bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased aortic atherosclerotic plaques in female apolipoprotein E-null (ApoE-/-) mice is associated with increased production of thromboxane A2 (93.17)
Authors: Smith Donald  D. , Tan Xiaoyu , Tawfik Ossama , Stechschulte Daniel J. , Dileepan Kottarappat N. 
Published: January 2023

Abstract
Prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) are products of the cyclooxygenase pathway and their production is increased in patients with atherosclerosis. In this study, we evaluated the influence of gender on PGI2 /TXA2 homeostasis and its impact on atherosclerosis progression using the ApoE-/- mouse model. ApoE-/- and C57BL/6 control mice were fed a normal diet or the high fat Western Diet for 3 months, and then blood, urine samples, and aortas were collected. The EIA analyses of 24-h urine samples for 11-dehydro TXB2 and 2,3-dinor-6-keto PGF1α indicated that female ApoE-/- mice produce 15-fold higher TXA2 (M=0.20; F=2.99 ng/mg creatinine) and approximately 50% less PGI2 (M=116; F=61 ng/mg creatinine) than males. The increase in urinary 11-dehydro TXB2 was also evident in wild type female mice maintained on normal diet. En face analyses of aortas showed marked increases in plaque formation in female ApoE-/- mice (male=9.9%; female=22.0%). Quantification of the H & E-stained cross sections of the aortic arch revealed 3 to 4-fold higher plaque thickness in female ApoE-/-mice. Interestingly, serum triglyceride and total cholesterol levels in ApoE-/- females were approximately 25% lower than males. The results suggest that the markedly elevated TXA2 production and reduced PGI2 production are gender-related proatherogenic risk factors in female ApoE-/- mice. Thus, a tightly regulated PGI2 /TXA2 homeostasis is critical for the prevention of cardiovascular disease. (Supported by NIH R01-HL070101 and the Carey Arthritis Fund)
Chemoattractant receptors and lymphocyte egress from extralymphoid tissues: changing requirements during the course of inflammation (94.21)
Authors: Debes Gudrun F , Brown Meghan N , Fintushel Sarah R , Hay Jack , Butcher Eugene C 
Published: January 2023

Abstract
Memory/effector T cells traffic efficiently through extralymphoid tissues entering from the blood and leaving via the afferent lymph. During inflammation, T cell traffic through the affected tissue dramatically increases, however, dynamics and mechanisms of T cell exit from inflamed tissues are poorly characterized. Here we show that, unexpectedly, large numbers of lymphocytes including T cells capable of producing IFN-γ and IL-17 leave the chronically inflamed skin, showing that memory/effector T cells also egress sites of inflammation. Whereas efficient egress from acutely inflamed skin required lymphocyte-expressed CCR7, chronic inflammation promoted CCR7-independent exit. CCR7-independent exit at late time points of inflammation was sensitive to pertussis toxin implying the contribution of alternative chemoattractant receptors. Our data suggest that CCR7 is an important receptor for lymphocyte egress from both resting and inflamed tissues, but that alternative exit receptors come into play during chronic inflammation allowing the egress of CCR7- as well as CCR7+ lymphocytes.
Enhanced Effector CD8 T Cell Development to IL-17 producing Cells in IFN-g Receptor Deficient Mice (96.11)
Authors: Kish Danielle D. , Fairchild Robert L. 
Published: January 2023

