bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphatic endothelial cells induce anergy of β-galactosidase specific CD4 T cells by providing antigen to CD11c cells (P1147)
Authors: Rouhani Sherin , Tewalt Eric , Davis Holly , Chen Lieping , Engelhard Victor 
Published: January 2023

Abstract
Lymphatic endothelial cells (LEC) express a variety of peripheral tissue antigens (Ags) and induce deletional tolerance of tyrosinase-specific CD8 T cells. LEC express MHC II molecules, suggesting they may tolerize CD4 T cells. We expressed β-galactosidase (β-gal) selectively in LEC using Lyve-1cre x β-galflox mice to investigate the ability of LEC to tolerize β-gal specific CD4 and CD8 T cells (Bg2 and Bg1, respectively). Using in vitro co-cultures and MHC I-/- bone marrow chimeras, we demonstrated that Bg1 CD8 T cells undergo deletional tolerance after recognizing Ag presented by MHC I molecules on LEC. Peptide-pulsed LEC induce Bg2 CD4 T cell proliferation in vitro, indicating LEC express functional MHC II. However, Bg2 cells proliferate when co-cultured with CD11c cells but not with LEC from β-gal+ mice. When Ag presentation is restricted to LEC in MHC II-/- bone marrow chimeras, Bg2 cells do not proliferate or upregulate CD69, CD25 or CD44. However, Bg2 cells do proliferate when transferred into chimeras with MHC II+ β-galneg bone marrow, demonstrating that hematopoietic cells acquire and present Ag from LEC. Bg2 cells activated in vivo by hematopoietic presentation of LEC-derived Ag do not proliferate in response to subsequent rechallenge, demonstrating that they have become anergic. Thus, LEC show a diminished ability to directly present MHC II Ags, but play an important role in CD4 tolerance by serving as a reservoir of Ag used by hematopoietic cells to induce anergy.
Unusual early onset of autoimmune thrombotic thrombocytopenic purpura in five children with Polynesian origin - in three combined with immunodeficiency (P4094)
Authors: Mansouri Taleghani Magnus , Bradbeer Peter , Cole Nyree , Chan George , Schaller Monica , Laemmle Bernhard , Kremer Hovinga Johanna A. 
Published: January 2023

Abstract
Autoimmune thrombotic thrombocytopenic purpura (aTTP) is a rare disease characterized by thrombocytopenia, microangiopathic hemolytic anemia and a variable degree of endorgan ischemia as well as an often relapsing course. Underlying is a severe ADAMTS13 deficiency due to inhibitory autoantibodies preventing normal processing of sticky, unusually large Von Willebrand factor multimers, to which platelets bind spontaneously. Acute episodes of aTTP typically occur in young women between 20-40 years of age and are rarely seen in children. Strikingly, over the last 7 years we observed aTTP with severe acquired ADAMTS13 deficiency in 5 children (aged 1-11 years) of Polynesian origin. The first 3 cases have hypogammaglobulinaemia requiring regular intravenous immunoglobulin (IVIG) infusions. At least 4 of the 5 cases have additional signs and symptoms indicative of a common variable immune deficiency syndrome (CVID), which in two cases (siblings) may have been demasked by rituximab used to treat their relapsing aTTP. Conclusions: Although cytopenias (mainly idiopathic thrombocytopenia, or Evans’ syndrome, both differential diagnosis of aTTP) and various autoimmune diseases have been reported in CVID the association with aTTP is novel (or underreported). Together with the common Polynesian ethnicity of the 5 cases and the unusual early aTTP onset this hints at new CVID underlying mechanisms. Further diagnostics and a search for mutual underlying defects are warranted.
Influence of background genes on Sjogren’s syndrome in interleukin 14 alpha transgenic mice (P4100)
Authors: Shen Long , Suresh Lakshmanan , Ambrus Julian 
Published: January 2023

