bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type I interferon increases the sensitivity of human immunodeficiency virus (HIV)-specific CD8+ T lymphocytes to CD95/Fas-mediated apoptosis (42.22)
Authors: Fraietta Joseph , Mueller Yvonne , Do Duc , Yang Guibin , Jacobson Jeffrey , Katsikis Peter 
Published: January 2023

Abstract
Innate immune responses elicited during acute and chronic HIV infection are critical to the control of viremia. Based on their well established antiviral effects, the production of type I interferon (IFN-alpha and IFN-beta) has long been considered a protective mechanism in HIV infection. However, it is possible that excessive IFN-alpha and IFN-beta production during HIV infection may impair HIV-specific CD8+ T cell responses and/or contribute to the loss of CD4+ T cells. We show here that CD4+ and CD8+ T lymphocytes from healthy donors and HIV+ patients are sensitized to CD95/Fas-induced death when pre-incubated with type I interferon for 72 hours. Importantly, IFN-alpha increased the sensitivity of HIV-specific CD8+ T cells from HIV+ individuals to CD95/Fas-mediated apoptosis. Apoptosis of CMV-specific and EBV-specific CD8+ T cells from the same patients was not augmented when exposed to IFN-alpha and subsequently stimulated with anti-CD95 antibody. Since CD4+ T cells and HIV-specific CD8+ T cells in HIV infection are known to be sensitive to CD95/Fas-mediated apoptosis, our studies suggest that these lymphocytes may be initially sensitized to CD95/Fas-induced death by type 1 interferon during acute HIV infection. The production of these anti-viral cytokines during chronic infection may further compromise CD4+ and HIV-specific CD8+ T cell survival.
Analysis of the assembly mechanism for multimeric lamprey VLRB antibodies (43.19)
Authors: Li Jianxu , Herrin Brantley , Guo Peng , Cooper Max 
Published: January 2023

Abstract
Instead of the immunoglobulin-type antigen receptors in jawed vertebrates, the surviving jawless vertebrates use variable lymphocyte receptors (VLRs) that are constructed with variable leucine-rich repeat (LRR) sequences to recognize antigens. Two VLR genes in lamprey and hagfish are somatically assembled during lymphopoiesis using a gene conversion-like mechanism in which highly diverse LRR flanking sequences are copied in serial fashion to construct mature VLRs. Lamprey have been shown to secrete polymeric VLRB antibodies that consist of 8-12 identical disulfide-linked subunits. The overall structure of VLRB antibodies resembles that of IgM antibodies in that both are composed of 4-6 dimers. Previous studies have shown that eight cysteines in the C-terminal hydrophobic region are involved in assembly of the multivalent VLRB antibodies through formation of disulfide bonds. We have characterized a panel of VLRB Cys to Ser mutants using site-directed mutagenesis to determine which cysteines are used for disulfide bond formation and VLRB polymerization. Two or more disulfide bonds were found to be essential for VLRB dimerization and polymerization. Our data further suggest that the carboxy-terminal cysteines 5, 6, 7, and 8 form the cornerstone for VLRB dimerization and polymerization, whereas cysteines 1, 2, 3, and 4 contribute to the stability of the polymer structure.
Effects of aging on B and T cell immunity in nonhuman primate (NHP) species (43.20)
Authors: Arteaga-Cortes Lourdes , Mayeux Jessica , Cantwell Angelene , Pasquali Amanda , Stacy Sue , Dube Peter , Rice Karen , Kraig Ellen 
Published: January 2023

Abstract
The ability of humans and rodents to mount effective immune responses declines with age. Yet, when old baboons (19-24 years) were immunized with LcrV, a protective antigen from Y. pestis, antibody titers were significantly higher than in immunized young animals (2½ years) [JI 181:109]. It may be that baboons are unusual, aging without losing immune competence or alternatively, that LcrV is enhancing humoral immunity in older animals. To address this, a second NHP species was tested; young (4 years), middle-age (11 years), and older (18-24 years) rhesus macaques were immunized with LcrV. Significant humoral responses were observed in all age groups, so like baboons, there was no loss of immune reactivity with aging. However, the greatly enhanced response in older baboons was not recapitulated in rhesus. To test the possibility that LcrV is unique, young (6 years), middle-age (12-13), and older (21-23) baboons were immunized with a second plague antigen, F1; a more typical response was seen whereby F1 antibody titers elicited in younger baboons were higher than those seen in the older cohorts. T cell proliferative and cytokine responses to these antigens have been assessed and no definitive age-associated changes were noted. On the other hand, circulating Tregs and some serum cytokines were higher in older NHPs. These experiments provide novel insights into aging effects on primate immunity and suggest a unique function for plague LcrV in enhancing responses in old animals.
Embryo vaccination using novel adjuvant formulation and Eimeria profilin-induced protective immunity against E. maxima infection (43.4)
Authors: Lillehoj H. , Lee S. , Jang S. , Hong Y. , Dominowski D. 
Published: January 2023

