bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor antigen cross-presentation by tumor dendritic cells is blocked at a post-processing stage but can be reversed by selected pro-apoptotic agents (88.23)
Authors: Robinson Bruce W S , McDonnell Alison M , Brown Matthew , Prosser Amy C , van Bruggen Ivonne , Currie Andrew J 
Published: January 2023

Abstract
Cross presentation defines the unique capacity of an antigen presenting cell (APC) to present exogenous antigen via MHC class I molecules to CD8+ T cells. This process serves a critical role in host anti-tumor immunity. Dendritic cells (DC), specifically the CD8α+ subset, are specialised cross-presenting cells; however there is little understanding of how different DC subsets contribute to anti-tumour immunity. In this study we have examined the cross-presentation of a marker tumour antigen (transfected HA) expressed by the murine AB1-HA cell line. We have found that tumor antigen is constitutively cross-presented in the draining lymph node throughout disease progression and that both CD8α+ and CD8α - DC subsets are responsible for the observed cross-presentation of HA antigen to CD8+ T cells. Interestingly, tumor-infiltrating DCs fail to cross present, though they are not deficient in tumor antigen uptake or processing. Importantly, a tumor apoptosis-inducing false nucleotide agent, gemcitabine, which primes for anti-tumor immunity, also reverses the defect in antigen cross presentation of tumor DCs. These data suggest that lymph node resident CD8α+ DC are not the sole DC subset capable of cross-priming against tumor antigens and that local cross-presentation within tumors ie. TCR restimulation of tumor-infiltrating CD8 T-cells may be essential for effective anti-tumor immunity. These data have important implications for tumor immunotherapy particularly the use of immunotherapy in conjunction with tumor apoptosis-inducing therapy.
Mechanism of MDSC induced T cell tolerance in cancer (88.26)
Authors: Nagaraj Srinivas , Schrum Adam , Cho Hyun-II , Celis Esteban , Gabrilovich Dmitry I 
Published: January 2023

Abstract
Tumor antigen-specific T-cell tolerance is a critical element of tumor escape. It is known that MDSC can induce antigen-specific CD8+ T cell tolerance in an experimental system with adoptive transfer of transgenic T cells. In this study we addressed the critical question whether a similar phenomenon can be observed in a "natural" non-transgenic experimental model. Balb/C mice were subcutaneously inoculated with two different tumor cell lines, a derivative A2L2 cell line, which expresses high levels of HER2/neu and the parental cell line 66.3. HER2/neu specific CD8+T cells were generated by immunization of mice with peptide. MDSC were able to tolerize antigen-specific T cells in vivo if they were collected from A2L2 but not from 66.3 tumor-bearing mice indicating the tumor-specific nature of T cell tolerance induced by MDSC. Next we investigated the type of signaling caused by MDSC in CD8+T cells that could lead to tolerance. MDSC dramatically reduced the ability of CD8+ T cells to respond to the specific peptide. However, study of various signaling molecules using different experimental systems and tests found that MDSC did not induce negative signaling in T cells. This conclusion was confirmed in adoptive transfer experiments with CD8+T cells expressing dual TCR: LCMV glycoprotein peptide gp33-41 and OVA-derived H-2Kb-restricted peptide ova257-264. We found that MDSC loaded with peptide specific for one TCR induced tolerance only against that specific epitope but CD8+ T cells retained the ability to respond to the peptide specific for the other TCR expressed on the same cell.
Deficiency of adipocyte fatty acid-binding protein, A-FABP, suppresses tumor metastasis (88.9)
Authors: Li Bing , Stout Robert D. , Suttles Jill 
Published: January 2023

Abstract
An association between inflammation and cancer is well-established and it has been shown that tumor infiltrating macrophages (TIM) play a supportive role in tumor development. Recent studies have found that expression of A-FABP by macrophages promotes their inflammatory function. Thus, in the present study we evaluated the influence of A-FABP expression on tumor growth and metastasis. Upon transplantation of the of the murine tumor cell lines LL/2, MC38 and E0771, we found significantly lower levels of tumor metastasis to the lung in A-FABP-/- mice as compared to wild-type mice. In the LL/2 model, decreased metastasis in A-FABP-/- mice was not associated with decreased growth of the primary tumor. Concentrating on the role of macrophages, we found that although wild-type and A-FABP-/- mice showed equal numbers of TIM, A-FABP-/- TIM were poor producers of inflammatory cytokines, including IL-6, TNFa and IL-23 as compared to wild-type TIM. Activation of the MAPKs p38, ERK1/2 and JNK, as well as activation of IKK and NFkB in response to interaction with tumors was diminished in A-FABP-/- macrophages. In addition, A-FABP-/- macrophages produced significantly lower levels of MMP, an established mediator of tumor metastasis, both in vitro and in vivo as compared to wild-type macrophages. These results suggest a critical role for A-FABP in macrophage activities that promote tumor metastasis.
Anti-CD3 antibodies induce tolerance to FVIII in Hemophilia A mice after FVIII plasmid-mediated gene therapy (89.19)
Authors: Peng Baowei , Ye Peiqing , Rawlings David J , Ochs Hans D , Miao Carol H 
Published: January 2023