Abstract
Interleukin 14 alpha transgenic mice (IL14aTG) mice on a C57BL/6 background mimic Sjogren’s syndrome (SS) seen in patients (Clin Immunol., 2009). Previous studies have demonstrated roles for lymphotoxin and type 1 interferon in the pathophysiology of the disorder (J.Immunol., 2006 and 2010). C57BL/6 mice respond to immunological challenges with TH1 &gt;&gt;TH2 responses whereas Balb/C mice respond to similar challenges with TH2 &gt;&gt; TH1 responses. We therefore examined the development of SS in IL14aTG mice on a Balb/c background. Histology of the salivary and lachrymal glands, spleen and lymph nodes were examined at 21 months of age. IL14aTG.Balb/C mice demonstrated only minimal infiltration of submandibular glands and minimal decrease in salivary gland secretions at 21 months of age. In contrast IL14aTG.C57BL/6 mice had dramatic infiltration of the submandibular and parotid glands by 12 months of age with loss of salivary gland secretions by 10 months of age. At 21 months of age 95% of IL14aTG.C57BL/6 mice had lymphoma while none of the IL14aTG.Balb/C mice had lymphoma. Evaluation of type 1 interferon, lymphotoxin and autoantibodies in the sera of IL14aTG.Balb/c mice are in progress. Development of SS in IL14aTG mice is markedly diminished with a Balb/c background compared to a C57BL/6 background. A TH1 program is central to the pathophysiology of SS. Further studies will elucidate particular genes that distinguish the development of SS in C57BL/6 mice compared to Balb/c mice.
Stage-specific binding profiles of cohesin in resting and switch-activated B cells at transcriptional control elements (P4396)
Authors: Günal Gamze , Paszkowski-Rogacz Maciej , Singaravelu Kalaimathy , Beyer Andreas , Buchholz Frank , Jessberger Rolf 
Published: January 2023

Abstract
The immunoglobulin (Ig) heavy chain locus comprises several higher order chromosomal interactions to facilitate stage-specific assembly of the Ig molecule. The cohesin complex acts together with CTCF to regulate long-range chromatin interactions important for transcriptional regulation during cell differentiation. We elucidated the binding profile of the cohesin complex in mature resting and switch-activated B lymphocytes by chromatin immuno-precipitation coupled with deep sequencing. Comparative genomic analysis revealed specific changes in patterns of cohesin binding to transcriptional control elements during Ig class switching. Specific binding changes of cohesin at B-cell specific gene loci suggest new cohesin-dependent regulatory pathways important for B cell maturation. Together with conserved cohesin/CTCF sites at the Igh locus, a prominent intronic cohesin/CTCF binding site at the Igh locus has been revealed. The functional mechanism of this mature B-cell specific regulatory site is yet to be elucidated by using chromosomal conformation capture assay. Our study shows that cohesin is involved in regulation of Ig class switching and will give rise to new insights of possible cohesin-dependent regulatory pathways of mature B cell development and class switching.
Recognition of CD47 on human hematopoietic stem cells results in improved human chimerism in xenografts and permits investigation of rare human progenitors in vivo. (P4469)
Authors: Huntington Nicholas , Di Santo James 
Published: January 2023

Abstract
Human immune system (HIS) mice represent an important biotechnology for fundamental human immunology research, disease models and drug development. The NOD mouse strain has been primarily used in the development of HIS mice as they possess several advantageous polymorphisms. NOD, but not Balb/c mice contain a polymorphism in Sirpα (an inhibitory receptor that prevents phagocytosis upon binding CD47) allowing NOD, but not Balb/c Sirpα to recognize human CD47 on engrafted cells. Despite this, Balb/c immunodeficient mice are still permissive to human engraftment and their use in human immune studies becoming more prevalent. To determine the importance of the CD47-Sirpα interactions in human hematopoietic reconstitution, we generated a congenic Balb/c Rag2-/-γC-/- HIS mouse expressing NOD Sirpα. A functional CD47-Sirpα interaction resulted in significantly higher human chimerism, with specific improvements in T cell, NK cell and progenitor reconstitution compared to HIS mice expressing only Balb/c Sirpα. Improved human reconstitution has allowed us to carefully study bone marrow resident human hematopoietic progenitors. We have identified 2 subsets of CD7+CD244.2+CD38+CD45RA+Lin-(CD56-) bone marrow precursors with either high or exclusive restriction to the NK cell lineage. Our results reveals the degree by which phagocytosis restricts xeno-engraftment and demonstrates a novel, highly sensitive xenograft model for human immunology studies.
Maternal methyl-donor supplementation protects against atherosclerosis in F1 ApoE-/- mice (P4424)
Authors: Yung Raymond , Delanaey Colin , Garg Sanjay , Fernandes Christopher , Allen Robert , Stabler Sally 
Published: January 2023