Abstract
Due to increasing concerns on the use of antibiotics in animal production system, development of alternative strategies for disease control in livestock and poultry is becoming important. Avian coccidiosis is caused by several distinct species of Eimeria which undergo intracellular development in different parts of gut reducing significant nutrient absorption. Our previous studies have shown significant protection against coccidiosis using recombinant Eimeria vaccines in laboratory models. This study was carried out to investigate the effect of immunizing 18-day-old embryos with Eimeria profilin protein in novel adjuvant formulation which is composed of Quil A, cholesterol, DDA, and carbopol (QCDC). Chickens which were immunized in ovo with Eimeria profilin/QCDC vaccine produced significantly higher antibody and cytokine responses, and showed better protection against live challenge infection with E. maxima compared to the control chickens which were immunized with Eimeria profilin protein alone. This study demonstrates the first immunological evidence to show immunoenhancing role of QCDC in poultry.
Titanium used in the prosthetic devices may act as an adjuvant driving Th2 cell differentiation (44.15)
Authors: Mishra Pankaj , Rozo Christina , Joseph Benevenia , Gause William 
Published: January 2023

Abstract
Inflammation contributing to periprosthetic osteolysis following joint replacement is a potential complication of arthroplastic surgery. The components of the prosthetic device that elicit inflammation and the characteristics of the innate and adaptive immune response that contribute to inflammation are as yet little studied. The prosthetic material Titanium (Ti) was examined for adjuvant properties. Mice were immunized with the Ti particle (12.5 mg) + LPS-free OVA protein (50 µg) and found to elicit elevated levels of serum IgE, IgG1 and IgG2a compared to OVA alone. CFSE labeled transgenic OVA-specific DO11.10 CD4+ cells were transferred to recipient BALB/c mice and inoculated i.p two days later with Ti plus OVA323-339 peptide or with OVA323-339 peptide alone. Five days after inoculation, CFSE fluorescence analysis showed that donor CD4+, KJ1.26+ DO11.10 T cells had undergone markedly more cell cycling in recipient mice receiving Ti+OVA compared to recipient mice administered OVA alone. OVA-specific ELISPOT assays of cell suspensions from draining lymph nodes showed marked increases in DO11.10 T cell IL-4 and lesser elevations in IFN-γ expression from mice inoculated with Ti + OVA compared to mice immunized with OVA peptide alone. These studies suggest that Ti can act as an adjuvant in vivo to induce naïve T cell differentiation to cytokine producing effector T cells indicating that this inert nanoparticle has potent inflammatory characteristics.
TNF-α Induces Endothelial Cell Expression of Intercellular Adhesion Molecule-1 (ICAM-1) Required for Recruitment of Antigen-Primed CD8 T Cells to Mediate Responses in the Skin (44.2)
Authors: Kish Danielle , Baldwin William , Fairchild Robert 
Published: January 2023

Abstract
Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten sensitization and challenge of the skin. Elicitation of CHS is initiated when hapten-primed CD8 T cells producing IFN-γ and IL-17 traffic to the challenge site and simulate endothelial cells (EC) to produce CXCL1/KC. KC is required for the neutrophil recruitment directing CD8 T cell infiltration through the EC where they are activated to induce the edema of CHS. Factors required for this KC production were tested. Hapten-immune CD8 T cells stimulated hapten-labeled EC to produce KC in vitro and this was blocked by antibodies to IFN-γ, IL-17, and ICAM-1 but not to TNFa. Immunohistochemical staining and qRT-PCR analyses indicated that hapten challenge induced ICAM-1 expression on skin challenge site EC and TNFa expression in both naïve and sensitized mice within 4 hrs of hapten challenge. Transfer of hapten-primed T cells to naïve wild-type but not ICAM-1 knockout mice induced KC production at 6 hrs after hapten challenge. In vivo treatment with antibodies to TNF-α or to ICAM-1 at the time of hapten challenge eliminated KC production, neutrophil infiltration, and CHS. Anti-TNF-α mAb significantly reduced ICAM-1 as well as IFN-γ, and IL-17 mRNA expression in the challenged skin of sensitized mice. Thus, hapten challenge stimulates TNFα production that induces the EC expression of ICAM-1 required for hapten-primed T cells activation to produce the IFN-γ and IL-17 that induces the EC to produce KC.
Non-T cells are required for a poised Th17 phenotype and elevated IL-17 secretion by T cells from type 2 diabetes patients. (44.3)
Authors: Jagannathan Madhumita , McDonnell Marie , Shin Hyunjin , Hasturk Hatice , Nikolajczyk Barbara 
Published: January 2023

