bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular mechanisms of Th1-mediated antigen cross-presentation: roles of Iigp1 and ingenol. (130.34)
Authors: Kariyone Ai , Ikutani Masashi , Nagai Yoshinori , Takatsu Kiyoshi 
Published: January 2023

Abstract
Antitumor immunity requires activation of CD8+ cytotoxic T cells (CTL) by antigen-presenting cells (APCs) through interaction with tumor antigen peptides on MHC class I molecules. Intracellular mechanisms on MHC class I-restricted soluble antigen presentation (cross-presentation) remain elusive. Peptide-25 of Ag85B induces Th1 cell response in I-Ab mice that facilitate CTL generation against unrelated Ovalbumin (OVA) peptide when co-immunized with OVA, indicating that Peptide-25 augments cross-presentation by APCs. In this presentation we will discuss about roles of Iigp1 and effects of various natural products on Th1-mediated enhancement of the cross-presentation. We evaluated the cross-presentation by 2-step culture system. At first, APCs were cultured with P25 TCR-Tg CD4+ T cells, Peptide-25, OVA or natural products for overnight. After the culture the OVA-pulsed APCs were harvested and cultured with OVA specific OT-I Tg CD8+ T cells for 3 days. The cross-presentation activity was evaluated by OT-1 proliferation and IFN-γ production. Results revealed an indispensable roles of IFN-γ and IFN-γ-inducible genes such as Iigp1 in the Th1-mediated cross-presentation. We also found that some of natural products such as ingenol derivatives augment the cross-presentation in an Th1-independent manner.
Quantitative assessment of soluble B7RP-1 in bound and unbound state in normal and Systemic Lupus Erythematosus patients’ plasma (130.4)
Authors: Bautista Ami , Zhou Lei , Zhang Ming , Sullivan Barbara , Belouski Shelley , Starcevic Marta , Kaliyaperumal Arunan , Chirmule Naren , Jawa Vibha 
Published: January 2023

Abstract
Membrane associated receptors can undergo shedding following cross-linking with ligand. B7RP-1 receptor is present on B-cells and macrophages and binds to the inducible costimulatory (ICOS) molecule on activated and memory T cells. ICOS binding can induce B7RP-1 receptor shedding. An electrochemiluminescence assay (ECLA) on the Meso Scale Discovery Sector Imager 6000 was validated to quantitate the soluble B7RP1 (sB7RP-1) levels in plasma from normal and Systemic Lupus Erythematosus (SLE) subjects. Comparing results of untreated samples or those pretreated with acetic acid enabled the detection of free sB7RP-1 and complexed sB7RP-1 (bound with ICOS or anti-B7RP-1 antibody). Using a bivalent Fc fused B7RP-1 receptor as the standard, the assay range was validated from 0.55 to 40 ng/mL with less than 30% total bias (%relative error plus %CV) at each level. Repeat measures of 51 subjects (normal and SLE) over day 1, 8, and 15 were analyzed. Utilizing the ratio of the sB7RP-1 levels quantified at day 8 or 15 compared to day 1 (post to pre), the natural variability between subjects and over time was statistically determined. No significant differences were noted between SLE and normal subjects, hence, the post to pre ratios were pooled and the range was set between 0.63 to 1.47, representing the 2.5% and 97.5% distributions, respectively. Hence, this assay can help monitor the extent of B7RP-1 shedding following ligand binding and it's potential to form an immunocomplex.
Neutrophils markedly influence the immune response to protein antigens in adjuvant (130.45)
Authors: Yang Chiao-Wen , Unanue Emil 
Published: January 2023

Abstract
Neutrophils (PMN) have a crucial role in innate immunity against microbial infections. In vitro experiments indicated that PMN dampened T cell proliferation. However, it is unclear if PMN affect adaptive immunity in vivo. Here we used protein immunization in various adjuvants as a model system to study how PMN modulate T cell priming. After immunization with Freund’s adjuvants or alum, PMN rapidly entered the draining lymph nodes (dLN), localizing to the cortical sinus where antigen accumulated. In mice lacking PMN, due to antibody-mediated depletion or genetic ablation, CD4 T cell priming was enhanced by 2-3 fold. We observed enhanced CD4 T cell responses to three different protein antigens (hen-egg white lysozyme, ovalbumin and listeriolysin-O); this effect was independent of the adjuvant and antigen dose. PMN depletion in mice lacking NADPH oxidase or inducible NO synthase still showed enhanced CD4 T cell responses. Dendritic cells (DCs) and macrophages in the dLN contained more antigen and presented more peptide-MHC complexes in the absence of PMN, suggesting antigen competition between PMN and antigen presenting cells (APCs). Finally, PMN-depletion enhanced CD4 T cell responses in mice immunized with antigen-loaded DCs, indicating that PMN migrating to the dLN had a negative effect on antigen bearing APCs. Together, these experiments showed that PMN influenced adaptive immune responses via modulation of antigen presentation.
IFN-γ suppresses antigen presentation by dendritic cells after infection (130.6)
Authors: Thacker Robert , Jordan Michael 
Published: January 2023

