bluuebunny/crossref_metadata_2025_split huggingface dataset:
8B4/20, A Private CD43 Epitope on Developing Human Thymocytes, Is Involved in Thymocyte Maturation
Authors: Fabbi Marina , Geginat Jens , Tiso Micaela , Ramarli Dunia , Parent David , Bargellesi Antonio , Remold-O’Donnell Eileen 
Published: January 2023

Abstract
The 8B4/20 Ag is a 120-kDa molecule whose expression on human thymocytes varies according to the differentiation stage: high density on immature CD3−/low thymocytes, reduced density on CD3medium and double-positive thymocytes, and absent on CD3high and single-positive thymocytes and on circulating T cells. In this paper we present immunological and biochemical evidence demonstrating that 8B4/20 Ag is a variant of CD43. We show that 8B4/20-expressing molecules, which are a subset of the CD43 molecules on thymocytes, are heterogeneous in charge, suggesting varying sialylation levels. The 8B4/20 epitope was mapped to the peripherally exposed N-terminal region of CD43, and the 8B4/20 antigenic determinant was characterized by requirement for the sialic acid exocyclic polyhydroxyl side chain, a feature shared with ligands of CD22. Altogether, 8B4/20-CD43 expression pattern and biochemical characteristics suggest its participation in carbohydrate-based interactions in the thymus. We therefore used specific Ab to mimic putative 8B4/20 interactions with natural ligand and examined the effect on isolated thymocytes. Treatment with 8B4/20 had no effect on in vitro apoptosis of isolated thymocytes. In contrast, 8B4/20 ligation enhanced the conversion of isolated thymocytes to differentiated phenotypes. Increased numbers were found in 8B4/20-treated cultures of CD3high and single-positive thymocytes and decreased numbers of CD3−/low and double-positive thymocytes, strongly suggesting that engagement of 8B4/20 delivers a positive signal that favors completion of the thymocyte maturation program. The ability of 8B4/20 mAb to drive thymocyte maturation in vitro suggests that CD43 molecules bearing the 8B4/20 epitope participate in early events of thymic selection.
IκBε-Deficient Mice: Reduction of One T Cell Precursor Subspecies and Enhanced Ig Isotype Switching and Cytokine Synthesis
Authors: Mémet Sylvie , Laouini Dhafer , Epinat Jean-Charles , Whiteside Simon T. , Goudeau Bertrand , Philpott Dana , Kayal Samer , Sansonetti Philippe J. , Berche Patrick , Kanellopoulos Jean , Israël Alain 
Published: January 2023

Abstract
Three major inhibitors of the NF-κB/Rel family of transcription factors, IκBα, IκBβ, and IκBε, have been described. To examine the in vivo role of the most recently discovered member of the IκB family, IκBε, we generated a null allele of the murine IκBε gene by replacement of all coding sequences with nlslacZ. Unlike IκBα nullizygous mice, mice lacking IκBε are viable, fertile, and indistinguishable from wild-type animals in appearance and histology. Analysis of β-galactosidase expression pattern revealed that IκBε is mainly expressed in T cells in the thymus, spleen, and lymph nodes. Flow cytometric analysis of immune cell populations from the bone marrow, thymus, spleen, and lymph nodes did not show any specific differences between the wild-type and the mutant mice, with the exception of a reproducible 50% reduction of the CD44−CD25+ T cell subspecies. The IκBε-null mice present constitutive up-regulation of IgM and IgG1 Ig isotypes together with a further increased synthesis of these two isotypes after immunization against T cell-dependent or independent Ags. The failure of observable augmentation of constitutive nuclear NF-κB/Rel-binding activity is probably due to compensatory mechanisms involving IκBα and IκBβ, which are up-regulated in several organs. RNase-mapping analysis indicated that IL-1α, IL-1β, IL-1Ra, and IL-6 mRNA levels are constitutively elevated in thioglycolate-elicited IκBε-null macrophages in contrast to GM-CSF, G-CSF, and IFN-γ, which remain undetectable.
Enhancement of Fcγ Receptor-Mediated Phagocytosis by Transforming Mutants of Cbl
Authors: Sato Norihito , Kim Moo-Kyung , Schreiber Alan D. 
Published: January 2023