Abstract
T lymphocytes play an important role in the pathogenic inflammatory response that accelerates atherosclerosis. Previously, we showed that F1 mice born to dams fed a diet supplemented with methyl donors (MS diet) during pregnancy and lactation had decreased T cell-mediated pro-inflammatory cytokine and chemokine responses. Here, we report feeding Apolipoprotein E (ApoE-/-) deficient dams with the MS diet during pregnancy reduces atherosclerotic plaques in F1 mice that are subsequently fed a high fat diet (HFD) after weaning. F1 mice from dams on the MS diet (F1-MS) had increased global T cell DNA methylation and reduced Ccr2 mRNA and protein expression in CD3+ T cells, but not in CD11b+ monocytes, relative to F1-control mice. CCR2 plays an important role in the recruitment of inflammatory cells to atherosclerotic vascular lesions. F1 litter size, HFD consumption, body weight, body fat, and serum thiol metabolite levels were similar between F1-MS and F1-control mice. However, F1-MS mice had higher serum HDL and lower LDL+VLDL levels compared to F1-control mice. F1-MS mice had lower serum levels of inflammatory cytokines (IL-17, TNF-α, IL-6), and F1-MS T cells cultured in vitro expressed lower levels of those cytokines compared to F1-control mice. Together, these data suggest that the pre-natal MS diet ameliorates development of atherosclerosis by inhibiting T-cell CCR2 expression, reducing inflammatory cytokine production and increasing serum HDL:LDL ratio.
Loss of homeostatic granulopoiesis in IKKβ-deficient mice (P4472)
Authors: Huang Howard , Wang Xingan , Yamamoto Sumiharu , Ibrahim Mohsen , Qiu Chang-Shen , Zhu Jihong , Krupnick Alexander , Kreisel Daniel , Gelman Andrew 
Published: January 2023

Abstract
BACKGROUND IL-1β-mediated neutrophilia has been observed in mice with an inducible deletion of IKKβ under non-homeostatic conditions. We investigated the effects of a constitutive IKKβ deletion from the hematopoietic compartment. METHODS Mice carrying loxP-flanked IKKβ alleles (IKKβfl/fl) were crossed with Vav1-iCre mice to target IKKβ expression in hematopoietic cells (IKKβΔ/Δ). Bone marrow (BM), blood, spleen and peripheral tissues were analyzed by histopathology and FACS. Methylcellulose colony-forming cell (CFU) assays were performed using Lin-c-kit+ myeloid progenitors (MP) and splenocytes. MP proliferation was measured by EdU incorporation. RESULTS IKKβΔ/fl mice are phenotypically indistinguishable from IKKβfl/fl (WT) mice. In contrast, IKKβΔ/Δ mice are born in non-Mendelian ratios, develop patchy alopecia, osteopetrosis, splenomegaly and stunted growth. IKKβΔ/Δ mice also show massive neutrophilia in BM, spleen, blood and peripheral tissues as well as a sharp increase in BM and spleen granulocyte CFUs relative to IKKβΔ/fl and WT controls. Unlike in IKKβΔ/fl or WT granulocyte macrophage progenitors (GMP), IKKβΔ/Δ GMPs proliferate more in response to G-CSF than to GM-CSF or IL-3 stimulation. Moreover, G-CSF stimulated IKKβΔ/Δ MP produce more neutrophils relative to IKKβΔ/fl and WT MP. CONCLUSIONS Our data indicate that IKKβ controls homeostatic granulopoiesis through regulating sensitivity to G-CSF signals in MP.
Histone H2A deubiquitinase MYSM1 is essential for dendritic cell development (P4488)
Authors: Won Haejung , Chou Yuchia , Wang Tao , Jones Lindsey , Huang Xue , Chen Si-Yi 
Published: January 2023

Abstract
The mechanisms controlling differentiation of dendritic cells remain largely unknown. Using knockout mouse model, we identified Mysm1 as a critical regulator in dendritic cell differentiation. Mysm1 knockout mice showed a global reduction of both conventional dendritic cells and plasmacytoid dendritic cells in lymphoid organs and non-lymphoid organs whereas development of granulocyte and macrophage was not severely affected. Hematopoietic progenitors and dendritic cell precursors were significantly decreased in KO mice, and the precursor cells from Mysm1 knockout mice were unable to develop DC upon Flt3L stimulation in vitro. The developmental defect of Mysm1-/- progenitor cells was associated with decreased Flt3 expression. Molecular studies indicate that Mysm1 de-represses transcription of Flt3 gene by regulating histone modifications and mediating the recruitment of transcription factor Pu.1 at the promoter. In conclusion, we have identified a regulator of dendritic cell development, Mysm1, and provided novel mechanism of epigenetic control in steady-state dendritic cell development.
IRF8 regulates lymphoid-myeloid lineage priming and commitment defined by an IRF8-EGFP reporter mouse (P4374)
Authors: Wang Hongsheng , Jain Shweta , Sun Jiafang , Morse, III Herbert 
Published: January 2023

