bluuebunny/crossref_metadata_2025_split huggingface dataset:
Formyl peptide receptor 1 is functionally expressed on human lens epithelial cells and promotes lens homeostasis (149.19)
Authors: Schneider Erich , Gaur Sonia , Murphy Philip , Gao Ji-Liang 
Published: January 2023

Abstract
Formyl peptide receptor 1 (FPR1) is a chemoattractant receptor specific for phagocytes, without clearly defined function for non-hematopoietic cells. We found that the lens of Fpr1-/- mice degenerates by 6 months of age without infection or inflammation. Thus, we hypothesized functional expression of FPR1 on lens epithelial cells, the only cell type present in lens. Flow cytometry, qPCR and PTX sensitive fMLF-induced calcium flux assays showed functional FPR1 expression in fetal human lens (FHL-124) cells and in the human lens epithelial cell line SRA 01/04. Despite strong anti-FPR1 binding to lens cells by FACS, similar to that observed for human neutrophils or hFPR1-transfected HEK 293 cells, fluorescent FPR1 ligand fNLFNYK-Fl only poorly bound to FHL-124 cells, with &gt; 80% non-specific binding; by contrast, human neutrophils and hFPR1-transfected HEK-293 cells exhibited &gt;70% specific binding. The KD of fNLFNYK-Fl at neutrophil FPR1 and hFPR1-transfected HEK-293 cells was 2-3 nM, but ~ 0.2 nM in FHL-124 cells. fMLF internalized ~80% of neutrophil FPR1, but only ~25% of FHL-124 FPR1. FPR1 protein in FHL-124 cells resisted siRNA-mediated knockdown, despite strongly reduced mRNA levels, and could only be detected by Western blot using alkali-stripped membranes, suggesting high-molecular complexes of FPR1 and peripheral membrane proteins. The data suggest different conformations of FPR1 in neutrophils versus lens epithelial cells and a key function in lens maintenance.
Differential up-regulation of CXCR3 on effector CD4+Foxp3- T cells and regulatory CD4+Foxp3+ T cells during blood-stage Plasmodium chabaudi AS infection (149.5)
Authors: Berretta Floriana , Piccirillo Ciriaco , Stevenson Mary 
Published: January 2023

Abstract
The chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are critical for trafficking of pathogenic CD8+ T cells to the brain during experimental cerebral malaria in Plasmodium berghei ANKA infected mice. We investigated the role of chemokines and their receptors during blood-stage P. chabaudi AS infection in C57BL/6 (B6) mice which control and resolve the infection with a peak of parasitemia at days 8-9 post infection (p.i.). Real-time PCR analysis revealed significantly increased CXCL9 mRNA expression in spleen cells at days 6, 8 and 11 p.i. while FACS analysis showed significantly increased CXCR3 expression on splenic CD4+ T cells at days 8 and 11 p.i. compared to naïve mice. To determine if CD4+ T cell populations differentially expressed CXCR3 during P. chabaudi AS infection, we examined CXCR3 expression on splenic CD4+Foxp3- T cells (Teffs) compared to CD4+Foxp3+ T cells (Tregs). In naïve mice, 15% of Tregs and 15% of Teffs were CXCR3+, at day 8 p.i., 30% of Tregs vs 45% of Teffs were CXCR3+, and at day 11 p.i., CXCR3+ Tregs were still 30% while CXCR3+ Teffs were 55%. Increased CXCR3 expression on Teffs correlated with increased protective CD4+Tbet+IFNγ+ Th1 cells in the spleen. These findings indicate that CXCR3 expression is up-regulated on both Teffs and Tregs during blood-stage malaria. Higher expression of CXCR3 on Teffs might allow these cells to migrate more efficiently to the spleen, the critical tissue for immune control and resolution of the infection.
CXCL17: a novel mucosal chemokine with antimicrobial activity (149.6)
Authors: Burkhardt Amanda , Kamdar Karishma , Tai Kenneth , Valle-Rios Ricardo , Hevezi Peter , Ouellette André , Zlotnik Albert 
Published: January 2023