Abstract
We report here the successful use of anti-CD3 antibodies to modulate the immune responses after gene therapy. Five consecutive medium doses of anti-CD3 treatment concomitant with factor VIII (FVIII) plasmid injection prevented the formation of inhibitory antibodies against FVIII and achieved persistent, therapeutic-level of FVIII gene expression in treated Hemophilia A mice. Moreover, repeated plasmid gene transfer is applicable in tolerized mice without eliciting immune responses. Anti-CD3 treatment significantly depleted both CD4+ and CD8+ T cells in treated mice and increased the frequency of CD4+CD25+FoxP3+ regulatory T cells (Tregs). Nevertheless, prior depletion of CD25+ T cells did not abrogated tolerance induction and adoptive transfer of CD4+CD25+ T cells of tolerized mice in early time points to syngeneic plasmid injected mice did not transfer the dominant tolerance. Furthermore, anti-CD3 treated mice could mount normal immune responses against both T-dependent and T-independent neo-antigens. Our data indicate that anti-CD3 immunomodulation can be a safe and effective strategy to prevent transgene-specific immune responses following gene therapy.
Antigen dose over-rides DC phenotype in the control of CD4+ regulatory T cell induction through reduced Akt/mTOR signaling (89.30)
Authors: Turner Michael S , Finn Olivera J , Morel Penelope A 
Published: January 2023

Abstract
There is no consensus regarding which features of dendritic cells (DC) are optimal for inducing Foxp3+ regulatory T cells (Treg). Immature DC (iDC) have been shown to induce Tregs in response to foreign and allo-antigens. However, in the autoimmunity setting, mature (mDC) induce tolerance to self antigens by inducing Treg expansion and Th2 differentiation.
We compared the induction of islet autoantigen-specific Treg by mDC, and iDC populations that have distinct phenotypes and cytokine profiles. CD4+ T cells from BDC2.5 TCR Tg mice were cultured in the absence of exogenous TGFβ or IL-2 with iDC or mDC pulsed with high- or low-affinity antigenic peptides.
DC presenting low peptide doses induced weak TCR signaling via the Akt/mTOR pathway, resulting in significant expansion of Foxp3+ Treg. Higher doses of antigenic peptide induced strong Akt/mTOR signaling and favored the expansion of Foxp3- Th cells. The inverse correlation of Foxp3 and Akt/mTOR signaling was also observed in DO11.10 (OVA) and VFT (MUC1) TCR-Tg T cells and could be recapitulated with anti-CD3/CD28 stimulation in the absence of any DC.
These studies indicate that the strength of Akt/mTOR signaling is a critical T cell-intrinsic determinant for Treg vs Th induction. Furthermore, appropriately adjusting the dose of antigenic peptide can override the effect that DC phenotype and cytokine production may play.
The link between aberrant regulatory DC subset with breaking of tolerance in CD48 deficient mice (89.31)
Authors: Tamir Ayala , Durgan Kevin , Latchman Yvette 
Published: January 2023

Abstract
Dendritic cells (DCs) are antigen presenting cells with a dual role of priming T cells response and induction of peripheral tolerance. While CD11chigh DCs normally stimulate immunity (sDCs), CD11clowCD45rbhigh DCs were recently characterized as a regulatory subtype (rDC), which maintains low levels of costimulatory molecules after maturation. We found rDC levels were at least 2 times lower in bone marrow and spleens of CD48-/- C57BL/6 mice compared to their WT counterparts. Previously, we observed that aging CD48-/- mice developed spontaneous lupus-like autoimmune disease, indicated in elevated levels of autonuclear antibodies. We have shown that treatment of bone-marrow derived DCs with the neuropeptide, vasoactive intestinal peptide (VIP) and IL-10 strongly expanded the rDCs subtype, which produced high and low levels of IL-10 and IL-12, respectively. VIP-treated DCs of WT mice produced significantly higher amounts of IL-10, compared to CD48-/- DCs. We have also demonstrated that adoptive transfer of sDCs and rDCs subtypes together with OT-II-derived CD4+ T cells into WT and CD48-/- mice induced inhibition of OT-II-CD4+ T cell expansion only when WT-derived rDCs were transferred, as compared to expansion induced by their sDCs counterparts. These data suggest that dysfunctional and lower levels of rDCs of CD48-/- mice may be responsible for the development of spontaneous SLE in these mice when they are older.
T-bet controls regulatory T cell function during type-1 inflammatory responses (89.33)
Authors: Koch Meghan A , Perdue Nikole R , Tucker-Heard Glady's , Killebrew Justin R , Urdahl Kevin B , Campbell Daniel J 
Published: January 2023