Abstract
IRF8 is a transcription factor critically involved in the differentiation of dendritic cells (DCs) and B cells. IRF8 is expressed in early hematopoietic progenitors, but it is not clear how IRF8 promotes these progenitors to commit to one lineage while preventing the development of alternative lineages. To better understand the functions of IRF8, we generated an IRF8-EGFP reporter mouse by replacing the stop codon of the Irf8 locus with the EGFP sequence. Flow cytometric analyses revealed progressive increases in expression of IRF8-EGFP from hematopoietic stem cells to progenitors destined to the granulocyte-macrophage pathway and to the common lymphoid progenitor pathway but not to the megakaryocytic-erythroid progenitor pathway. Cells committed to the B lineage expressed high levels of IRF8-EGFP, which is in sharp contrast with thymic T cells that expressed negligible levels of IRF8-EGFP. Unexpectedly, IRF8-EGFP expression in pre-pro-B cells was extremely heterogeneous, ranging from background to 4 logs above background. Furthermore, we identified an IRF8-EGFPbri population that expresses B220 with the potential to generate B cells, plasmacytoid DCs and myeloid cells in vivo. Finally, DC progenitors including common DC progenitors and pre-cDCs were marked by extremely high expression of IRF8-EGFP. Taken together, these data revealed a sequential expression pattern of IRF8-EGFP in early hematopoietic progenitors coinciding with lineage priming and commitment.
Inhibition of HMGB1 delays tumor progression, reduces MDSC-mediated immune suppression, and diminishes MDSC-macrophage cross-talk (P2001)
Authors: Parker Katherine , Horn Lucas , Clements Virginia , Sinha Pratima , Yang Huan , Li Jianhua , Tracey Kevin , Ostrand-Rosenberg Suzanne 
Published: January 2023

Abstract
Tumor-induced immune suppression is driven by immune suppressive cells including Myeloid-Derived Suppressor Cells (MDSC). MDSC are present in most patients with cancer. They block T cell activation and drive type 2 immunity. Cross-talk with macrophages enhances MDSC secretion of pro-tumor molecules such as IL-10 and decreases macrophage production of IL-12. Because the alarmin HMGB1 is increased in many cancers, we are determining if HMGB1 drives MDSC. Treatment of BALB/c mice with 4T1 mammary carcinoma with HMGB1 inhibitors Glycyrrhizin or Ethyl Pyruvate reduced lung metastases, while treatment of C57BL/6 mice with MC38 colon carcinoma with an HMGB1 neutralizing antibody (2G7) reduced MDSC levels in the blood, spleen, and tumor. BALB/c mice carrying 4T1 tumor cells down-regulated for HMGB1 by shRNA had an extended survival time relative to mice with irrelevant shRNA 4T1 tumor. Treatment of MC38 tumor-bearing mice with the anti-inflammatory A box domain of HMGB1 reduced primary tumor growth. In in vitro experiments, HMGB1 inhibitors decreased cross-talk-induced IL-10 production by MDSC and IL-6 production by macrophages, and reduced MDSC suppressive potency for T cells. HMGB1 inhibitors also reduced MDSC differentiation from bone marrow progenitor cells. These findings indicate that full-length HMGB1 drives tumor progression, while the anti-inflammatory A box domain counteracts full-length HMGB1 and reduces tumor growth and MDSC accumulation.
Attenuated NK cell killing to hepatoma cells increases the mortality via decreased expression levels of MICA, CD112 and CD155 during UPR (P2023)
Authors: Chen Lihua , Gong Jiuyu , Fang Liang , Jin Boquan 
Published: January 2023

Abstract
Natural killer (NK) cells play important roles in anti-tumor immunity. Here, we demonstrate that the unfolded protein response (UPR) attenuated the sensitivity of hepatoma cells to NK cell cytotoxic activity by decreasing the expression levels of MHC class I-related chain A/B (MICA/B), CD112 and CD155 in human hepatocellular carcinoma (HCC) cells. The decreased expression levels of MICA/B, CD112 and CD155 were due to the involvement of the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1α (IRE1α) pathways. In addition, the IRE1α pathway contributed to the increased expression levels of the ER-associated degradation (ERAD)-related molecule HRD1 and facilitated the degradation of MICA/B, CD112 and CD155. Moreover, we found that low levels of MICA/B, CD112 and CD155 expression were significantly associated with poor prognosis in patients with HCC. Thus, our results provide molecular, cellular and clinical evidence demonstrating a novel NK cell-associated immune evasion mechanism, and indicate that targeting this immune evasion pathway may be meaningful in treating patients with HCC.
Tumor-induced STAT3 hyperactivation creates a dendritic cell differentiation block by significantly downregulating protein kinase C βII expression (P2003)
Authors: Farren Matthew , Spangler Haley , Netherby Colleen , Carlson Louise , Abrams Scott , Lee Kelvin 
Published: January 2023