Abstract
The mucosal immune network is a crucial barrier preventing pathogens from entering the body. The network of immune cells that mediates the defensive mechanisms in the mucosa is likely shaped by chemokines. Chemokines attract a wide range of immune cells to various sites of the body. Chemokines have been divided into homeostatic or inflammatory depending upon their expression patterns. Additionally, several chemokines have also been shown to mediate direct killing of invading pathogens. An example of the latter is CCL28, a mucosa-associated chemokine that exhibits antimicrobial activity against a range of pathogens. CXCL17 is the last chemokine ligand to be described, and the 17th member of the CXC chemokine family. We have identified CXCL17 as a novel, homeostatic, mucosa-associated chemokine. Its strategic expression in mucosal tissues suggested that it is a barrier protein involved in the maintenance of the homeostasis and/or sterility of the mucosa. To test this hypothesis, we tested CXCL17 in various antimicrobial assays against a panel of pathogenic and opportunistic bacteria, and compared it with CCL28. Our results indicate that CXCL17 has strong antimicrobial activity and that its mechanism of antimicrobial action involves direct killing of the bacteria. We conclude that CXCL17 is a novel antimicrobial chemokine that likely plays significant roles in protecting the mucosa from bacterial invasion, and in shaping the microbiome in the intestine.
Critical roles of chemokine receptor CCR10 in regulating memory IgA responses in intestines (149.7)
Authors: Hu Shaomin , Yang Kangkang , Xiong Na 
Published: January 2023

Abstract
CCR10 is expressed by nearly all the intestinal IgA-producing plasma cells and was suggested to position these cells into the lamina propria. However, the in vivo function of CCR10 in the process is unclear and interfering with CCR10 or its ligand did not affect the intestinal IgA production under homeostatic conditions or during infection. Using CCR10-knockout/EGFP-knockin (CCR10EGFP/EGFP) mice we generated recently, we investigated expression and effect of CCR10 on IgA+ cells of different differentiation stages. We found that in the CCR10EGFP/EGFP mice IgA+ plasma cells were defective in migration to the intestine; but there was a compensational increase in generation of IgA+ plasma cells within intestinal isolated lymphoid follicles, resulting in normal levels of intestinal IgA production and increased localization of IgA+ plasma cells in bone marrow and other internal lymphoid organs under homeostatic conditions and in primary responses to the C. rodentium infection. In addition, the CCR10-deficiency also impaired maintenance of IgA+ memory B cells specifically in the intestine. As a result, IgA memory responses to the bacterial re-infection were severely compromised in the CCR10EGFP/EGFP mice. These findings demonstrate that CCR10 is critical in IgA memory responses by regulating migration and maintenance of IgA+ plasma cells and memory B cells and provide a mechanistic basis to manipulate the CCR10/ligand axis for the vaccine development against mucosal pathogens.
Recognition of a dendritic cell ligand by an MCMV-encoded MHC-I-like protein (154.17)
Authors: Revilleza Maria Jamela , Mans Janet , Iizuka Koho , Mage Michael , Carey Rosalene , Boyd Lisa , Natarajan Kannan , Margulies David 
Published: January 2023

Abstract
Mouse cytomegalovirus (MCMV), a valuable model for studying virus-host interactions, encodes several glycoproteins with predicted MHC-I structure, which may function as immunoevasins. We recently determined the crystallographic structure of a member of this family, m153, and showed that this is a cell surface homodimeric protein with structural similarity to MHC-I, which is expressed independently of beta-2m or peptide. To determine the role of m153 in the viral infection of the host, we wished to identify host proteins with which m153 interacts. We constructed both a birA-tagged version of m153 for staining experiments as well as a reporter cell containing the m153 extracellular domain fused to the human T cell receptor zeta chain. Using both approaches we show that CD11c+ splenic dendritic cells (DCs) and bone marrow-derived DCs express a cell surface ligand for m153. To our knowledge this is the first example of a putative viral immunoevasin that targets a DC expressed molecule. We describe our efforts to identify this molecule using a variety of approaches, including antibody blocking, cDNA library screening, and pull-down experiments on DC lysates. Identification of the m153 ligand on DCs offers to elucidate mechanisms the host employs to defend against viral infection, and also to clarify the evolution of viral immunoevasion of the immune response. This research was supported by the Intramural Research Program of the NIH, NIAID.
HCV impairs human T cell responses via MDSC induction. (154.2)
Authors: Tacke Robert , Hahn Young 
Published: January 2023

