bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaginal type-II mucosa acts as an inductive site during the generation of primary CD8+ T cell mucosal immune responses (P3186)
Authors: Wang Yichuan , Sui Yongjun , Steel Jason , Morris John , Berzofsky Jay 
Published: January 2023

Abstract
It is widely believed that primary immune induction in type-II mucosa (vagina, mouth & cornea) occurs in the draining LNs due to a lack of mucosa-associated lymphoid tissue. In this process, naïve T cells located in the draining LNs are primed by antigen (Ag)-bearing dendritic cells migrating from the Ag-exposed mucosa. Primed T cells then travel to the mucosal site through the bloodstream. In contrast to this paradigm, we show that vaginal mucosa itself can act as an immune inductive site for generation of primary CD8+ T cell mucosal immunity. As evidence, we found that naïve CD8+ T cells routinely migrated to the female reproductive tract and that Ag-specific CD8+ T cells could be generated in the LN-deficient mice after intravaginal immunization. Further, the adoptively transferred naïve OT-1 CD8+ T cells were activated in the vaginal mucosa but not in the draining LNs at 24 hours after intravaginal immunization, even in the presence of FTY720, a drug blocking the egress of T cells from LNs. In addition, the Ag-bearing cells isolated from immunized vaginal mucosa were able to stimulate naïve TCR-transgenic RT-1 CD8+ T cells to secret IFN-γ and undergo proliferation. Finally, vaginal mucosa largely supported the expansion of Ag-specific CD8+ T cells. In conclusion, we present evidence for a new paradigm for primary CD8+ T cell immune induction in type-II mucosa of the vagina, one that occurs locally without the help of draining LNs or mucosa-associated lymphoid tissue.
HVEM is a TNF family receptor that is a crucial regulator of epithelial and lymphocyte responses in the mucosal immune system (P3192)
Authors: Kronenberg Mitchell , Shui Jr-Wen , Takahashi Daisuke , Larange Alexandre , Kim Gisen , Zahner Sonja , Vela Jose-Luis , Cheroutre Hilde 
Published: January 2023

Abstract
HVEM is a TNF super family receptor, and previously we showed that epithelial HVEM is required for innate immune responses to pathogenic bacteria in the intestine and lung, and that it acts by enhancing epithelial Stat3 activation (Nature 488:222, 2012). Now, we show that HVEM is also an important regulator of lymphoid cells in the mucosal immune response. IL-17 and IL-22 are protective cytokines after oral infection with Citrobacter rodentium. Mice deficient for HVEM have a reduced IL-22 response by innate lymphoid cells (ILC) in the colon lamina propria at early times after infection. The adaptive immune response is also affected, with reductions in IL-17 and IL-22 by colonic lamina propria CD4+ T cells at days 9-21 after infection. The role of HVEM in mucosal lymphoid cells is more important for controlling bacterial burden and pathology at later times after infection, with the HVEM-dependent epithelial response acting earlier. Also striking, however, is the strong decrease in all intestinal epithelial lymphocyte populations (IEL) in mice deficient for HVEM, at steady state, even in the absence of infection. This reflects a decreased proliferative potential of IEL when HVEM is not expressed. Collectively, our findings establish HVEM as a crucial regulator of the mucosal immunity, affecting IEL homeostasis, innate epithelial responses and innate and adaptive responses by lamina propria lymphocytes.
Inflammatory monocytes are critical for induction of a polysaccharide-specific antibody response to an intact bacterium (P3046)
Authors: Chen Quanyi , Snapper Clifford 
Published: January 2023