Abstract
Type 2 Diabetes (T2D) has recently been identified as a chronic inflammatory disease with changes in immune cell function. Th17 cells and their major product, IL-17, have been implicated in multiple chronic inflammatory diseases. However, the relationship between Th17s and T2D has not been reported. Pro-inflammatory cytokines hyper-secreted by T2D patient monocytes promote Th17 activation. These data suggest a functional link between Th17s and monocytes in T2D. To identify such a link, we first showed that fresh ex vivo T cells from T2D patients have molecular signatures of Th17 cells. T2D T cells stimulated in the context of peripheral blood mononuclear cells (PBMCs) activated Th17 signature genes and elevated IL-17 secretion. In contrast, LPS stimulation of PBMCs from T2D patients failed to elevate IL-17 secretion, indicating that increased monocyte cytokine production, characteristic of T2D, does not further stimulate Th17 cells. Unexpectedly, continuous co-culture of T cells with the non-T cell fraction was required to maintain elevated Th17 function. These data indicate a crucial role for non-T cells in maintaining the Th17 phenotype and elevating IL-17 production in T2D. We conclude the interaction between T cells and non-T cells, most likely monocytes, promotes inflammation in T2D through previously unappreciated mechanisms.
Clonotypic structure of human memory alpha-T cell repertoires to influenza in elderly individuals (45.20)
Authors: Gil Anna , Yassai Maryam , Naumov Yuri 
Published: January 2023

Abstract
The age-associated thymic atrophy and reduced repertoires of naïve T cells could be confounding factors of high morbidity and mortality of older populations due to the seasonal influenza infections. Given that influenza A viral epitope M158-66 induces robust CD8 T cell responses among middle-aged populations, we examined clonotypical α-TCR repertoires among older blood donors. Previously we reported that α-TCR repertoires in middle-age individuals are polyclonal where M158-66 specific T cells were selected as memory cells due to expression JA42 α -chains with poly-G/S/A runs in the CDR3. In the present study we compare α-TCR repertoires between middle-aged and older individuals in respect to Vα family usage and clonotypical diversities. Using CDR3α- spectratyping and sequencing, we found that middle-aged adults possess stable polyclonal response to influenza where diverse JA42 CD8 T cells are distributed among eleven Vα families and VA27 family was dominated in vitro response. In contrary, with aging such dominance was still present in some but not all individuals. Two subjects responses to M158-66 was mediated by VA12.1 family, which represents minor component in the middle-aged cohort. In addition to reduced diversity of VA families, the older subjects posses reduced diversity of JA42 clonotypes. Therefore, we concluded that influenza re-exposure during lifetime induces clonotypical exhaustion of T cells leading to reshaping of T cell repertoire.
Protective effects of monomeric and dimeric forms of the 2G12 neutralizing antibody against HIV-1 infection in a modified humanized mouse model (45.28)
Authors: Luo Xin , Lei Margarida , Feidi Rana , West Anthony , Balazs Alex , Yang Lili , Baltimore David 
Published: January 2023

Abstract
Broadly neutralizing anti-HIV antibodies are rare and have proved hard to elicit with any immunogen. Designer antibodies, on the other hand, are unnatural and have to be introduced through the engineering immunity approach. Yet, it is important to evaluate both types of anti-HIV antibodies in vivo to identify potential HIV vaccine candidates. In this study, we have used a modified humanized mouse model to investigate the protective effects of 2G12 versus a mutant of the antibody that favors dimer formation. Our results showed that while 2G12 was able to prevent CD4 loss and decrease HIV viral load at concentrations higher than 70 μg/mL upon HIV infection, the dimer mutant showed a similar potency at concentrations between 10~15 μg/mL, possibly due to an increased avidity and/or stability of the dimer versus the monomer. We also found that an initial concentration of 2G12 dimer at around 40 μg/mL through one single injection was more effective than a sustained dimer concentration of 10 μg/mL to prevent CD4 loss and to delay the increase of viral load. HIV escape mutants were detected in the presence of either monomeric or dimeric forms of 2G12, indicating that both antibodies have pressured HIV to mutate and the addition of other antibodies such as b12 may be required to provide a sterilization effect against HIV. Collectively, we have identified a more potent variant of 2G12 in vivo, which can be used as part of an antibody cocktail to prevent HIV infection.
Nanogel antigen delivery system for adjuvant-free intranasal vaccines (46.16)
Authors: Nochi Tomonori , Yuki Yoshikazu , Takahashi Haruko , Sawada Shinichi , Mejima Mio , Kohda Tomoko , Harada Norihiro , Kataoka Nobuhiro , Kong Il Gyu , Sato Ayuko , Tokuhara Daisuke , Kurokawa Shiho , Takahashi Yuko , Tsukada Hideo , Kozaki Shunji , Akiyoshi Kazunari , Kiyono Hiroshi 
Published: January 2023