Abstract
Hepatitis C virus (HCV) is highly efficient in establishing persistent infection, which leads to the development of chronic liver disease and hepatocellular carcinoma. Impaired T cell responses with reduced IFN-γ production have been reported to be associated with HCV persistent infection. Extracellular HCV core is a viral factor known to cause HCV-induced T cell impairment via its suppressive effect on the activation and induction of pro-inflammatory responses by antigen presenting cells (APCs). Recently, myeloid derived suppressor cells (MDSC) have been shown to be crucial regulators of T cell responses. In this report we examine the accumulation of MDSCs in human PBMCs following exposure to extracellular core. We show that HCV core induces the activation of STAT3 in human APCs. Importantly, co-cuture of HCV core-treated CD33+ APCs with CD4 T cells suppresses autologous CD4 T cell proliferation and IFN-γ production in response to TCR stimulation. This suppression is partially rescued by STAT3 inhibitor WP1066, as well as by reactive oxygen species (ROS) inhibitor, catalase. In contrast, inhibitors to arginase-1 and iNOS do not affect T cell responsiveness. These results suggest that HCV core -mediated STAT3 activation promotes in the accumulation of CD33+ MDSC, resulting in ROS-mediated suppression of T cell responsiveness. The accumulation of these MDSC may facilitate the establishment of HCV chronic infection.
CIITA enhances HIV-1 attachment to CD4+ T cells leading to enhanced infection and cell depletion (154.27)
Authors: Porter Kristen , Kelley Lauren , Nekorchuk Michael , Jones James , Hahn Amy , de Noronha Carlos , Harton Jonathan , Duus Karen 
Published: January 2023

Abstract
Activated CD4+ T cells are more susceptible to HIV infection than resting T cells; the reason for this remains unresolved. Induction of CIITA and subsequent expression of the MHC class II isotype HLA-DR are hallmarks of CD4+ T cell activation; therefore, we investigated the role of CIITA expression in T cells during HIV infection. CIITA-expressing SupT1 cells display enhanced virion attachment in a gp160/CD4-dependent manner, resulting in increased HIV infection, virus release, and T cell depletion. Although increased attachment and infection of T cells correlated with HLA-DR surface expression, Ab blocking, transient expression of HLA-DR without CIITA, and short hairpin RNA knockdown demonstrate that HLA-DR does not directly enhance susceptibility of CIITA-expressing cells to HIV infection. Analysis of the remaining MHC class II isotypes, HLA-DP and HLA-DQ, MHC class I isotypes, HLA-A, HLA-B, and HLA-C, and the class II Ag presentation genes, invariant chain and HLA-DM, demonstrate that these proteins likely do not contribute to CIITA enhancement of HIV infection. Finally, we demonstrate that in activated primary CD4+ T cells as HLA-DR/CIITA expression increases there is a corresponding increase in virion attachment. Overall, this work suggests that induction of CIITA expression upon CD4+ T cell activation contributes to enhanced attachment, infection, virus release, and cell death through an undefined CIITA transcription product that may serve as a new antiviral target.
Granzyme B inhibits translation of viral proteins and viral replication through proteolytic cleavage of the eukaryotic initiation factor 4 gamma 3 (154.35)
Authors: Marcet-Palacios Marcelo , Duggan Brenda , Shostak Irene , Barry Michele , Wilkins John , Yanagiya Akiko , Sonenberg Nahum , Bleackley R. 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTL) are the major killer of virus-infected cells. Granzyme B (GrB) from CTL induces apoptosis in target cells by cleavage and activation of substrates such as caspase-3. However, while undergoing apoptosis, cells can still produce infectious viruses unless a mechanism exists to specifically inhibit viral production. Using proteomic approaches, we found a novel GrB target that plays a major role in protein synthesis: eukaryotic initiation factor 4 Gamma 3 (eIF4G3). We hypothesized a novel role for GrB to arrest translation of viral proteins by targeting eIF4G3, which contains the GrB recognition sequence IESD1408S. We showed that GrB specifically cleaves eIF4G3 since the mutant eIF4G-Δ, with Ala substituted for D1408, was resistant to GrB degradation. Translational inhibition by GrB was reversed by the inclusion of eIF4G-Δ, showing that eIF4G3 is the critical GrB substrate involved in translation. In Jurkat cells, GrB or CTL treatment resulted in reduced rate of translation. We infected Jurkat cells with vaccinia virus (VV) and showed that viral protein synthesis and viral replication was inhibited in response to GrB or CTL. Transfection of eIF4G-Δ reversed the halt in protein synthesis induced by GrB. This demonstrated for the first time that GrB could prevent the production of VV by targeting the translational machinery of the host. These results represent a major new insight into what constitutes an effective CTL response to a virus-infected cell.
Two functionally-distinct subsets of CD4+CD39+ Treg in patients with HIV-1 infection (154.36)
Authors: Schuler Patrick , Macatangay Bernard , Schilling Bastian , Harasymczuk Malgorzata , Rinaldo Charles , Whiteside Theresa 
Published: January 2023