Abstract
Regulatory T cells (TR) expressing the transcription factor Foxp3 play a critical role in preventing autoimmunity and restraining immune responses during infection. To accomplish these tasks, several subsets of TR work in concert to maintain normal immune homeostasis in secondary lymphoid tissues and at peripheral sites. However, the molecular basis underlying the phenotypic and functional differences of TR subsets remain obscure. Here, we show that during type 1 inflammatory responses, Foxp3+ TR upregulate the TH1-specifying transcription factor T-bet. These Foxp3+T-bet+ cells retain regulatory function, and do not produce the pro-inflammatory TH1 cytokine IFN-γ. Within TR, T-bet directs expression of the TH1-associated chemokine receptor CXCR3, and T-bet+ TR accumulate at sites of microbial replication in mice during persistent infection with Mycobacterium tuberculosis. T-bet-deficient TR show diminished proliferation and are outcompeted by wild type TR during strong TH1 responses in vivo. Furthermore, T-bet expression by TR is required for their proper homeostasis and function during TH1-driven autoimmunity. Thus, our data define a unique population of CD4+ T cells in which the activities of Foxp3 and T-bet are overlaid, resulting in functional TR capable of expanding during type-1 inflammation and suppressing TH1 responses in vivo.
(NIH -DK072295, AI067750, AI069889)
Role of the PKCλ/ι in Th2 establishment and airway hyperresponsiveness (90.11)
Authors: Yang Jun-Qi , Diaz-Meco Maria T. , Moscat Jorge 
Published: January 2023

Abstract
The differentiation of T cells along different lineages is central to the control of immunity. In order to investigate the role of PKCλ/ι, a member of atypical protein kinase C, in T cell function, we used a conditional gene knockout system by loxP-Cre recombination to selectively delete PKCλ/ι in activated T cells. With this system, we found that PKCλ/ι was necessary for Th2 cytokine production. Upon anti-CD3 plus anti-CD28 stimulation, IL-4 and IL-13 production from CD4+ T cells was significantly reduced in conditional KO mice as compared to their WT littermates. However, PKCλ/ι was not involved in Th1 cytokine secretion. T cell proliferation was impaired in conditional PKCλ/ι KO mice. Furthermore, deficiency of PKCλ/ι inhibited OVA-induced allergic airway inflammation in vivo. Our data demonstrated that the activation of the transcription factors NFAT and NF-¿B was impaired in PKCλ/ι-deficient activated T cells. In addition, we presented genetic knockout evidence in ex vivo experiments with primary T cells that PKCλ/ι was critical for the control of cell polarity during T cell activation. Therefore, PKCλ/ι emerges as a critical regulator of Th2 cell activation.
PD-1 localization in the immunological synapse is different in exhausted as compared to effector LCMV specific CD8 T cells (90.12)
Authors: Duraiswamy Jaikumar , Pryshchep Sergey , Ha Sang-Jun , Goronzy Jorg J , Ahmed Rafi 
Published: January 2023

Abstract
Understanding the molecular basis of ineffective T cell response during chronic viral infections may provide new therapeutic targets. Our studies in lymphocytic choriomeningitis virus (LCMV) infection provided the first indication that programmed death-1 (PD-1) pathway regulate T cell dysfunction during chronic infection. These findings were extended to HIV, SIV, HBV and HCV infections and suggest that in vivo blockade of PD-1 pathway may provide a therapeutic approach for human chronic infections. However, further studies are needed to determine how best to modulate PD-1 signaling to activate anti-viral T cells while minimizing immunopathology. Understanding these signaling effects would be greatly advanced by direct imaging of PD-1 in relation to signaling structures in the immunological synapse. Using LCMV model, we investigated PD-1 localization at the T:DC synapse by direct imaging of PD-1 in relation to T cell receptor by confocal microscopy. We compared P14 (LCMV gp33-specific) effector and exhausted cells from mice infected with LCMV Armstrong and clone 13 strains, respectively. Here we show that PD-1:TCR co-localization at the T:DC synapse is different between exhausted and effector CD8 T cells. Our study provides important informations on molecular mechanisms behind T cell exhaustion and may help to identify novel targets to modify PD-1 signaling for the treatment of human chronic infections.
Cycloastragenol extends T cell proliferation by increasing telomerase activity (90.30)
Authors: Valenzuela Hector F. , Fuller Thomas , Edwards Jim , Finger Danielle , Molgora Brenda 
Published: January 2023