Abstract
IFN-γ has repeatedly been shown to increase antigen presentation in macrophages and dendritic cells (DCs). In the course of our studies investigating the influence of IFN-γ on antigen presentation during acute LCMV infection, we discovered novel suppressive effects of this cytokine on antigen presentation. We observed that after infection, the administration of an anti-IFN-γ ab on day 3 unexpectedly enhanced the ability of day 6 DCs to activate CD8+ and CD4+ T cells in vitro. In the presence of DCs isolated from these mice, T cells produce 5-10 times more IFN-γ, as compared to controls. Presentation of exogenously administered antigens is also heightened. Differences are not due to variability in viral load or antigen levels. Loading DCs with peptide reduced the differences in IFN-γ production down to 2 fold, suggesting variable costimulation played a minimal role in the observed phenomena. Inhibition and knockout studies have led us to conclude that neither IFN-γ induced production of 2,3 IDO nor NO production is responsible for the observed suppression. Evidence suggests the suppression may be due to an increase in SOCS-1 but further investigation is required. While these findings are at odds with the conventional understanding of the role of this cytokine as a promoter of antigen presentation (via upregulation of MHC molecules and immunoproteasome expression, etc.) they potentially explain much of its poorly understood disease and immune response-limiting effects.
Concurrent up-regulation of activation/maturation receptors and IFN-α by plasmacytoid dendritic cells in response to HSV and HIV (130.8)
Authors: Awoyomi Temitayo , Singh Sukhwinder , Fitzgerald-Bocarsly Patricia 
Published: January 2023

Abstract
Plasmacytoid dendritic cells (pDC) produce high levels of interferon-α (IFN-α) when stimulated with viruses; this viral stimulation also leads to modulation of functional surface receptors crucial for antigen presentation. These receptors, which include CD40, CD62L, CD80, CD83 and CD86, are important for pDC trafficking and T cell activation. In this study, we investigated whether the same pDC that produce IFN-α also modulate these surface receptors or whether they represent distinct subpopulations. pDC were stimulated with HSV-1 or HIV-1 and using flow cytometry, we observed a time-dependent increase in the co-expression of these activation/maturation markers and IFN-α expression. Up-regulation of CDs 40, 80, 83 and 86 were concurrent with IFN-α production in a subpopulation of pDC, while pDC shed CD62L and expressed IFN-α in response to virus. We also found that some pDC do not concurrently produce IFN-α and up-regulate surface receptors: they either produced IFN-α or expressed the activation markers. It is unclear whether these cells that carry out a single function represent distinct subpopulations of pDC or whether they were captured along a continuum: i.e., pDC that first produce IFN-α then mature into non-IFN-producing antigen presenting cells. Further studies will be done to tease apart the progression of expression of these markers, their dependence on IFN-α production and implications for diseases like HIV that suppress pDC function and alter pDC phenotype.
Contribution of autophagy to MHC-II mediated presentation of viral antigens (130.9)
Authors: Comber Joseph , Eisenlohr Laurence 
Published: January 2023

Abstract
Conventionally, major histocompatibility complex (MHC) class II molecules present peptides derived from exogenous sources of antigen. However, it is now accepted that endogenous antigen can also be processed for MHC class II peptide presentation. Several pathways of endogenous presentation have been reported, including macroautophagy. Here we used siRNA mediated knockdown to determine whether autophagy plays a role in the MHC class II-restricted immune responses to two different viral infections. Reduction of Atg7, a key ubiquitin- like enzyme catalyzing autophagosome expansion, did not significantly alter global MHC class II mediated presentation of epitopes derived from influenza or vaccinia viral infections. As a positive control, the autophagy protein LC3 was fused to the influenza specific MHC class II restricted epitope “Site-1”. In this context, presentation of the epitope was reduced by both chemical and siRNA mediated inhibition of autophagy. Taken together the results indicate that although individual epitopes can be presented on MHC class II via autophagy, the contribution of this pathway to the total MHC class II restricted response to viral infection may be limited.
Mam-A2.4 DNA vaccination leads to generation of effector phenotype CD8+ T cells and results in tumor regression. (131.1)
Authors: Lerret Nadine , Rogozinska Magdalina , Jaramillo Andres , Marzo Amanda 
Published: January 2023