Abstract
Although inflammatory monocytes (IM) [CD11b+Ly6Chi] play important roles in cell-mediated host protection against intracellular pathogens, their impact on humoral immune responses to extracellular bacteria are unknown. IM, localized largely in the splenic marginal zone of naïve CD11b-Diphtheria toxin receptor (DTR) bone marrow chimeric mice, were selectively depleted following treatment with DT, including no reduction of peritoneal B1a or B1b cells, which express CD11b. Depletion of IM resulted in a marked reduction in the polysaccharide (PS)-specific, T cell-independent IgM and T cell-dependent IgG responses to heat-killed Streptococcus pneumoniae (Pn) with no effect on the Pn protein-specific IgG response, or on the PS- and protein-specific IgG responses to a pneumococcal conjugate vaccine. IM acted largely within the first 48 h to induce the subsequent PS-specific IgM and IgG response. Adoptive transfer of highly purified IM from WT mice into DT-treated CD11b-DTR mice restored the PS-specific Ig response to Pn. IM were phenotypically and functionally distinct from circulating CD11b+CD11clowLy6G-/C- cells (i.e. “blood DC”) previously described to play a role in Ig responses to Pn. These data are the first to establish a critical role for IM in the induction of an Ig response to an intact extracellular bacterium.
AFLP analysis of a natural population of native Hawaiian Honeycreepers (Hemignathus virens) reveals candidate markers for tolerance to avian malaria (Plasmodium relictum) (P3066)
Authors: Farias Margaret , Bianchi Kiara , Atkinson Carter , Ohora Donna , Txakeeyang Ann , Bonnel Caroline , Jarvi Susan 
Published: January 2023

Abstract
A better understanding of host defenses against malaria is important, but most studies have traditionally focused on resistance and/or immunological mechanisms that limit parasite burden. Host tolerance mechanisms are thought to minimize physiological damage caused by both the parasite itself and immunopathology without directly affecting parasite burden. On Hawai`i Island, low elevation populations of amakihi (Hemignathus virens) appear to have recently evolved tolerance mechanisms against avian malaria (Plasmodium relictum). Under comparable parasite loads, low elevation amakihi have lower mortality, greater fitness, lower reticulocyte levels and lower heterophil to lymphocyte ratios than high elevation amakihi. Thus, distinct host defense mechanisms are likely operating in low vs. high elevation amakihi. To search for genes involved in host defense, AFLP analysis was completed. Group significance tests (Bionumerics v 2.0) reveal genetic distinction between groups (p = 0.000). Band frequency comparisons between low and high elevation `amakihi (Fisher’s exact test and Pearson’s chi-square test with Yate’s continuity correction, R v 2.11.1) revealed ten band classes with significantly higher (p &lt; 0.05) frequencies in low vs. high elevation birds and 13 band classes with higher frequencies in high vs. low elevation birds. Isolation and sequencing of these candidate bands is underway and may provide a better understanding of host defense mechanisms in natural populations.
Next generation sequencing reveals major histocompatibility complex class II alleles associated with survival to avian malaria (Plasmodium relictum) in Hawaiian honeycreepers (Drepanidinae) (P3089)
Authors: Jarvi Susan , Farias Margaret , Txakeeyang Ann , McFarland Tom , Atkinson Carter 
Published: January 2023

Abstract
While most species of Hawaiian honeycreeper are highly susceptible to avian malaria, populations of the Hawaii amakihi (Hemignathus virens) are thriving at low elevations despite high infection rates of Plasmodium relictum. Due to their critical function in adaptive immunity, proteins encoded by Mhc genes may play a role in the recently evolved host defense mechanisms in these populations. A 454 Roche platform was used to generate 44,014 sequences representing 158 Mhc alleles from 46 captive amakihi involved in experimental challenges to avian malaria and 88 wild amakihi originating from Hawaii Island. Analysis of an NJ tree revealed 6 clusters of alleles occurring most often in surviving amakihi, and a significant association between survivorship and the presence of one or more alleles from these clusters was detected (p = 0.00006). Several of these alleles were also found in higher frequencies in low vs. high elevation populations. A similar analysis of 6,417 sequences representing 31 Mhc alleles from 19 experimentally infected i`iwi (Vestiaria coccinea) revealed a significant association between survivorship and the presence of one or more alleles from two clusters (p = 0.02). This is the first documentation of an Mhc association with survival to malaria in Hawaiian honeycreepers and is expected to enhance our understanding of host-parasite interactions in this natural disease system while also providing a predictive tool for conservation and management.
Macrophage migration inhibitory factor plays a role in the maturation of conventional dendritic cells in acute Toxoplasma gondii infection (P3054)
Authors: Rodriguez-Sosa Miriam , Hernández-Hernández Fidel de la Cruz , González Calixto Cecilia , Juárez-Avelar Imelda , Saavedra Rafael , Olgín Efraín , Ruiz-Rosado Juan de Dios 
Published: January 2023