Abstract
Contact hypersensitivity (CHS) is a CD8 T cell mediated immune response to skin sensitization and challenge with hapten. In wild-type (WT) mice, hapten-primed CD8 T cell populations producing IFN-g and IL-17 are required for elicitation of CHS. This study tested the role of the IFN-g receptor (IFN-gR) in CHS to 2,4-dinitrofluorobenzene (DNFB). The magnitude of responses in sensitized IFN-gR-/- and WT mice were similar 24 hr after challenge but were markedly extended in duration in the IFN-gR-/- mice. CD8 T cell depletion abrogated CHS in both WT and IFN-gR-/- mice. Sensitization of WT mice induced high numbers of CD8 T cells producing IFN-g and IL-17 that were detected on day 5 but were reduced to naïve levels by day 8. In contrast, sensitization of IFN-gR-/- mice induced 2.5 more IFN-g producing and 5 fold more IL-17 producing CD8 T cells on day 5 and these levels were only slightly decreased on day 8. These increases were associated with increased cellular infiltration into the hapten challenged skin site of sensitized IFN-gR-/- vs. WT mice through 48 hr post-challenge. Treatment of sensitized IFN-gR-/- mice with anti-IL-17 but not anti-IFN-g mAb during challenge attenuated the CHS response. Thus the absence of IFN-g receptor signaling dysregulates CD8 T cell priming for CHS, increasing the development of hapten-specific CD8 T cells producing IL-17 which mediate CHS without the need for IFN-g.
Characterization of neutralizing anti-mouse IL-15 antibodies (96.15)
Authors: Xia Dong , Smith Carole , Shaffer Kathy , Butz Eric 
Published: January 2023

Abstract
IL-15 is believed to play a central role in the pathogenesis of a wide variety of disease states. We have developed neutralizing anti-mouse IL-15 antibodies from IL-15-null mice immunized with E.coli-derived recombinant mIL-15. Monoclonal antibodies M96 and M95 blocked the mIL-15-induced proliferation of CTLL-2 cells in vitro. In a mouse acute GVHD model, M96 inhibited donor CTL expansion and limited donor anti-host cytotoxic activity. In normal mice M96 induced a profound loss of NK cells and, though the total number of CD8 T cells, CD4 T cells, and B cells was not affected by M96, there was a slight reduction in the number of memory CD8 T cells in M96-treated mice. During time course studies, mice treated with 10μg of M96 lost about 50% of NK cells from the spleens within the first day and 95% of NK cells were eliminated by day 4. By day 14 the mice had recovered about 75-80% of their splenic NK cells, and by day 28 splenic NK cell levels were indistinguishable from untreated controls. We believe that M96 will be a useful tool for dissecting the roles of IL15 in normal homeostasis and inflammatory diseases.
Modulation of human pDC function by IFN-Lambda (IL-29) (97.17)
Authors: Gallagher Grant E. , Gallagher Grant , Megjugorac Nicholas 
Published: January 2023

Abstract
The Type III family of IFNs comprises three members, IFN-λ1, 2 and 3 (IL-29, IL-28A&B, respectively). Each signals through the same heterodimeric receptor complex, which consists of the binding and signaling subunit (IL-28Rα) plus the IL-10Rβ chain. We have identified high levels of IL-28Rα mRNA in plasmacytoid DC (pDC) from peripheral blood, and hypothesized that IFN-λ plays in important role in pDC maturation and development. Others have treated monocyte-derived DC with IFN-λ and reported an increased ability to generate Treg cells. However, there are no data regarding its effects on additional DC subsets or in fresh, untouched populations. We have previously reported on the differential regulation of costimulatory and homing molecules on pDC and mDC by IFNλ. Here, we show, using allogeneic MLRs, that IFN-λ alters the immunostimulatory capacity of pDC, which then inhibit production of hallmark cytokines of T cell polarization, including IFN-γ and IL-13. Not only does IFN-λ exert variable effects on DC surface molecule expression, but also regulates DC activation and downstream activity.
Cell cycle progression following naïve T cell activation is independent of Jak3/gc cytokine signals (97.6)
Authors: shi min , Lin Tsung , Appell Kenneth , Berg Leslie 
Published: January 2023