Abstract
Tumor mediated blockade of dendritic cell (DC) differentiation is a large component of cancer induced immunosuppression, contributing to tumor outgrowth. Tumors impair DC differentiation via factors that hyperactivate STAT3 in DC progenitors, though the mechanisms by which this occurs are largely unknown. PKCβII is essential in DC differentiation, and we test here if tumor driven STAT3 hyperactivation downregulates PKCβII expression, and if this is the mechanism underlying impaired DC differentiation. Myeloid cells from tumor bearing mice have significantly decreased PKCβII expression. Culture in tumor conditioned media (TCM) significantly decreased PKCβII expression and significantly impaired phorbol ester driven DC differentiation in human monocytes and in a human cell line model (KG1). In KG1, this was dependent on PKCβII downregulation: enforced PKCβII expression preserved phorbol ester driven DC differentiation in the face of TCM. Interestingly, PKCβII overexpression and/or activation also antagonized TCM-driven STAT3 activation. STAT3 drives this decreased PKCβII expression: TCM induced STAT3 activation and drove 4.5 fold higher STAT3 binding to the PKCβ promoter (compared to media control, p&lt;0.001). Mutation of a STAT3 consensus binding site in the promoter eliminates the ability of STAT3 to impair PKCβ promoter activity. Together, these observations argue that tumor driven STAT3 hyperactivation inhibits DC differentiation by downregulating PKCβII.
Anti-inflammatory effects of myeloid-derived suppressor cells and macrophage crosstalk contribute to tumor progression (P2043)
Authors: Beury Daniel , Parker Katherine , Ostrand-Rosenberg Suzanne 
Published: January 2023

Abstract
Myeloid-Derived Suppressor Cells (MDSC) polarize macrophages (MΦ) to a Type II tumor-promoting phenotype via MDSC-MΦ crosstalk. However, the role of inflammation in MDSC-MΦ crosstalk is not well defined. To determine the role of inflammation, we utilized wild type, IL-6-/-, and IL-10-/- mice bearing syngeneic 4T1 mammary carcinoma. MΦ and 4T1-induced MDSC express IL-6 and IL-10 receptors, suggesting that they have the potential to respond to both cytokines. To determine if IL-6 and IL-10 contribute to tumor progression by modulating MDSC-MΦ crosstalk, MDSC from 4T1-bearing wild type or IL-10-/- mice were cultured with MΦ from wild type or IL-6-/- mice. MDSC were anti-inflammatory and decreased MΦ production of IL-6. IL-6 is important in vivo since 4T1-bearing IL-6-/- mice have extended survival and delayed primary tumor growth vs. wild type mice. Anti-inflammatory effects are exacerbated by MΦ themselves, since their production of IL-6 increases MDSC production of IL-10. However, MΦ-produced IL-6 affects MDSC indirectly, as exogenous IL-6 does not increase MDSC IL-10 production. Although IL-10 is classically considered as an anti-inflammatory cytokine, it contributes to tumor progression because 4T1-bearing IL-10-/- mice have delayed primary tumor growth and extended survival vs. wild type mice. These data demonstrate that MDSC have anti-inflammatory effects and that MDSC-MΦ cross-talk contributes to the overall milieu of IL-10 and IL-6 within the tumor microenvironment.
TNF signaling drives myeloid-derived suppressor cell accumulation (P2051)
Authors: Qin Zhihai 
Published: January 2023

Abstract
TNF, an inflammatory cytokine that is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. We previously reported that tumors implanted in TNF receptor-deficient (Tnfr-/-) mice are spontaneously rejected; however, the molecular mechanisms underlying this rejection are unclear. Here we report that TNF signaling drives the peripheral accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs expand extensively during inflammation and tumor progression in mice and humans and can enhance tumor growth by repressing T cell-mediated antitumor responses. Peripheral accumulation of MDSCs was drastically impaired in Tnfr-/- mice. Signaling of TNFR-2, but not TNFR-1, promoted MDSC survival through upregulation of cellular FLICE-inhibitory protein (c-FLIP) and inhibition of caspase-8 activity. Loss of TNFRs impaired the induction of MDSCs from bone marrow cells, but this could be reversed by treatment with caspase inhibitors. These results demonstrate that TNFR-2 signaling promotes MDSC survival and accumulation and helps tumor cells evade the immune system.