Abstract
All normal human somatic cells have a finite number of times that they can divide and when this limit is reached cells are described as cellular senescent. Telomere shortening has been attributed as a main mechanism for cellular aging and for the lack of cellular functions associated with aging. Unlike what is seen in most somatic cells, in activated T cells telomerase activity is upregulated, resulting in increased telomere length. However, this brief period of telomerase induction only delays cellular senescence. Naturally, there is a great deal of interest in finding inducers of telomerase that may help delay the onset of cellular aging. There are various nutraceuticals that claim to both increase the health of individuals and delay the onset of cellular aging. We tested the nutraceuticals resveratrol and cycloastragenol for their ability to enhance T cell functions in vitro. In this study we evaluated the effect of these compounds on cellular proliferative capacity, levels of telomerase activity, surface markers and cytokine secretion of human CD4 and CD8 T cells. Our results show that cycloastragenol moderately increase telomerase activity and proliferative capacity of both CD4 and CD8 T cells. These preliminary results suggest that nutraceuticals inhibit the onset of CD4 and CD8 cellular senescence.
Exosomes secreted from human neural stem cells suppress T cell activation (90.33)
Authors: Kim Su Young , Cho Hyoung-Soo , Yang Seung-Ha , Shin Jin-Young , Kim Jung-Sik , Park Chung-Gyu 
Published: January 2023

Abstract
Exosomes are 50-100 nm diameter small membrane vesicles secreted from a variety of cells. Although exosomes express a common set of proteins, their protein composition is quite unique and varied significantly. Therefore, their function seems to be dynamic and determined by cell type specific proteins. Human neural stem cells (hNSCs) have been reported to have a therapeutic potential for neuro-regeneration in neurodegenerative disorders. However, the underlying mechanisms of neuroprotective effects of hNSCs are not still clear. In this study, we demonstrated that culture supernatant of hNSC, HB1.F3, can suppress the activation and proliferation of human T cells by apoptosis and cell cycle arrest. More interestingly, we found that exosomes secreted by hNSCs and included in culture supernatant play a critical role in the suppression of T cells by inducing G0/G1 arrest. Therefore, we here suggest that hNSCs has an immunomodulatory effect on T cells without cell-to-cell contact and a possible mechanism is mediated by secreted exosomes.
SHIP-deficient dendritic cells suppress T cell proliferation via a nitric oxide independent mechanism (91.9)
Authors: Antignano Frann , Hamilton Melisa , Cohen Carla , Ho Victor , Krystal Gerald 
Published: January 2023

Abstract
Dendritic cells (DCs) are potent stimulators of the immune system but can also be powerful inducers of tolerance. Previous studies have shown that myeloid DC precursors are capable of suppressing T cell proliferation through a contact and nitric oxide (NO) -dependent mechanism. In addition, GM + IL-4, but not Flt3L, -derived DCs have been reported to suppress T cell proliferation by inducing T cell apoptosis. The SH2-containing inositol 5'-phosphatase (SHIP) is a potent suppressor of the PI3K pathway with known functions in regulating myeloid cell development and survival. However, little is known of SHIP's role in the suppressive ability of DC subsets. In this study we co-cultured polyclonally activated T cells with bone marrow derived DCs or DCs isolated from the spleens of WT and SHIP-/- mice to determine SHIP's role in DC-induced T cell suppression. We found that both WT and SHIP-deficient DCs derived with GM-CSF ± IL-4 profoundly suppress T cell proliferation while Flt3L-derived and splenic DCs do not. The mechanism of suppression proved to be contact dependent for WT and SHIP-deficient GM-CSF DCs. However, unlike WT, SHIP-deficient DCs do not produce detectable levels of NO. These results suggest a novel mechanism of myeloid DC-induced T cell suppression at work in SHIP-deficient DCs.
This research is funded by an NCIC grant held by GK.
IFNbeta inhibits DC migration in vitro and in vivo (92.2)
Authors: Yen Jui-Hung , Ganea Doina 
Published: January 2023