Abstract
T cell proliferation following activation is an essential aspect of the adaptive immune response. Multiple factors, such as TCR signaling, costimulation, and signals from cytokines each contribute to determine the magnitude of T cell expansion. In this report, we examine in detail the role of Jak3/γc-dependent cytokines in promoting cell cycle progression and proliferation of naïve T cells. Using naïve CD4+ T cells from Jak3-deficient mice and wild type CD4+ T cells treated with a small molecule inhibitor of Jak3, we find that these cytokine signals are not required for proliferation; instead they are important for the survival of activated T cells. In addition, we show that the percentage of cells entering the cell cycle and the percentage of cells in each round of cell division are comparable between Jak3-deficent and wild-type T cells. Further, cell cycle progression and the regulated expression of key cell cycle proteins are independent of Jak3/γc cytokine signals. These findings hold true over a wide range of TCR signal strengths. However, when CD28 costimulatory signals, but not TCR signals, are limiting, Jak3-dependent cytokine signals become necessary for the proliferation of naïve T cells. As CD28 signaling has been found to be dispensable for autoreactive T cell responses, these data suggest the potential for interfering with autoimmune T cell responses by inhibition of Jak3 signaling.
Modulation of Toll-like receptor-stimulated dendritic cell cytokine production by exogenous osteopontin. (98.32)
Authors: Contractor Nikhat , Frantz David C 
Published: January 2023

Abstract
Osteopontin (OPN) is a pleiotropic cytokine produced by mast cells, macrophages, activated T cells, NK T cells and dendritic cells and is present at high levels in human milk. Several studies in OPN-deficient mice have suggested a role for OPN in the development of Th1 and Th17 mediated immune responses. Dendritic cells (DC) are central regulators of T helper cell responses, however, it is unknown whether exogenous OPN supplied by milk plays a role in the differentiation of DC upon activation by signals through the TLRs. To address this question, we assessed the role of OPN in the LPS and CpG induced cytokine responses in bone marrow derived dendritic cells (BMDC). In the presence of OPN, the production of LPS and CpG stimulated IL-10, IL-6 and TNFα by BMDC was reduced in a dose dependent manner. OPN had no effect on LPS or CpG stimulated IL-12p40 or IL-12p70 production. OPN by itself did not induce IL-12p40, IL-12p70, IL-10, IL-6 or TNFα production by BMDC. These data suggest that exogenous OPN can modulate dendritic cell responses to TLR stimulation, and suggest a mechanism by which orally ingested OPN might influence the function of the intestinal immune system. Further studies are required to determine whether T helper cell polarization is affected by OPN treatment of BMDC, as well as to determine if exogenous OPN has similar inhibitory effects on cytokine production by tissue derived DC.
Bcl2, PDGFRβ and M-CSF are upregulated in monocytes from SLE patients with defective HDL and atherosclerosis (99.42)
Authors: Skaggs Brian J , Sahakian Lori , Grossman Jennifer M , FitzGerald John , Hahn Bevra H , McMahon Maureen A 
Published: January 2023

Abstract
Purpose: Our previous studies suggest a defective form of HDL, pro-inflammatory HDL (piHDL), as an SLE-specific risk factor for developing atherosclerosis. We examined monocyte transcript differences in women with SLE that have piHDL and carotid artery plaque to SLE/no piHDL/no plaque and SLE/+piHDL/no plaque patients.
Methods: Monocytes were isolated from patient PBMC by Ficoll and magnetic bead separation. Transcript levels of atherosclerosis-specific genes were examined by real-time PCR-based arrays (SA Biosciences). Data reported are from 15 SLE/no piHDL/no plaque, 14 SLE/+piHDL/+plaque, and 14 SLE/+piHDL/no plaque patients. mRNA changes were also measured in the human monocyte cell line THP-1 after piHDL treatment.
Results: Bcl2, PDGFRβ and M-CSF are significantly upregulated in SLE/+piHDL/+plaque versus SLE/no piHDL/no plaque, suggesting piHDL plays a role in blocking monocyte apoptosis signals. MCP-1 and ICAM-1 were only upregulated in SLE/+piHDL/no plaque patients, suggesting a piHDL-driven inflammatory transition to atherosclerosis. Inflammatory genes were also upregulated in THP-1 cells treated with piHDL.
Conclusions: PDGFR, M-CSF, and Bcl2 are upregulated in SLE/piHDL/plaque patients and could be novel targets in the treatment of increased atherosclerosis observed in SLE patients.
CM1 Enhances Proinflammatory cytokine Production in Peripheral Blood Mononuclear Cells and Synovial Fluid Mononuclear Cells from Rheumatoid Arthritis Patients (99.53)
Authors: Bae Seyeon , Kang Jae Seung , Kim Hye Min , Maeng Hyung Gun , Kong Joo Myoung , Lee Na Eun , Hwang Young Il , Lee Wang Jae 
Published: January 2023