AbstractPhagocytosis mediated by FcγR plays an important role in host defense. The molecular events involved in this process have not been completely defined. The adapter protein Cbl has been implicated in FcγR signaling, but the function of Cbl in phagocytosis is unknown. Here we show that overexpression of the transforming mutants of Cbl, Cbl-70Z, and v-Cbl, but not wild-type (wt) Cbl, enhance phagocytosis mediated by FcγR in COS cells. Cbl-70Z, but not Cbl-wt, also enhanced FcγR-mediated phagocytosis in P388D1 murine macrophage cells. Cbl-70Z did not affect tyrosine phosphorylation or in vitro kinase activity of Syk, indicating that Syk may not be the direct target of Cbl-70Z in the enhancement of phagocytosis. A point mutation (G306E) in the phosphotyrosine domain of Cbl-70Z, as well as a C-terminal 67-aa deletion, partially abolished the enhancing effect on FcγR-mediated phagocytosis. A double mutant of Cbl-70Z containing both the G306E mutation and the C-terminal deletion completely lacked the ability to enhance phagocytosis. Thus, both the phosphotyrosine binding domain and the carboxyl-terminal tail were required for optimal enhancement of phagocytosis by Cbl-70Z. Functional phosphatidylinositol 3-kinase was required for Cbl-70Z to enhance phagocytosis, since wortmannin, a phosphatidylinositol 3-kinase inhibitor, inhibited FcγR-mediated phagocytosis in the presence of Cbl-70Z. These studies demonstrate that mutants of Cbl can modulate the phagocytic pathway mediated by FcγR and imply a functional involvement of c-Cbl in Fcγ receptor-mediated phagocytosis.
15-Deoxy-Δ12,1412,14-prostaglandin J2 Inhibits the β2 Integrin-Dependent Oxidative Burst: Involvement of a Mechanism Distinct from Peroxisome Proliferator-Activated Receptor γ Ligation
Authors: Vaidya Sanskruti , Somers Elizabeth P. , Wright Samuel D. , Detmers Patricia A. , Bansal Vinay S. 
Published: January 2023

Abstract
15-Deoxy-Δ12,14-PGJ2 (dPGJ2) is a bioactive metabolite of the J2 series that has been identified as a ligand for peroxisome proliferator-activated receptor γ (PPARγ) and has received attention for its potential antiinflammatory effects. Because neutrophils express cell-surface receptors for PGs, the effect of dPGJ2 was tested on an inflammatory response that should not require PPARγ, the oxidative burst made by adherent human neutrophils. dPGJ2 inhibited adhesion-dependent H2O2 production with an IC50 of 1.5 μM when neutrophils were stimulated with TNF, N-formylnorleucylleucylphenylalanine, or LPS. Inhibition by dPGJ2 occurred during the lag phase, before generation of peroxide, suggesting blockade of an early signaling step. Indeed, dPGJ2 blocked adhesion of neutrophils to fibrinogen in response to TNF or LPS with an IC50 of 3–5 μM. dPGJ2 was more potent at inhibiting the adhesion-dependent oxidative burst than several other PGs tested. Further, dPGJ2 did not appear to act through either the DP receptor or receptors for PGE2. PG receptors modulate cAMP levels, and the inhibition of adhesion and oxidative burst by dPGJ2 was enhanced in the presence of 3-isobutyl-1-methylxanthine, a cAMP phosphodiesterase inhibitor. A potent PPARγ agonist (AD-5075) did not inhibit peroxide production or adhesion, nor did it change the IC50 for dPGJ2 inhibition. These studies suggest that dPGJ2 may interact with an unknown receptor on neutrophils, distinct from PPARγ, to modulate the production of reactive oxygen intermediates.
The Reaction of the White Blood Cells to Specific Precipitates
Authors: Cromwell H. W. , Centeno J. A. 
Published: January 2023

Summary
When fresh normal citrated blood is mixed with a protein and its specific antibody, the polymorphonuclears, lymphocytes and mononuclears become strikingly vacuolated. This vacuolation is definitely associated with the product of the antigen-antibody reaction since (a) it does not occur if the precipitate is removed before the whole blood is added, and (b) the reaction does occur when the whole blood is added to the thoroughly washed precipitate suspension.
Non-specific particulate matter, as heat-coagulated protein, collodion particles and charcoal particles, does not stimulate the reaction.
Phagocytosis of sensitized B. typhosus and pneumococcus by the same types of cells has been observed with marked vacuolation of the polymorphonuclears and mononuclears. The vacuolation appears more slowly than with the specific precipitate and seems not to occur in the lymphocytes at all.
It is considered that the specific precipitate is probably phagocyted and that the vacuoles are associated in some manner with its subsequent digestion.
These observations are significant in pointing out the probable importance of phagocytosis in determining the fate of the specific precipitate in vivo.
Cellular immune response to Hantaan virus nucleocapsid protein during the acute phase of hemorrhagic fever with renal syndrome: negative correlation with disease severity (128.13)
Authors: Wang Meiliang , Wang Jiuping , Zhu Yong , Xu Zhuwei , Yang Kun , Yang Angang , Jin Boquan 
Published: January 2023