Abstract
Interferon β (IFN β) is a widely approved therapeutic option for the treatment of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). However, the molecular mechanisms underlying the effects of IFNβ in MS/EAE are still not fully understood. In EAE, the major players are encephalitogenic CD4+ T cells and perivascular myeloid dendritic cells (DC). Therefore, migration of both peripheral T cells and DC into the CNS is essential for development of EAE/MS. Migration of DC from the inflammatory site to draining lymph nodes for antigen presentation and activation of naïve T cells, and to the CNS during chronic neuroinflammation requires CCR7 and MMP-9 expression. In this study, we report for the first time that IFNβ inhibits CCR7 expression and MMP-9 production in DC matured with a cytokine cocktail (TNFα+IL-1+IL-6+PGE2). In addition, DC matured in the presence of IFNβ exhibit a lower migratory capacity compared to mature DC. STAT-1 signaling is essential for IFNβ-mediated inhibition of CCR7 and MMP-9 expression, and subsequent DC migration. Our in vivo data also show that mice treated with IFNβ have a lower number of DC migrating to the draining lymph nodes following exposure to FITC as compared to controls. In conclusion, our results provide an addition mechanism for the beneficial effect of IFNβ in MS/EAE through the inhibition of mature DC migration. This work is support by NIH 2RO1AI052306
Eosinophil-derived IL-16 induction of FIZZ1 expression in alveolar epithelial cells is mediated by CD9 (93.11)
Authors: Liu Tianju , Huaux Francois , Choi Yoon Young , Ullenbruch Matthew , Phan Sem H 
Published: January 2023

Abstract
Recruited eosinophils in pulmonary fibrosis can play a role in tissue remodeling but its role is not fully understood. A novel secreted protein, found in inflammatory zone 1 (FIZZ1) is highly induced in bleomycin-induced lung injury. It is primarily localized to lung epithelial cells and mononuclear phagocytes. It has potential fibrogenic properties due to its ability to induce myofibroblast differentiation and enhance fibroblast resistance to apoptosis. In this study, the ability of eosinophils to regulate epithelial FIZZ1 expression was analyzed. Eosinophil and alveolar epithelial type II cell (AEC) co-cultures induced AEC FIZZ1 expression, which was significantly suppressed only by antibodies to IL-16. Cytokine array analysis confirmed that eosinophils from fibrotic lung expressed IL-16. Moreover IL-16 stimulated AEC FIZZ1 expression in a dose dependent manner, and AECs were found to express CD9, a putative IL-16 receptor. Suppression of CD9 expression by CD9 siRNA significantly inhibited AEC FIZZ1 expression by 67%. However antibodies to CD9 stimulated FIZZ1 expression indicating perhaps that antibody binding could activate CD9 signaling. These findings suggest that eosinophil-derived IL16 is capable of regulating FIZZ1 expression in AECs via binding to CD9. This may represent another pathway by which eosinophils could promote tissue fibrosis.
Supported by NIH grants HL28737, HL31963, HL 52285 and HL77297
Development of a human in vitro blood-nerve barrier model (94.20)
Authors: Ubogu Eroboghene E , Yosef Nejla , Xia Robin H 
Published: January 2023

Abstract
Phenotypic and functional differences exist between vascular endothelium from different tissues and between microvascular and macrovascular endothelial cells from the same tissue. Little is known about cellular interactions at the blood-nerve barrier (BNB). An in vitro BNB (IVBNB) model was developed using primary human endoneurial endothelial cells (pHEndECs) freshly isolated and purified from decedent sciatic nerves via endoneurial stripping, connective tissue enzymatic digestion and density centrifugation. pHEndECs are spindle shaped, contact inhibited, differentiate to form capillary-like tubes, are Ulex Europaeus Agglutinin 1 and von Willebrand Factor positive and endocytose acetylated low density lipoprotein. They also express alkaline phosphatase, γ-glutamyl transpeptidase, glucose transporter-1, p-glycoprotein and low levels of cellular adhesion molecules. Culturing pHEndECs on collagen coated transwell inserts was used to develop the IVBNB. High transendothelial electrical resistances (~160Ω.cm2; maximal 12 days after seeding) and low solute permeability to fluoresceinated high molecular weight (70 kDa) dextran (~0.7%) were seen. Electron microscopy demonstrated intercellular tight junctions and 50-100 nm-diameter pinocytic vesicles. These features are consistent with the BNB. This model provides an avenue to study mechanisms of leukocyte entry into peripheral nerves.