a strategy to decrease MYL9 expression by melanoma cells may improve the efficacy of NK cell–based immunotherapy.
Knockout immune regulator FGL2 in tumor cells impairs tumor progression in the CNS by facilitating CD103+ dendritic cell differentiation
Authors: Yan Jun , Zhao Qingnan , Gabrusiewicz Konrad , Kong Ling-Yuan , Xia Xueqing , Wang Jian , Ott Martina , Xu Jingda , Davis Eric Richard , Huo Longfei , Rao Ganesh , Sun Shao-Cong , Watowich Stephanie S , Heimberger Amy B. , Li Shulin 
Published: January 2023

Abstract
Although many studies link brain tumor progression to oncogene activation and tumor-suppressor gene inactivation in tumor cells, few studies implicate immune regulatory gene expression in tumor cells in arbitrating brain tumor progression. Here we show that fibrinogen-like protein 2 (FGL2) is highly expressed in glioma stem cells and primary glioblastoma (GBM) cells. FGL2 knockout (FGL2KO) in GL261, DBT, and LLC tumor cells did not affect tumor cell proliferation in vitro or tumor progression in immunodeficient NSG mice, but completely impaired GBM progression in immune-competent C57bl/6 mice. This impairment was reversed in mice with a defect in Batf3 (a key transcription factor for CD103+ DCs differentiation). Mechanistic studies revealed that FGL2KO in tumor cells induces CD103+ DCs differentiation in both the central nervous system (CNS) and in tumor draining lymph nodes (TDLN). The increased CD103+ DCs population in the CNS and TDLNs induce CD8+ T cells priming and activation and thereby gliomas regress. More specifically, the presence of FGL2 in tumor cells inhibited granulocyte-macrophage colony-stimulating factor (GM-CSF)–induced CD103+ DC differentiation by suppressing NF-κB, STAT1/5, and p38 activation. These findings are relevant to GBM patients because a low level of FGL2 expression with concurrent high GM-CSF expression is associated with higher CD8B expression and longer survival. These data provide a rationale for therapeutic inhibition of FGL2 in brain tumors.
Dendritic cells present cancer-derived p:MHCI molecules to prime anti-tumor CD8 T cells
Authors: MacNabb Brendan , Kline Douglas , Chen Xiufen , Tumuluru Sravya , Kline Justin 
Published: January 2023

Abstract
Migratory CD103+ dendritic cells (DCs) initiate anti-tumor CD8+ T cell responses by presenting tumor antigens on class I major histocompatibility complex (MHCI) molecules. Given that CD103+ DCs are adept at cross-presenting antigens, the current paradigm is that they present tumor antigens via classical TAP-dependent cross-presentation. However, recent studies have shown that DCs can present cellular antigens by other means, including by acquiring and presenting intact peptide:MHC (p:MHC) complexes from other cells, a mechanism known as cross-dressing. To assess the role of antigen cross-dressing in priming spontaneous anti-tumor CD8+ T cell responses in vivo, the murine MHCI molecule H2-Kb was knocked out in B16 melanoma and C1498 leukemia cell lines. Engraftment of these syngeneic tumors expressing Kb-restricted model antigens into C57BL/6 mice revealed a defect in antigen-specific CD8+ T cell priming when the cancer cells lacked Kb. While the absence of Kb expression by the tumor did not alter the level of costimulatory molecules on DCs or the cytokine milieu of the draining lymph node, it was correlated with a reduction in p:MHCI molecules for a model tumor antigen, SIINFEKL, presented by CD103+ DCs. Further, tumor-derived GFP-tagged Kb molecules were readily observed on the surface of DCs isolated from the tumor, and the presentation of acquired tumor-derived p:MHCI complexes by migratory DCs from tumor-draining lymph nodes of Kb/Db−/− and Tap1−/− mice was sufficient for ex vivo CD8+ T cell priming. Together, these data address a critical knowledge gap in tumor antigen presentation, and highlight a previously under-appreciated pathway as a crucial and non-redundant mechanism of CD8+ T cell activation by DCs.
Effector T cell stimulation using Staphylococcal enterotoxin G and I loaded HLA transgenic dendritic cells
Authors: Knopick Peter Leo , Riha Nathan , Biswas Nivedita , Nilles Matthew , Bradley David S 
Published: January 2023