Abstract
The cellular immune response to Hantaan virus (HTNV) is incompletely understood, especially in humans. To investigate the cellular immunity during acute HTNV infection, the magnitude of T cell response to HTNV nucleocapsid protein was quantitated by direct ex vivo IFN-γ ELISPOT using overlapping peptides. We found that the combined frequencies of HTNV-specific T cells at early time point were significantly higher in patients with mild or moderate hemorrhagic fever with renal syndrome (HFRS) than in those with severe or critical HFRS (P = .006). Moreover, these frequencies were higher in patients with subsequent mild renal failure (maximum serum creatinine level, =707 μmol/L) than in those with subsequent severe renal failure (maximum serum creatinine level, &gt;707 μmol/L) (P = .006). Kinetic analysis showed that a decrease in the serum creatinine level during the acute phase of illness was often accompanied by an increase in the magnitude of IFN-γ-producing T cells. These data suggest that IFN-γ-producing T cells may help reduce the risk of progression to acute renal failure caused by HTNV infection. This work was supported by grants from the National Natural Science Foundation of China (No.30471625).
MHC class I Dk gene expression licenses Ly49G2+ NK cell function and rescues MCMV susceptibility (128.19)
Authors: Xie Xuefang , Brown Michael G 
Published: January 2023

Abstract
NK cell-mediated murine CMV (MCMV) resistance is under H-2k genetic control in MA/My mice, however the underlying gene(s) is unclear. We generated a panel of intra-H-2 recombinant congenic mouse strains to map a 0.3-Mb critical interval in the H-2 class I D subregion. The interval spans 30 genes including the class I Dk gene. Because Ly49 NK cell receptors are licensed by and responsive to MHC class I molecules, Dk is a positional candidate. Thus, a 10-kb Dk genomic DNA was cloned and injected into MCMV susceptible (Cmvs) (MA/My.L-H2b x C57L)F1 blastocysts. A transgenic founder (Tg3-Dk) mouse was healthy and competent in germline transgene transmission. We separately backcrossed Tg3-Dk to both C57L and MA/My.L-H2b Cmvs genetic backgrounds and found that Dk was expressed at the cell surface of leukocytes only in Tg3-Dk offspring. Importantly, Tg3-Dk gene expression conferred virus resistance; Tg3-Dk offspring spleens had ~1000-fold lower MCMV at 90 h after infection than non-transgenic littermate controls. MCMV resistance in this system may need Dk-licensed Ly49G2+ NK cells. In support, we have found that Ly49G2+ NK cells are selectively licensed in, and preferentially expand and become activated during MCMV infection in Dk-expressing C57L.M-H2k(R7) congenic mice. This is under study in Tg3-Dk mice. We conclude that Dk gene expression is essential in H-2k MCMV resistance. Supported by NIH R01 AI50072.
Assessment of Ebola Specific Antibody Responses in Vaccinated Macaques (128.20)
Authors: Lear Calli  Marie , Olinger Gene G. 
Published: January 2023

Abstract
Ebola virus (EBOV) infection causes severe disease accompanied by high mortality rates. Several vaccine platforms have shown promise in protecting against Ebola exposure; however, there are no licensed vaccines or therapies approved and available for human use. A vaccine approach utilizing Venezuelan equine encephalitis virus (VEE) replicon particles (VRP) expressing filovirus protein(s) was the first vaccine approach that provided complete protection against Marburg infection in non-human primates (NHP). We evaluated the ability of VEE replicons expressing the glycoprotein (GP), nucleoprotein (NP), VP24, VP30, VP35, and VP40 to protect against Ebola Zaire (ZEBOV) exposure in NHP by various routes of administration, intramuscular (IM) versus subcutaneous (SC). To further evaluate protective efficacy, NHP were vaccinated IM or SC with VEE replicon expressing the viral glycoprotein or expressing all six proteins. Protective efficacy was demonstrated in the both cynomolgus macaques and rhesus macaques. Enzyme-Linked ImmunoSorbent Assays (ELISA) were developed using the whole antigen or recombinant Ebola GP to assess vaccine induced immunity against EBOV. The ELISA based assay assessing humoral responses did not accurately predict protection. The protection generated by the VEE replicon expression of Ebola proteins demonstrates the efficacy of the vaccines platform and warrants further evaluation as a human use vaccine. Further studies are needed to develop accurate correlate of immunity assays.
Impact of TLR deletion on brain pathology in a mouse model of encephalitis (128.22)
Authors: Drescher Kristen M. , Schemmel Andrew , Leland Korey 
Published: January 2023