Abstract
Mammaglobin-A (Mam-A) is a breast cancer-associated antigen expressed by approximately 80% of human breast tumors. Recently, seven epitopes derived from Mam-A were identified that bind HLA-A2 and are naturally presented by breast tumors, making these potential targets for immunotherapy. We show that epitope-specific, rather then full-length Mam-A DNA vaccination induces more effective tumor regression in vivo. Spleen cells from C57Bl/6 HLA-A2 mice, vaccinated with either full-length Mam-A DNA or epitope DNA (Mam-A2.1, Mam-A2.2, Mam-A2.4 and Mam-A2.6), were transferred into SCID-beige mice bearing tumors derived from the AU-565 (HLA-A2+/mammaglobin-A+) breast cancer cell line. Our results show that antigen-specific CD8+ T-cells derived from both full-length and epitope-specific DNA vaccination were initially capable of causing regression. However, only vaccination with Mam-A2.4 leads to long-term tumor regression, which can be further enhanced by low-dose total body irradiation of the tumor-bearing host. Furthermore, vaccination with Mam-A2.4 leads to the generation of CD8+ T-cells with an effector phenotype. These data demonstrate the potential of Mam-A single epitope DNA vaccination combined with low-dose total body irradiation as a therapy for the treatment and/or prevention of breast cancer.
Adoptive co-transfer of tumor specific CD4+ T cells awakens host protective immunity to MHC-II- ovarian cancer through CD40-mediated licensing of dendritic cells and CCL5 secretion. (131.14)
Authors: Nesbeth Yolanda , Martinez Diana , Toraya Seiko , Scarlett Uciane , Cubillos-Ruiz Juan , Rutkowski Melanie , Conejo-Garcia Jose 
Published: January 2023

Abstract
The effect of adoptive cell transfer (ACT) on endogenous anti-tumor immunity remains largely unknown. We previously showed that transferring tumor-primed T cells into tumor-bearing mice awakened endogenous antitumor mechanisms and induced the rejection of otherwise lethal ovarian cancers when coupled with depleting tumor-associated immunosuppressive dendritic cells (DCs). Here we elucidate this arousal of host responses to be due to the licensing of host DCs by co-transferred CCL5-secreting CD4+ T cells that recruit host antitumor immune cells. Tumor-primed CD4+ T cells significantly delayed tumor progression and directly activated host tumor-resident DCs which subsequently activated tumor-exposed C8+ T cells. These effects were long-lived, as host T cells obtained from mice treated with ACT were protective against secondary challenge with the same tumor. Disrupting CD40-CD40L interactions during ACT impaired DC maturation and ability to stimulate tumor-infiltrating CD8+ T cells. Similarly, abrogating CCL5 secretion reduced DC maturation and the survival increases obtained from ACT. The absence of CCL5 and CD40 further reduced the protective phenotype of the host cells against secondary challenge with the same tumor. Our data unveil a CD40-dependent mechanism of transferring immunity from adoptively transferred CCL5-secreting CD4+ T cells to host immune cells, causing sustained antitumor effects, and advance the field towards developing more potent anti-tumor therapies.
Nanoparticle [Gd@C82(OH)22]n induces dendritic cell maturation and promotes Th1 immune responses (131.2)
Authors: Yang De , Zhao Yuliang , Guo Hua , Li Yana , Tewary Poonam , Zhang Ning , Oppenheim Joost 
Published: January 2023