Abstract
Staphylococcal enterotoxins (SE) induce powerful T cell stimulation with specificity for the variable beta (Vβ) region of the T cell receptor (TCR). Additionally, MHC in mice (H2) and humans (human leukocyte antigen; HLA) differ in binding superantigens and, in turn, provide different T cell activating potentials. We have previously demonstrated that SEG and SEI, administered together, elicited progression free survival of B16–F10 challenged HLA-DQ8 (DQ8; DQA1*0301 and DQB1*0302) transgenic mice. C57BL/6 (B6) mice did not benefit from SEG/SEI given post B16–F10 challenge, as expected, given a markedly reduced T cell proliferation in the B6 mice compared to the DQ8 mice. We provide evidence here of the potential of dendritic cells (DCs) to be the vector for a SEG and SEI immunotherapy. Primary antigen presenting cells, DCs and monocytes, were isolated from the bone marrow of DQ8 or HLA-DR3 (DRB1*0301) transgenic mice. SEG/SEI loaded DQ8 and DR3 DCs drove a strong B6 CD8 T cell response at low T cell:DC ratios; whereas both DQ8 and DR3 DCs at a high T cell:DC ratios activated CD4 T cells. Collectively, these data support incorporating SEG and SEI into the current DC based immunotherapeutic strategies to induce a stronger and direct anti-cancer T cell response.
Inhibition of SHP-1 expands the repertoire of anti-tumor T cells available to respond to checkpoint blockade therapy
Authors: Snook Jeremy , Soedel Ashleigh , Williams Matthew A 
Published: January 2023

Abstract
The presence and activity of CD8+T cells within the tumor microenvironment is essential for the control of tumor growth and impediment of cancer progression. Utilizing B16 F10 melanoma tumors that express altered peptide ligands of OVA257–264, we measured high- and low-affinity OVA-specific responses following adoptive transfer of OT-1 CD8+T cell into tumor-bearing mice. As expected, we found that TCR affinity positively correlated with the frequency of OT-1 tumor infiltrating lymphocytes (TILs). The differences in TCR affinity inversely corresponded to in vivo tumor growth rate. We next sought to determine whether checkpoint blockade therapy (CB: anti-PD-1; anti-CTLA-4) could enhance the recruitment of low affinity T cells. However, CB only increased the frequency of OT-1 TILs responding to high affinity antigens, while failing to alter the response or protective capacity of intermediate to low affinity T cell responses. To explore whether lowering TCR activation threshold could enhance the breadth and magnitude of the anti-tumor T cell response, we used shRNA to knock down Src homology region 2 domain-containing phosphatase 1 (SHP-1) in OT-1 T cells prior to tumor antigen exposure. Unlike CB, SHP-1 knockdown increased the magnitude and effector function of both low affinity and high affinity OT-1 T cells. When SHP-1 knockdown was combined with immunotherapy, we observed an additional boost in the OT-1 response, as well as enhanced tumor control by intermediate to low-affinity OT-1s. We conclude that targeting TCR activation threshold expands the repertoire of T cells available to respond to conventional CB, leading to enhanced control of tumor growth.
Guadecitabine, in combination with a TLR9 agonist, promotes anti-cancer immunity in BALB/c mice bearing 4T1 mouse mammary carcinoma
Authors: Smith Timothy M , Martin Rebecca 
Published: January 2023

Abstract
The classical approach to vaccine development establishes an effective, lasting memory response by challenging an organism with an antigen/adjuvant combination to prime the immune system against the antigen challenge. However, with respect to cancer vaccine development, this approach has often failed to elicit positive outcomes. This is, in part, due to the ability of tumor cells to downregulate specific antigens and forego immune surveillance. The objective of this study is to develop a treatment strategy that induces expression of cancer testis antigens (CTAs) on tumor cells while eliciting a strong and lasting immune response against these CTAs. CTAs are derived from proteins only expressed in immune-privileged sites under normal conditions, but de novo expression can be induced following treatment with a DNA methyltransferase inhibitor, such as guadecitabine (GUA). Previous publications have shown that intratumoral injections of a TLR9 agonist, CpG, results in an immune response against antigens expressed within the treated tumor. Our experiments have shown that 4T1 cells, a mouse mammary carcinoma, treated in vitro with GUA resulted in increased expression of CTAs as measured by flow cytometry. In addition, BALB/c mice challenged with 4T1 cells then treated with GUA + CpG resulted in depletion of myeloid derived suppressor cells and significantly reduced tumor burden. Tumor-bearing mice that received GUA treatment followed by adoptive T-cell therapy (ATC) also had significantly smaller tumors compared to the ATC only group. These findings warrant further investigation into whether treatment with GUA prior to treatment with CpG results in a lasting memory response against CTAs.
Glycogen synthase kinase 3 (GSK-3) synergizes with immune-checkpoint blockade (ICB) to overcome tumor resistance due to unique tumor infiltrating T-cell subsets as revealed by mass cytometry (CyTOF)
Authors: Krueger Janna , Taylor Alison , Motta Vinicius , Stagg John , Watson Ian , Rudd Christopher E 
Published: January 2023