Abstract
Ectonucleotidases CD39 and CD73 are expressed on the surface of regulatory T cells (Treg) and cleave ATP to immunosuppressive adenosine. CD39 could potentially serve as a new functional marker for Treg isolation. The frequency and absolute numbers of CD4+CD39+ T cells were determined in 32 HIV+ patients and in 10 healthy donors (HD). CD4+ T cells were negatively selected by magnetic beads PBMC. CD39+ Treg cells were then isolated by biotin-conjugated anti-CD39 Abs and anti-biotin magnetic beads. T cells were phenotyped by flow cytometry for CD39+, CD73+, FOXP3+, CCR4+, CD127neg, CD49dneg, and CD121a+. CFSE-based proliferation assays and ATP hydrolysis were used to measure Treg functions. Cytokine expression in CD4+CD39+ T cells was determined by Luminex. HIV-patients on and off anti-retroviral regimen had a significantly lower absolute number of CD39+CD25+ Treg and CD39+CD25neg T cells (p&lt;0.05) than HD. The CD4+CD39+ T cell populations isolated on immunobeads contained two cell subsets: FOXP3+CD25+ Treg hydrolyzed exogenous ATP and suppressed CD4+ T cell proliferation, which was reversed by blocking ectonucleotidase activity. In contrast, the FOXP3negCD25neg T cells were CD127+CD49d+ and expressed IFNg, TNFa, and IL-10. The presence of two distinct CD4+CD39+ cell subsets in PBMC is a general phenomenon seen in normal donors, as well as patients with HIV and cancer. This suggests that phenotypic and functional plasticity characterizes the human Treg subset.
Self MHC class I licensed NK cells enhance adaptive CD8 T cell viral immunity (154.5)
Authors: Stadnisky Michael , Xie Xuefang , Coats Ebony , Bullock Timothy , Brown Michael 
Published: January 2023

Abstract
MHC class I (MHC I) is essential to NK and T cell effector and surveillance functions. However, it is unknown if MHC I polymorphism influences adaptive immunity through NK cells. Previously, we found that MHC I Dk, a cognate ligand for the Ly49G2 inhibitory receptor, was essential to NK control of murine (M)CMV infection. Here we assessed the significance of NK inhibitory receptor recognition of MCMV on CD8 T cells in genetically defined MHC I Dk disparate mice. We observed that Dk-licensed Ly49G2+ NK cells stabilized and then enhanced conventional dendritic cells (cDC) recovery following infection. Further, licensed NK support of cDC recovery was essential to enhance the tempo, magnitude and effector activity of virus-specific CD8 T cells. Minimal cDC and CD8 T cell number differences after low dose MCMV in Dk disparate animals further implied that licensed NK recognition of MCMV imparted qualitative cDC changes to enhance CD8 T cell priming.
Soluble flagellin, FliC, induces an Ag-specific Th2 response, yet promotes T-bet-regulated Th1 clearance of Salmonella typhimurium infection (155.5)
Authors: Cunningham Adam , Bobat Saeeda , Flores-Langarica Adriana , Hitchcock Jessica , Marshall Jennifer , Kingsley Robert , Gil-Cruz Cristina , Letran Shirdi , López-Macías Constantino , Alexander James , MacLennan Ian 
Published: January 2023

Abstract
Clearance of disseminated Salmonella infection requires bacterial-specific Th1 cells and IFNg production and Th1-promoting vaccines are likely to help control these infections. Consequently, vaccine design has focused on developing Th1-polarizing adjuvants or Ag that naturally induce Th1 responses. In this study we show that, in mice, immunization with soluble flagellin (sFliC) induces Th2 responses as evidenced by Ag-specific GATA-3, IL-4 mRNA and protein induction in CD62Llo CD4+ T cells without associated IFNg production. Despite these Th2 features, sFliC immunization can enhance the development of protective Th1 immunity during subsequent Salmonella infection in an Ab-independent, T cell-dependent manner. Salmonella infection in sFliC-immunized mice resulted in augmented Th1 responses, with greater bacterial clearance and increased numbers of IFNg-producing CD4+ T cells, despite the early Th2 features induced to sFliC. The augmented Th1 immunity after sFliC immunization was regulated by T-bet although T-bet is dispensable for primary responses to sFliC. These findings show there can be flexibility in T cell responses to some subunit vaccines. These vaccines may induce Th2-type immunity during primary immunization yet promote Th1-dependent responses during later infection. This suggests that designing Th1-inducing subunit vaccines may not always be necessary since this can occur naturally during subsequent infection.
SA-4-1BBL and monophosphoryl lipid A as an adjuvant system for the development of effective therapeutic cancer vaccines (156.10)
Authors: Srivastava Abhishek , Sharma Rajesh , Zhao Hong , Yolcu Esma , Shirwan Haval 
Published: January 2023