Abstract
The role of the inflammatory cytokine MIF has been implicated on inflammatory immune response during toxoplasmosis, where an inflammatory immune response, initiated by high levels of the cytokine IL-12 produced by mature DCs, is required to control the infection. Previously we have demonstrated that MIF knockout mice are highly susceptible to T. gondii infection, due to low IL-12 levels in serum, which in turn, may be associated with a deficient maturation of DCs in the acute infection by this parasite. Therefore, the aim of this study was to determine the role of MIF on the maturation of conventional DCs during the acute infection by T. gondii. To accomplish this goal, through flow cytometry, we analyzed the maturation (IL-12 intracellular and CD40 expression) of different conventional DCs subpopulations (CD11c+ CD11b-high, CD11c+ CD11b-low and CD11c+ CD8α+) in spleens from infected and non-infected MIFKO and WT mice 24 or 48h after ip infection with T. gondii. The results demonstrated that conventional DCs subpopulations CD11c+ CD11b-high and CD11c+ CD8+α from MIF KO mice showed a lower percentage of cells producing IL-12 and reduced expression of CD40, respectively, compared to WT conventional DCs. These evidences suggest that MIF could modulate the maturation of certain subpopulations of conventional DCs during acute T. gondii.
Vaccination with GD3 synthase provides tumor protection against melanoma in mice (P4461)
Authors: Hammer Adam , Eby Jonathan , Gilbert Emily , Kahn Safia , Dilling Daniel , Le Poole I. 
Published: January 2023

Abstract
Expression of GD3 synthase (GD3s) in cells defines upregulated GD3 expression by melanoma tumor cells. GD3 presented in the context of CD1d is recognized by invariant NKT cells, which can generate cytokines conducive to anti-tumor responses. We hypothesized that DNA vaccination with GD3s could induce effective anti-tumor responses targeting GD3. C57BL/6 mice were subjected to weekly gene gun vaccination introducing DNA encoding either GD3s and adjuvant HSP70i, or TRP-1 ee/ng and HSP70i, versus empty vector DNA as control groups. Mice were challenged with 2.5x105 B16 mouse melanoma cells. Tumor growth was followed and any remaining tumor was resected for fluorocytometric analysis of immune infiltrates and cytokine expression by qRT-PCR. hGD3s-based vaccination provided similar protection from a B16 tumor challenge as the positive control group (60 and 62% reduced tumor sizes at 19 days, respectively). hGD3s vaccinated mice showed increased NKT abundance (2.27% ) compared to TRP-1 (1.11%) or empty vector (0.74%) among vaccinated mice. Increased CD8+ (3.3-fold), and CD4+ (1.2-fold) compared to the negative control group were also observed, combined with an increased abundance in IL-4 and IL-17 transcripts. In conclusion, GD3s based vaccination provided anti-tumor protection associated with inflammatory cytokine expression and increased (NK)T cell recruitment to tumor sites, offering an attractive concept for melanoma treatment.
Adenovirus vector-specific cellular immunity induced by engineered human dendritic cells in vitro and in vivo (P4434)
Authors: Butterfield Lisa , Naveh Hadas 
Published: January 2023