Abstract
We have shown that the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) is a major regulator of programmed cell death-1 (PD-1) transcription and expression in T-cells (Taylor et al., 2016, Immunity). Further, small molecule inhibitors (SMIs) increased Tbx21 transcription for enhanced Tbet expression which suppressed Pdcd1 transcription in CD8+cytolytic T-cells. SMIs against GSK-3 are as effective as anti-PD-1 blocking antibody in the control of spontaneous pulmonary metastasis of B16 melanoma and EL-4 lymphoma cells (Taylor et al., 2018, Cancer Research). This introduced a new chemical approach to down-regulate PD-1 for the treatment of cancer. In addition, GSK-3 effects in Tbet expression can induce the expression of interferon-γ1 (IFNγ1) and granzyme B (GZMB) for enhanced cytolytic T-cell (CTL) killing of tumors suggesting that GSK-3 SMIs might synergize with check-point blockade.
We now show that GSK-3α/β inhibition can cooperate with anti-PD-1 blockade to overcome tumor resistance. Using high dimensional profiling of tumor infiltrated lymphocytes (TILs) with mass cytometry (CyTOF), we show that the synergy of GSK-3 SMI and anti-PD-1 is accompanied by 2 specific findings: (i) an increase in the presence of a unique subset of CD8+ TIL effector-memory T-cells beyond that observed with anti-PD-1 alone, and (ii) the significant decrease of a subset of CD4+ suppressor regulatory T-cells (Tregs) not observed with anti-PD-1 alone. Our findings offer a small molecule approach for synergy with anti-PD-1 that leads to an increase in CD8+ T-cells and the marked decrease of Tregs in tumors.
Splenic CD169+ marginal zone macrophages directly cross-prime CD8+ T cells in vivo using a vacuolar processing pathway
Authors: Van Endert Peter M , Mauvais François-Xavier , Hamel Yamina , Diana Julien , Garfa Meriem 
Published: January 2023

Abstract
Cross-priming of CD8+ T cells is of critical importance in triggering CD8+ T cell responses against pathogens and tumors. It is commonly thought that conventional type 1 dendritic cells (cDC1) cross-prime with unequalled efficacy, conferred to them by a proteasome and TAP-dependent pathway. Here we present data challenging the unique cross-priming efficacy of both the cDC1 subset and the proteasome/TAP-dependent pathway. Splenic CD169 macrophages are strategically placed in the marginal zone for capture of blood-borne pathogens. However, they are considered unable to directly cross-present and to depend on antigen transfer to cDC1 for cross-priming. We have developed a protocol for purification of CD169 macrophages. Extensive characterization shows that these cells display morphology, phenotype and gene expression distinguishing them clearly from cDC1, cDC2, plasmacytoid DC and red pulp macrophages. In vitro, CD169 cells cross-present soluble, receptor-targeted and phagocytosed antigen with equal or better efficiency than cDC1. Remarkably, this is achieved through a vacuolar, BFA and epoxomicin-independent pathway. Using intravital biphoton microscopy, 3D light sheet imaging and antigen targeting to CD169, we show that CD169 macrophages establish long-lasting antigen-dependent contacts with cognate CD8+ T cells that result in T cell activation in situ and generation of triple-positive effector as well as memory cells. Therefore, splenic CD169 macrophages represent a second set of myeloid cells equipped for highly efficient cross-priming. The biological role of cross-priming by these cells as well as their cooperation with cDC1 cells are under investigation.