Abstract
TAAs based subunit vaccines have compromised efficacy due to their weak immunogenic nature and various immune evasion mechanisms employed by the progressing tumors. To overcome these limitations, we herein used costimulatory molecule SA-4-1BBL and toll-like receptor 4 agonist MPL with distinct modes of action as a novel adjuvant system. A single immunization with both adjuvants and E7 TAA resulted in eradication of established E7 expressing TC-1 tumors in 100% of mice. Similarly, a single vaccination with survivin, a bona fide self-TAA, resulted in control/eradication of established 3LL pulmonary metastases. Combined adjuvants had better therapeutic efficacy over the individual adjuvants, while SA-4-1BBL as monotherapy significantly outperformed MPL. The therapeutic efficacy of combined adjuvants and SA-4-1BBL as monotherapy was correlated with potent Th1 responses and increased intratumoral CD8+ Teff/CD4+FoxP3+ Treg cell ratio. Surprisingly, MPL as monotherapy did not improve the intratumoral CD8+ Teff/Treg cell ratio as compared to controls, and depletion of Treg cells improved the efficacy of MPL from 50 to 100%. Taken together, these data demonstrate the utility of SA-4-1BBL/MPL as a promising adjuvant system for the development of therapeutic cancer vaccines with significant clinical potential.
Intranodal injection of tumor-derived autophagosomes (DRibble) in conjunction with anti-OX40 showed potent anti-tumor efficacy in murine 4T1 breast cancer (156.7)
Authors: Li Yuhuan , Cui Zhihua , Pang Puiyi , Shu Suyu , Weinberg Andrew , Fox Bernard , Urba Walter , Hu Hong-Ming 
Published: January 2023

Abstract
Tumor-derived autophagosomes, referred as DRibbles, are novel cancer vaccines that enable efficient cross-presentation of a variety of tumor-associated antigens including SLiPs and DRiPs. We have previously showed that DCs loaded with DRibbles is therapeutic in treating mice with B16F10 melamoma and 3LL Lewis lung cancer. Here we assessed the effect of route of DRibble administration and engagement of OX40 signaling on T-cell activation. We developed an effective DRibble and anti-OX40 combination immunotherapy regimen to treat 4T1 breast cancer. We report that intranodal(i.n.)administration of DRibbles was 10~100 folds more effective to induce T-cell expansion than the subcutaneous route(s.c.).Engagement of OX40 further enhanced antigen-specific CD8+ T-cell proliferation,survival,and acquisition of effector T-cell phenotype (KLRG1 expression). When DRibble i.n. was combined with anti-OX40 to treat BALB/c mice bearing 13-day established 4T1 tumor, all of the mice showed regression, and 60% of the mice were cleared of tumor. Robust TAA-specific immune response was detected in mice cured after vaccination with DRibble and anti-OX40. Anti-OX40 increased frequency of tumor antigen-specific T cells in the spleen, and CD8+/CD4+ T cells in the PBMC of peripheral blood. Thus DRibble vaccine in combination with anti-OX40 is an effective immunotherapy regimen to treat breast cancer. Clinical trials of the DRibble vaccine have begun in our cancer center.
IFI16 acts as a nuclear danger sensor and induces the inflammasome in response to Kaposi’s sarcoma associated herpesvirus (KSHV) infection (157.8)
Authors: Kerur Nagaraj , Veettil Mohanan , Sharma-Walia Neelam , Bottero Virginie , Sadagopan Sathish , Otageri Pushpalatha , Chandran Bala 
Published: January 2023

Abstract
Inflammasomes sense diverse classes of foreign molecules in the cytoplasm and induce caspase-1 activation and IL-1β maturation. Whether such a sensing mechanism exists in the nucleus is not known. Nuclear replicating herpesvirus KSHV is associated with Kaposi Sarcoma (KS) that is characterized by a microenvironment of inflammatory cytokines including IL-1β. How the caspase-1 inflammasome, which is required for IL-1β maturation is induced during KSHV infection is not known. Here we demonstrate that during de novo KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with ASC and procaspase-1 to form a functional inflammasome. This complex was initially detected in the nucleus and subsequently in the peri-nuclear area. Caspase-1 activation by KSHV was reduced by IFI16 and ASC silencing but not by AIM2 knockdown. Our studies reveal a new function of IFI16 as a nuclear danger sensor and demonstrate that the inflammasome’s danger sensing functions extend into the nucleus.