Abstract
Recombinant adenovirus has been used in gene transfer applications, including cancer immunotherapy and infectious disease. Immunity to the adenoviral vector is known to include a potent humoral response; however, the cellular response is poorly characterized. Here, we evaluated the virus-specific response to an AdV encoding three melanoma tumor antigens (Tyrosinase, MART-1 and MAGE-A6 (AdVTMM2)) in healthy donors and patients with melanoma. CD4+ and CD8+ T cell responses were followed weekly by multi-cytokine ELISPOT assays (IFN-gamma, IL-2, IL-10 and TNF) and flow cytometric analysis in vitro. NK cells and Treg were also assessed. We found a strong type 1-skewed response with INFg secreted by CD4+ cells beginning within 7 days of stimulation and carrying through 3 weekly stimulations. Strong type 1 CD8+ T cell immunity was also detected to the virus. Treg increased transiently and an activated, INFg-producing subset of NK cells became evident. Melanoma patient cells also show a type-1 CD8+ T cell and CD4+ T cell response to the adenovirus. While strong, these virus-specific responses did not mask responses to the melanoma antigens. Melanoma patients vaccinated with the engineered DC vaccine in a new clinical trial respond immunologically to both the viral vector and encoded melanoma antigens, and show modulation of NK cells and Treg post-vaccination. Therefore, AdV-engineered DC promote a strong type 1 virus- and melanoma antigen-specific response, in vitro and in vivo.
A novel rabies virus-based glioma immunotherapeutic strategy targeting survivin (P4440)
Authors: Bongiorno Emily , Morin-Brureau Melanie , Barkhouse Darryll , Faber Milosz , Dietzschold Bernhard , Hooper D. 
Published: January 2023

Abstract
The poor prognosis of glioblastoma multiforme even after resection, chemotherapy and radiation has led to an interest in immunotherapy which necessitates consideration of the blood-brain barrier (BBB). Attenuated rabies viruses (RABV) induce BBB modifications that allow immune effectors to reach the CNS without immunopathology. We have shown that induction of a CNS response to an attenuated RABV can significantly prolong the survival of mice bearing intracranial GL261 tumors. This extended survival is associated with delayed tumor growth and an increase in mRNA levels of T and B cell markers and IFN-γ in CNS tissue. However it is not yet known whether the delayed tumor growth is a result of non antigen-specific effects of the antiviral response or due to BBB modifications that facilitate contact between the tumor cells and immune system. To provide a more selective target for the immune response, we have engineered a recombinant RABV to express human survivin. Survivin, an inhibitor of apoptosis protein (IAP), is preferentially expressed at high levels in certain types of cancer cells including gliomas and has been successfully used as a target in GL261 immunotherapies. The expression of survivin by RABV is expected to promote the delivery of tumor-reactive immune effectors into CNS tissues.
Enhanced immunotherapeutic effect of B cell based vaccine transduced with modified adenoviral vector (P4443)
Authors: Kim Eun Kyung , Song Bo Yeong , Chae Min Ji , Seo Hyung Seok , Park Young Jun , Yun Chae Ok , Kang Chang Yuil 
Published: January 2023

Abstract
For successful clinical outcome of tumor immunotherapy, proper generation of strong immune responses against tumor antigen is required. Cell based vaccine is one of the strategy to induce appropriate immune responses. In previous studies we established NKT ligand loaded, adeoviral antigen transduced-B cell based anticancer cellular vaccine that efficiently induced a wide spectrum of immune responses against tumor antigen. However the lack of the coxsakivirus-adenovirus receptor(CAR) on B cells limits the adenoviral Ag gene delivery. In this study, we established a modified adenoviral vector(Ad-k35) whose fiber structure was substituted with adenovirus serotype 35, encoding truncated breast cancer antigen Her2/neu(Ad-k35HM), to enhance tumor antigen gene delivery to B cells. Using Ad-k35HM, we observed increased expression of tumor antigen on both human and mouse B cells. And Ad-k35HM transduced B cell vaccine elicited antigen specific strong cellular and humoral immune responses and these responses was further enhanced with additional loading of derivative of NKT ligand KBC009. Ad-k35HM transduced, KBC009 loaded B cell vaccination efficiently suppressed in vivo established tumor growth in a mice model. These findings showed modified adenoviral vector Ad-k35 could be appropriate for the preclinical and clinical development of B cell based anticancer immunotherapy.
A general requirement for FcγRIIB co-engagement of agonistic anti-TNFR antibodies (P4449)
Authors: Li Fubin , Ravetch Jeffrey 
Published: January 2023