Abstract
CM1 (centrocyte/-blast marker 1) is expressed on the surface of activated peripheral blood mononuclear cells (PBMCs). Recently, we found that the production of prostaglandin E2 (PGE2) from activated PBMCs was increased by CM1 stimulation via the activation of nuclear factor kappa B (NF-kB). Therefore, this study was attempted to investigate the roles of CM1 in the regulation of rheumatoid arthritis (RA). PBMCs were purified from healthy donors, RA patients and degenerative osteoarthritis (OA) patients, and knee joint synovial fluid mononuclear cells (SFMCs) were purified from RA patients. The expression of CM1 on PBMCs and SFMCs were analyzed by flowcytometry. The production of inflammatory cytokines and PGE2 by CM1 stimulation was measured by ELISA and chromatin immunoprecipitation (ChIP) assay and immunoblotting were performed to examine signaling mediators for inflammatory cytokines by CM1 stimulation. CM1 is highly expressed on PBMCs and SFMCs from RA patients, but not from OA patients. TNF-alpha, IL-1 alpha/beta, IFN-gamma and PGE2 production were markedly increased in PBMCs and SFMCs of RA patients upon CM1 stimulation. The phosphorylation of p38 MAPK was increased in PBMCs and SFMCs from RA patients in a time dependent manner after CM1 stimulation. In addition, the binding of NF-kB to the promoters of TNF-alpha and IL-1 beta after CM1 stimulation was also confirmed by the ChIP assay. Our results strongly suggest that CM1 may play a critical role in the disease progression of RA via the induction of disease-related proinflammatory cytokines and PGE2 production.
Role of complement activation component C5a on tumor progression (100.9)
Authors: Gunn Lacey , Cai Yihua , Ding Chuanlin , Hu Xiaoling , Hansen Richard , Aggarwal Deep , Yan Jun 
Published: January 2023

Abstract
Enhancement of anti-tumor mAb immunological mechanisms for tumor destruction may be obtained by promoting complement activation. However, complement activation components, such as C5a, trigger inflammation and chronic inflammation promotes tumor growth. Recently, it has been shown that C5a in the tumor could recruit and activate myeloid-derived suppressor cells to inhibit the anti-tumor CD8 T cell response. However, this effect was observed in only one tumor model. We chose to address the role of C5a on tumor growth by transfecting tumor cells with C5a. A human ovarian carcinoma, SKOV-3, and a murine lymphoma, RMA, were transfected which allows us to study C5a in an immunocompromised xenograft model and an immunocompetent syngeneic model. In vitro growth kinetics observed revealed no significant difference between C5a, control vector (CV), or wild-type cells. In both models, tumor-bearing mice with C5a-transfected tumor cells have significantly less tumor burden as compared to CV tumors. In the xenograft model, CD11b+DX5+ NK cells were significantly more and VEGF and arginase levels were significantly less in C5a expressing tumors. The syngeneic lymphoma model revealed C5a modulates tumor-infiltrating CD11b+ cells to produce more IL-12 and there is a greater influx of NK and CD4 T cells. Thus our studies demonstrate C5a chemoattracts innate NK cells and downregulates negative mediators in the xenograft model while in the syngeneic model C5a promotes shift to a Th1 response.
A distinct role of CD4+ Th17 and Th17-stimulated CD8+ CTL in induction of antitumor immunity and experimental autoimmune encephalomyelitis (101.5)
Authors: Ankathatti Munegowda Manjunatha , Xiang Jim 
Published: January 2023