Abstract
The innate immune response represents the host's first line of defense to infection. The toll-like receptors (TLRs) are a family of pattern recognition receptors triggered by specific pathogen-associated molecular patterns (PAMPs). To examine the role of TLRs in a mouse model of viral encephalitis, mice with defects in TLR-2, TLR-3 or TLR-4 were intracerebrally infected with Theiler's murine encephalomyelitis virus (TMEV) to determine the impact of TLR deletion on the extent of disease. At day 16 post-infection, a timepoint when limited pathology is observed in TMEV-infected wild-type control animals, extensive brain pathology was observed in TLR-2 and TLR-3 knockout mice. While pathology was observed in TLR-4 knockout mice following TMEV infection, the pathology was less than that observed in the TLR-2 and TLR-3 knockout animals. TLR-4 knockout mice mounted more robust antibody responses to TMEV the other strains of mice, suggesting that this mechanism of virus clearance may account for the reduced level of pathology observed in these animals.
Support: National Multiple Sclerosis Society (RG3870A3); Department of Defense (PR064574)
HIV infection inhibits granulysin expression by memory CD8+ T cells (128.26)
Authors: Hogg Alison E , Ji Jiaxiang , Lancaster Katrina L , Cloyd Miles W , Endsley Janice J 
Published: January 2023

Abstract
The hallmark of HIV infection is severe immuno-suppression and an increased susceptibility to many infectious agents including M. tuberculosis. Granulysin is expressed by cytotoxic T cells (CTL) and is strongly lytic against susceptible and drug resistant strains of M. tuberculosis. We hypothesized that the reduced CTL activity observed following HIV infection may, in part, be due to suppression of granulysin. We and others have shown that granulysin expression is regulated by common γc cytokines IL-2, IL-15 and IL-21. We used an in vitro model, in which we infected PBMC from healthy donors with HIV. We found that induction of granulysin in CD8+ T cells following stimulation with IL-2, IL-15 or IL-21 was reduced in PBMC infected with HIV. Moreover, we observed that phosphorylation of STAT5, a downstream signaling molecule crucial for the induction of granulysin by IL-2 and IL-15 was also reduced by HIV infection. In an antigen-specific memory response, using PBMC from PPD+ donors, we found that expression of granulysin by memory CD8+ T cells following PPD stimulation was inhibited in HIV-infected PBMC. Our results suggest that suppression of granulysin in response to γc cytokines and specific TB antigen by HIV may be one mechanism for the increased susceptibility of HIV+ patients to TB infection and could represent an important avenue for immune intervention.
Identification of CD8 T lymphocyte responses to HHV-8/KSHV Proteins (128.28)
Authors: Lepone Lauren , Rappocciolo Giovanna , Knowlton Emilee , Piazza Paolo , Jais Mariel , Jenkins Frank , Rinaldo Charles 
Published: January 2023

Abstract
Objectives: CD8 T cells producing more than one cytokine or cytotoxicity factor, i.e. polyfunctional, have been shown to relate to control of HIV-1 infection. As it is currently not clear if polyfunctional CD8 T cells have a role in controlling HHV-8 infection, we investigated CD8 T cell cytokine responses to multiple lytic and latency viral proteins.
Methods: T cells were stimulated with dendritic cells from HHV-8 seropositive subjects that were loaded with overlapping peptides derived from gB and K8.1 lytic proteins, and K12 and LANA-1 latency proteins, and screened for IFNγ production by extended culture ELISPOT. Positive peptides were assessed for production of IFNγ, IL2, TNFα, MIP1β and CD107a by flow cytometry.
Results: ELISPOT and flow cytometry revealed new, potential HLA A*0201 9mer epitopes for each protein. In HHV-8 seropositive healthy donors controlling infection, the predominant CD8 T cell response to protein epitopes was monofunctional, with a portion of CD8 T cells being polyfunctional.
Conclusions: This demonstrates that HHV-8 proteins predominantly induce single factors in CD8 T cells from healthy, HHV-8 seropositive individuals, with a portion of T cells producing 2 or more of these factors. These immunogenic regions of the viral proteins could be important in immunopathogenesis of KSHV/HHV-8 and progression to Kaposi's sarcoma. (U01-AI35041, R01 CA82053, T32 AI065380-04)
An Altered T-cell Repertoire Mediates Heterologous Immunity and Protection from Epstein-Barr Virus Infection (128.32)
Authors: Watkin Levi , Quigley Maire , Aslan Nuray , Sullivan John L , Luzuriaga Katherine , Selin Liisa K 
Published: January 2023