Abstract
[Gd@C82(OH)22]n, a fullerene-based nanoparticle of approximately 22 nm in saline solution, has been previously shown to exhibit anti-tumor effect in mouse tumor-bearing models with little toxicity, however, the underlying anti-tumor mechanism(s) remains elusive. Here we report that [Gd@C82(OH)22]n could induce phenotypic maturation of dendritic cells (DC) by stimulating DC production of cytokines including IL-12p70, upregulating DC costimulatory (CD80, CD83, and CD86) and MHC (HLA-A,B,C and HLA-DR) molecules, and switching DCs from CCL5-responsive to CCL19-responsive phenotype. In addition, [Gd@C82(OH)22]n-treated dendritic cells became functionally mature as illustrated by their capacity to activate allogeneic T cells. When mice were immunized with ovalbumin in the presence [Gd@C82(OH)22]n, [Gd@C82(OH)22]n enhanced ovalbumin-specific Th1-polarized immune responses as evidenced by predominantly increased production of IL-1β, IL-2, and IFNγ. Thus, [Gd@C82(OH)22]n nanoparticle is a potent activator of dendritic cells and Th1 immune response, which contributes to its potent anti-tumor effect.
Vaccination with survivin as a self TAA and SA-4-1BBL is effective in eradicating established lung carcinomas in CD8+ T cell and NK cell dependent manner (131.29)
Authors: Sharma Rajesh , Srivastava Abhishek , Yolcu Esma , Shirwan Haval 
Published: January 2023

Abstract
Costimulatory ligands of TNF family have great potential as adjuvant for therapeutic vaccines due to their critical role in the expansion of T cells, survival, and long-term memory. Particularly, 4-1BBL has the most potent T cell activity among the TNF costimulatory members. However, the use of 4-1BBL as the immunomodulatory component of conventional therapeutic vaccine has been limited due to its lack of activity in soluble form. We have recently generated a chimeric 4-1BBL with streptavidin (SA-4-1BBL) that exists as tetramers/oligomers with potent activity in soluble form. We herein formulated a subunit protein based vaccine containing SA-4-1BBL and survivin as an autologous tumor associated antigen. The therapeutic efficacy of this vaccine was tested in the transplantable survivin expressing 3LL metastatic lung tumor model. Vaccination with the survivin and SA-4-1BBL resulted in the eradication of established 3LL tumors in 75% of the animals. Importantly, animals with successful immunotherapy developed a robust NK cell cytotoxicity, antigen specific T cell proliferation, and IFN-γ and IL-2 responses. Depletion of various immune cell types demonstrated the indispensable role of CD8+ T cells and important role of NK cells for vaccine efficacy. Chimeric SA-4-1BBL hence prime CD8/NK cell axis for tumor eradication and has potential to be used as a specific immunological adjuvant to develop therapeutic vaccines against tumors with well characterized tumor associated antigens.
RNA nanoparticle vaccines: combining cytokine activation with antigen and CTL peptide delivery to improve vaccine efficacy (131.4)
Authors: McCormick Alison , Wykoff-Clary Sherri , Kaur Hardeep 
Published: January 2023

Abstract
We have used an RNA nanoparticle system to test the hypothesis that co-expression of a tumor antigen-cytokine fusion, with or without a co-delivered tumor CTL epitope, can improve anti-tumor immunity to a self antigen. Our initial studies demonstrated that a Semliki Forest Virus (SFV) bGal RNA expression vector could be modified to allow for in vitro coat protein RNA encapsidation by a distant alphavirus family member, Tobacco Mosaic Virus (TMV). Encapsidated RNA stimulated robust targeted immune cell uptake and activation, including dendritic cells. In response to vaccination, encapsidation significantly improved humoral and cellular immune responses compared to naked RNA, including IFNg activation , and protection from challenge with a lethal dose of bGal expressing tumor. More recently, our goal is to test efficacy of encapsidated RNA in a Non-hodgkin’s murine lymphoma tumor self-antigen system using the A20 expressing tumor. We have constructed a variety of SFV A20 scFv antigen-cytokine fusions, and are co-developing an A20 CTL surface antigen fusion. In vitro expression will be confirmed, and mice will be immunized and tested by ELISA and ELISpot for functional B and T cell immune activation. This nanoparticle RNA system generates vaccine compositions that are easy to customize, easy to produce, and facilitates intracellular delivery of unique nucleic acid/protein antigen combinations that should improve vaccine efficacy against a weakly immunogenic tumor.
Pre-transplant treatment with a GM-CSF-secreting myeloid leukemia cell vaccine combined with autologous BMT significantly improves the graft-versus-leukemia response (131.43)
Authors: Zilberberg Jenny , Friedman Thea , Korngold Robert 
Published: January 2023