Abstract
Th17 and CD8+ cytotoxic T lymphocytes(CTL) cells eradicate established tumors and induce experimental autoimmune encephalomyelitis(EAE). To assess their potential relationship, we generated ovalbumin(OVA) or myelin oligodendrocyte glycoprotein(MOG) specific Th17 cells by in vitro cultivation of OVA-pulsed dendritic cells(DCova) with CD4 T cells derived from T cell receptor transgenic OTII mice or MOG peptide-pulsed splenocytes with CD4 T cells purified from MOG immunization induced EAE C57BL/6 mice. We found these Th17 cells expressed transcriptional factor RORγt and secreted IL17. We also found that OVA-specific Th17 cells which acquired major histocompatibility complex/peptide(pMHC) I and costimulatory molecules by DCova activation stimulated OVA-specific CTL response and antitumor immunity against OVA-expressing BL6-10ova tumor. The stimulatory effect is mediated by acquired CD80 costimulation and targeted to CD8 T cells in vivo via acquired pMHC I complexes. Th17-stimulated CTL, but not the Th17 cells shown to have no in vitro killing activity play a major therapeutic role in eradication of early stage of BL6-10ova tumors(3mm dia). We also found that MOG-specific Th17 cells stimulated MOG-specific CTL responses, and both Th17 cells and Th17-stimulated CTL are involved in induction of EAE with a major pathogenic role played by the former. In total our data elucidate a distinct role of Th17 cells and Th17-stimulated CTL in induction of antitumor immunity and EAE.
The role of NFATc1 in tumor T cell responses to lung cancer (101.6)
Authors: Reppert Sarah , Boross Ildiko , Koslowski Michael , Türeci Özlem , Lehr Hans-Anton , Glimcher Laurie H. , Finotto Susetta 
Published: January 2023

Abstract
Nuclear factor of activated T cells (NFAT) proteins represent a Ca2+/calcineurin- regulated family of transcription factors that control T cell differentiation processes. Specifically NFATc1 and NFATc2 are highly expressed in peripheral T cells and activate the IL-2 and IL-4 promoters, suggesting that the Ca2+-regulated calcineurin/NFAT cascade controls alternative pathways of T cell activation and peripheral tolerance. NFATc1 is strongly activated upon antigen dependent T cell receptor engagement and induces genes that are involved in T cell effector function. In this study we describe that patients affected by lung Adenocarcinoma showed increased NFATc1 mRNA and protein levels in their lungs suggesting an involvement of NFATc1 on lung tumor development. To define the role of NFATc1 on lung cancer we start to analyze NFATc1 deficient mice in a murine model of lung Melanoma. Since NFATc1-deficient mice die at the embryonic stage, we bred conditional NFATc1 mice with CD4-Cre mice to gain insight into the role of NFATc1 in tumor T cell responses. Our preliminary results in this model showed a reduced tumor area in NFATc1-deficient mice compared to wild type mice. We also demonstrated here, that naïve T cells, isolated from NFATc1-deficient mice, produced less IL-17 under Th17- skewing conditions compared to those isolated from wild-type mice indicating a pathogenetic effect mediated by NFATc1 via IL-17 in lung tumor that must be further investigated.
The role of human Dectin-1 in eliciting antigen specific CD8+ T cell responses (130.35)
Authors: Ni Ling , Li Xiao-Hua , Ingrid Gayet , Duluc Dorothee , Klucar Peter , Clayton Sandra , Zurawski Sandy , Palucka Karolina , Zurawski Gerard , Banchereau Jacques , Oh SangKon 
Published: January 2023