Abstract
Previously we have reported that cross-reactive memory CD8 T cells specific for the Flu-M158-66 epitope (GILGFVFTL) respond to the EBV-BMLF1280-288 epitope (GLCTLVAML) during the course of EBV infection and contribute to the onset of infectious mononucleosis. Recently we have found that the memory CD8 T cells specific for the Flu-M158-66 are also cross-reactive to an additional EBV epitope, EBV-BRLF1109-117 (YVLDHLIVV). Here we sought to determine the cross-reactive properties of the Flu-M158-66 specific cells in EBV sero-negative individuals. CD8 T cells cultured in the presence of the cross-reactive EBV epitopes preferentially expanded the Flu-M158-66 specific cells. Although these expanded cells did not stain with EBV pentamers they were able to produce cytokine in response to EBV peptides. Additionally these cells were capable of killing autologous EBV infected targets. Interestingly the T cell repertoire demonstrated unique characteristics including nearly complete domination by a single Vβ17 and Vα27clonotype with a unique CDR3 motif. Taken together these data suggest that an altered T cell repertoire could mediate protection against viral infection.
γδT Cell Promotes Maturation of Dendritic Cell During West Nile Virus Infection (128.4)
Authors: Fang Hao , Welte Thomas , Zheng Xin , Wang Tian 
Published: January 2023

Abstract
γδ T cells are important for early control of West Nile virus (WNV) dissemination. TCRδ-/-(γ δT Cell Deficient) mice also have reduced CD8+ T cell memory response and are more susceptible to secondary WNV infection. Here, we investigated the role of γδ T cells in regulation of CD4+ T cell response following WNV challenge. We found that dendritic cells (DCs) of WNV infected TCRδ-/-mice had reduced levels of CD40, CD80, CD86 and major compatibility complex (MHC) II expression and IL-12 production than wild-type mice. We also detected a significant viral load in WNV infected γδ T cells. Infected γδ T cells produced high levels of IFN-γ and proinflammatory cytokines, including TNF-α and IL-6, which were known to promote DC maturation. Nevertheless, levels of Toll-like receptors (TLR) 2, 3, 4 and 7 in these cells were not different from those of non-infected, suggesting a TLR-independent activation following infection. Naïve DCs co-cultured with γδ T cells from WNV infected mice or from in vitro infection had higher levels of costimulating molecules, MHC class II expression and IL-12 production. Co-culture of CD4+ T cells purified from OT II transgenic mice and DCs from WNV infected TCRδ-/-mice induced less IFN-γ and IL-2 than those of wild-type mice. Overall, these data suggest that WNV induced γδ T cell activation might promote DC maturation and initiate CD4+ T cell priming in a TLR independent manner. (Supported by NIH grant R01 AI072060)
Enhancing potency of anti-HIV chimeric immune receptor (CIR) (128.5)
Authors: Selliah Nithianandan , Skowron Gail , Lu Li , Yang Wen , Junghans Richard P 
Published: January 2023

Abstract
Immunotherapies that have the potential to eradicate reservoirs of HIV infected cells may be useful to suppress or cure HIV/AIDS. in combination with current antiviral drug therapies. T cells expressing chimeric immune receptors (CIR) through gene modification ("designer T cells") can be redirected to kill HIV-infected cells. Previously, an anti-HIV CIR, CD4-ζ (1st generation), was created to bind to HIV-1 gp120 antigen through its CD4 extracellular domain and induction of signaling through cytoplasmic CD3ζ chain. However, the adoptive transfer of autologous CD4-ζ T cells to HIV/AIDS patients failed to control the viral infection in clinical trials. To improve potency, our laboratory has created 2nd generation anti-HIV designer T cells that incorporate CD28 costimulation (CD4-CD28-ζ). 2nd generation designer T cells kill HIV-Env expressing Jurkat cells and HIV-1 infected CEM-SS cells as well or better than 1st generation designer T cells. Stimulation with anti-CD4 mAb induces more IL2 production in 2nd generation than 1st generation designer T cells. In addition, 2nd generation designer T cells showed significantly better proliferative response upon culture with HIV-Env expressing HeLa cells or HIV-1 infected CEM-SS cells. These data suggest that gene modified CD8+ T cells could be an effective therapy to eradicate HIV+ cells during and after anti-retroviral therapy. We hypothesize that CD28 domain in the CIR will confer a benefit of longer T cell survival after infusion into HIV patients.
Research supported by NIH, R21.