Abstract
The tumor necrosis factor receptor (TNFR) superfamily members are type I transmembrane proteins widely expressed on both normal and malignant tissues and control essential biological processes including cell apoptosis, activation, and proliferation1. A number of TNFR signaling pathways have been reported to be beneficial in immune and antitumor responses. For example, CD40 mediated immunostimulatory effects and DR5 mediated direct apoptotic effects display potent antitumor activity through distinct mechanisms. Agonistic antibodies targeting TNFRs have therefore been extensively investigated as a therapeutic approach to trigger TNFR signaling pathways in antitumor responses. Despite their impressive performance in animal models, clinical results of these agonistic anti-TNFR antibodies appear to be disappointing. Our studies on the role of the Fc for agonistic anti-CD40 and anti-DR5 antibodies, and the FcγR binding properties of other agonistic anti-TNFR antibodies suggest an explanation for this discrepancy between the pre-clinical animal studies and clinical application of these agonistic antibodies. It is now apparent that agonistic anti-TNFR antibodies display a general requirement for FcγRIIB co-engagement for their in vivo activity and the selection of the appropriate Fc was not taken into consideration in the advancement of therapeutic versions of these antibodies into the clinic.
Identification of a novel Th1 promoting vaccine adjuvant from natural products (P4451)
Authors: Reiman Jennifer , Zenack Dusan , Pham Ngoc , Engwerda Christian , Quinn Ronald , Good Michael 
Published: January 2023

Abstract
One of the great obstacles to vaccine development is the lack of adjuvants that can safely and appropriately stimulate human immune cells. There are a limited number of adjuvants that have been approved for use in human vaccines. In the USA, all but one of the adjuvanted vaccines uses aluminum salts (alum) and these promote T helper (TH) 2 but not TH1 immunity. For this screen we have utilized Eskitis's Nature Bank library as a source of compounds. This library consists of over 200,000 natural product fractions derived from a collection of over 45,000 samples of plants and marine invertebrates from Australia, China, and Papua New Guinea. Mice on a C57BL/6 background that express the IL-12p40 promoter linked to yellow fluorescent protein (YFP) have been utilized as a source of dendritic cells (DCs). Splenic DCs were cultured in the presence of Nature Bank fractions or with toll like receptor-9 (TLR9) agonist CpG 1826. Cultures were assayed for IL-12 production by measuring YFP using a Perkin Elmer Operetta high content screening system and analyzed with Harmony software. Only a single compound was identified in our screen of over 20,000 fractions and it robustly activated DCs (86% compared to 11% for CpG positive controls) to become IL-12 positive. We have preliminary structural data on the compound and are subsequently testing “compound A” for immunogenicity and adjuvant activity utilizing in vitro and in vivo assays with mice, as well as human monocyte derived DC cultures.
Neutrophil extracellular traps are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis (P4061)
Authors: Carmona-Rivera Carmelo , Khandpur Ritika , Vivekanandan-Giri Anuradha , Gizinski Alison , Yalavarthi Srilakshmi , Knight Jason , Friday Sean , Li Sam , Patel Rajiv , Thompson Paul , Chen Pojen , Fox David , Pennathur Subramaniam , Kaplan Mariana 
Published: January 2023

Abstract
The early events leading to the development of rheumatoid arthritis remain unclear but formation of autoantibodies to citrullinated antigens is considered a key pathogenic phenomenon. Neutrophils isolated from patients with various autoimmune diseases display enhanced extracellular trap formation, a phenomenon that externalizes autoantigens and immunostimulatory molecules. We investigated if aberrant NETosis occurs in RA, its triggers and deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and synovial fluid RA neutrophils. NETosis correlated with ACPA levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. During NETosis, neutrophils externalized citrullinated autoantigens implicated in RA pathogenesis, while anti-citrullinated vimentin antibodies potently induced NET formation. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant immune responses in the joint and in the periphery and perpetuate pathogenic mechanisms in this disease.
Nucleic acid-containing amyloid fibrils potently induce Type I interferon and stimulate systemic autoimmunity (P4075)
Authors: Cao Wei , Di Domizio Jeremy , Dorta-Estramera Stephanie , Gagea Mihai , Li Ping , Bi Liqi , Gilliet Michel 
Published: January 2023

Abstract
The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms. In systemic lupus erythematosus, type I IFN (IFNI) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Amyloid precursor proteins can form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFNα/β production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of selfantigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid-containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.