Abstract
Dectin-1 recognizing fungal pathogens and mycobacteria, delivers intracellular signals to activate DCs. Here we report that Dectin-1 expressed on human DCs possesses unique immunological function that potentiates antigen-specific CD8+ T cell responses. We first generated an agonistic anti-Dectin-1 monoclonal antibody (mAb), which recognized Leu192-Asn202 in Dectin-1 and efficiently bound to both in vitro monocyte-derived DCs and in vivo CD1c+ skin dermal DCs, but not Langerin cells. Syk-dependent activation by anti-Dectin-1 mAb induced DCs to upregulate T cell costimulatory molecules, particularly CD70 and 4-1BBL, as well as cytokines and chemokines. This signaling via Dectin-1 allowed DCs to potentiate both memory and naïve CD8+ T cell responses by promoting their expansions and functional activities. Furthermore, both neo- and non-self-antigens delivered to DCs via Dectin-1 resulted in potent antigen-specific CD8+ T cell responses. This was largely dependent on CD70 and 4-1BBL upregulated by the signaling via Dectin-1. We also demonstrated that Dectin-1-mediated activation of DCs did not promote Foxp3+ and IL-10-producing regulatory CD4+ T cell responses, but potentiated CD4+ helper T cell function for inducing effector CD8+ T cells. We conclude that Dectin-1 on human DCs has unique function for eliciting antigen-specific CD8+ T cell responses by taking up antigens and delivering intracellular signals favoring effector CD8+ T cell responses.
Flagellin does not promote a CD8+ T cell response to the SIINFEKL epitope (130.42)
Authors: Bates John , Graff Aaron , Mizel Steven 
Published: January 2023

Abstract
Flagellin, the ligand for TLR5, is a potent adjuvant for CD4+ T cell-dependent humoral immune responses and has been reported by several groups to promote CD8+ T cell responses in vivo. However, other groups have failed to detect an effect of flagellin on the CD8+ T cell response. In an attempt to resolve this controversy, we created a protein composed of the SIINFEKL epitope and flanking amino acids fused to the N-terminus of full length Salmonella flagellin for use with TCR transgenic OT-I mice. We found that the CD8+ T cell stimulatory activity of this protein was, as expected, dependent on proteasome processing and was markedly more potent than ovalbumin by itself. However, the adjuvant effect of the fusion protein was TLR5 and IPAF independent. A fusion peptide containing the hypervariable region Salmonella or Pseudomonas flagellin and the SIINFEKL epitope also stimulated antigen-specific CD8+ T cell activation. These results are consistent with the conclusion that flagellin does not promote antigen-specific CD8+ T cell activation. Since the flagellin fusion protein containing the SIINFEKL epitope was far superior to ovalbumin as an inducer of CD8+ T cell activation, it is likely that uptake and processing of the SIINFEKL epitope by antigen-presenting cells is enhanced outside the context of ovalbumin.
Targeting CD73 to improves tumor immunotherapy (131.23)
Authors: Zhang Bin , Jin Dachuan , Fan Jie , Wang Long , Thompson Linda , Liu Aijie , Daniel Ben , Shin Tahiro , Curiel Tyler 
Published: January 2023

Abstract
During tumor progression, tumor cells foster a tolerant microenvironment and the activation of many immunosuppressive mechanisms that act in concert to counteract effective immune responses. Therefore, to accomplish cancer immune eradication, tumor-induced immunosuppression must be overcome. We demonstrate that CD73 is widely expressed on many tumor cell lines and upregulated in cancerous tissues with active enzymatic activity. Notably, CD73 expression in malignant cancer patients is closely associated with poor immune status of tumor infiltrating effector T cells. Because CD73 catalyzes AMP breakdown to immunosuppressive adenosine, we propose that CD73-generated adenosine prevents tumor destruction by inhibiting antitumor immunity. We confirmed this hypothesis by showing that inhibition of CD73 by selective inhibitor APCP slowed tumor growth and increased mice survival, and more importantly, augmented CTL therapy of cancer. Using genetic ablation of CD73 on tumor cells by siRNA and CD73 deficient mice, we found that both tumor and host CD73 synergistically controlled tumor progression by impairing antitumor T cell immunity. Thus, counteracting adenosinergic effects of CD73 in the tumor microenvironment represents a novel and feasible strategy of cancer treatment and is complementary to other approaches directed at improving the immune function of antitumor T cells such as adoptive T cell therapy or dendritic cell vaccines.