Abstract
We investigated the effect of vaccination with a GM-CSF-secreting myeloid leukemia cell line MMB3.19 (GM-MMB3.19) on graft-versus-leukemia (GVL) responses in the syngeneic C57BL6 (B6) → B6 bone marrow transplantation (BMT) model against MMB3.19 (B6 origin) challenge. Our approach of recipient vaccination prior to BMT differed from current treatment designs in that no post-BMT de novo donor immune reconstitution was required. The contribution of host vs. donor T cells in the development of GVL responses were dissected by treatment of some groups with anti-CD4 and CD8 mAb to deplete host T cells (HTD group) prior to injection s.c with irradiated GM-MMB3.19 cells. Mice were exposed to 850 cGy 7 days later and underwent BMT, with or without additional donor lymphocytes (DL). On day 1 post-BMT, mice were challenged with MMB3.19 cells (i.p). A single pre-BMT treatment with irradiated GM-MMB3.19 significantly improved the survival rate of tumor-challenged DL mice (50%), compared to DL alone (0-12%; p&lt;0.01). Vaccinated mice receiving no DL also had increased survival vs. DL alone (33%, p&lt;0.05), an advantage which was eliminated in the HTD group. Hence, a single pre-transplant dose of GM-MMB3.19 cells can significantly improve survival of MMB3.19 challenged mice undergoing syngeneic BMT, suggesting that both host immune cells surviving recipient lethal irradiation and mature donor T cells given at time of BMT constitute significant components of the GVL effect.
Integration of HSP90 inhibitors in combinational immunotherapy targeting receptor tyrosine kinases (RTKs) in cancer (131.45)
Authors: Rao Aparna , Kawabe Mayumi , Storkus Walter 
Published: January 2023

Abstract
Background: Receptor tyrosine kinases (RTKs) and HSP90 play important roles in tumor growth, survival and metastasis. An effective therapeutic approach would promote decreased expression of RTKs on tumor cells, while increasing presentation of RTK-derived peptides in tumor cell MHC class I complexes, thereby enhancing the efficacy of anti-RTK CD8+ T effector cells. Aim: We are assessing the safety and effectiveness of the HSP90 inhibitor 17-DMAG in enhancing anti-tumor immunotherapy with RTK-specific T cells in murine tumor models. Methods: We tested the effect of 17-DMAG on tumor cell viability, proliferation and expression of RTK and the MHC I antigen-processing machinery in vitro. We also assessed the effect of 17-DMAG on DC phenotype and function. Results: 17-DMAG facilitated a dose-dependent reduction in RTK expression, but had no adverse effects on the antigen-processing machinery of the tumors. Anti-RTK CD8+ T cells exhibited improved recognition of DMAG-treated tumor cells in vitro. However, 17-DMAG treatment of DC resulted in decreased co-stimulatory molecule expression, IL-12p70 production and allo-stimulatory capacity by these APC in vitro. Conclusion: 17-DMAG treatment promotes immunologically-preferred alterations in tumor cells, but potentially adverse effects on DC functions in vitro. In vivo studies are warranted to assess the net anti-tumor impact of combinational immunotherapies integrating 17-DMAG.
Expanding Dendritic Cell Life Span and Enhancing VLP Vaccine Efficiency by Ginkgolides via Neutralization of ROS and Inhibition of p-JNK (131.5)
Authors: Zhang Sheng , Cubas Rafael , Chen Changyi , Yao Qizhi 
Published: January 2023

Abstract
Dendritic cells (DCs) play a critical role in initiating immune activation and/or tolerance in the host. This is dependent on the generation of reactive oxygen species (ROS). However high levels of ROS trigger activation-induced apoptosis (AIA) of DCs. Ginkgolides are known, strong antioxidants and we wanted to determine whether, with the help of Ginkgolides, virus-like particle (VLP)-matured DCs could increase vaccine efficiency. The generation of ROS and the apoptosis of DC was determined. Flow cytometry analysis was used to assess the activation and maturation of DCs. Specific antigen presentation by DCs was measured by ELISA and CTL assays. We found that VLPs stimulate the activation and maturation of DCs as demonstrated by the increased expression of CD40, CD54, CD86, and I-A. Staining of DHE showed that VLPs trigger ROS production and JC-1 staining demonstrated that this activation induced the apoptosis of DCs. Ginkgolides were shown to decrease the levels of ROS, inhibit p-JNK, inhibit apoptosis, and promote the longevity of DCs. Ginkgolide treatment also demonstrated an enhancement of antigen presentation to CD4+ T cells and cross-priming to CD8+ T cells by DCs. Further evidence also showed that administration of Ginkgolides increased the efficiency of VLP vaccination in vivo. Our results suggest that Ginkgolides have a notable potential to protect DCs from AIA while expanding their life span to prolong antigen presentation and enhance VLP vaccine efficiency.