Abstract
Nanotechnology is an innovative method of freely controlling nanometer-sized materials. The recent outbreak of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce antigen-specific both mucosal and systemic immune responses. However because of lacking the effective antigen delivery system to aero-digestive mucosa, co-administration of mucosal adjuvant mediating protective but also undesired immunity is continuously needed. Here we developed a novel intranasal vaccine-delivery system with a nanometer-sized hydrogel (“nanogel”) consisting of a cationic type of cholesteryl group-bearing pullulan (cCHP). A nontoxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells (DCs) after its release from the cCHP nanogel. Vigorous botulinum neurotoxin A (BoNT/A)-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid (TT) with cCHP nanogel induced strong TT-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.
Comparison of antibody responses induced by a virus-like particle-based vaccine upon intramuscular, pulmonary, and vaginal delivery. (48.14)
Authors: Hunter Zoe , Smyth Hugh , Durfee Paul , Chackerian Bryce 
Published: January 2023

Abstract
Virus-like particles (VLPs) can be used as platforms to increase the immunogenicity of antigens that are normally poorly immunogenic, such as self-antigens. We have developed a bacteriophage VLP-based vaccine that targets the HIV coreceptor CCR5 and shown that, following intramuscular administration, it induces high-titer serum antibodies against CCR5 that can inhibit HIV/SIV infection. We have also assessed the ability of this vaccine to induce mucosal immune responses, which is desirable as many pathogens, including HIV, infect at mucosal surfaces. In rats, both intramuscular and pulmonary immunization induced high titer IgG and IgA against the vaccine in the serum, but only the aerosolized vaccine induced CCR5-specific IgA locally in the lung and remotely in the genital tract. We will also present data comparing the magnitude of this "secondary" response in the genital tract to the IgA response invoked following direct immunization of the genital mucosa with different VLP platforms, including VLPs from a virus (human papillomavirus) that normally infects in the genital tract and bacteriophage Qβ VLPs. Our results provide a general method for inducing broad systemic and mucosal antibody responses using VLP-based immunogens.
The effect of altering the homeostatic regulation of alveolar macrophages (48.7)
Authors: Lyonga Daphne , Wissinger Erika , Hussell Tracy 
Published: January 2023

Abstract
The lungs are constantly bombarded by inhaled antigen, both innocuous and harmful. In order to avoid a detrimental over-exuberant response to the myriad of harmless particles inhaled daily, the lung micro-environment is highly regulated. Alveolar macrophages are held in a state of tight suppression by CD200R, TGF-B and IL-10 signalling, and by the nuclear macrophage regulator PPAR-gamma. An absence of any of these immune modulators can severely impact on this tight macrophage regulation. When challenged with LPS in vitro, CD200R-/- alveolar macrophages produce higher levels of IL-6 and TNF compared to wild type controls; and an absence of PPAR-gamma in alveolar macrophages leads to Th1-associated pulmonary inflammation. Here we block IL-10R signalling at homeostasis using an IL-10R mAb and aim to investigate how this impacts on the phenotype of murine alveolar macrophages, whether they become more or less regulatory, classically or alternatively activated. Preliminary data suggests that an absence of IL-10R signalling affects the phenotype of alveolar macrophages at homeostasis. During a subsequent influenza infection and importantly, after IL-10R blockade has ceased, we see a heightened immune response in the IL-10R mAb-treated animals relative to controls. This indicates that even temporarily altering lung homeostasis can affect the outcome of a subsequent infection.
Cell Contact Facilitated Delivery of IL-2 from Dendritic to T Regulatory Cells (49.14)
Authors: Kulhankova Katarina , Rouse Todd , Nasr Mohamed , Field Elizabeth 
Published: January 2023

Abstract
CD4+CD25+ T regulatory lymphocytes (Tregs) play an important role in maintaining immune homeostasis and require IL-2 for their development, expansion, maintenance, and function. Because Tregs do not produce IL-2, they must obtain it from a paracrine source. The identity of a cell providing IL-2 to Tregs is controversial, and the manner in which IL-2 is delivered to Tregs is not well understood. We found that Treg in vitro inhibitory function depends on IL-2 produced by dendritic cells (DCs). By confocal microscopy of in vitro cultures we documented that CD25 (IL-2Rα) concentrated at the JAWSII (DC hybridoma) - RD6 (Treg hybridoma) contact sites, internalized DC material co-localized with CD25 in the RD6, and Tregs internalized IL-2 from transfected DCs. Tregs cultured with WT, but not IL-2 KO DCs, up-regulated CD25 and Foxp3 in contact-dependent manner. To examine IL-2 trafficking between DCs and T cells we examined co-cultures of IL-2mCherry transfected DCs and Treg or T effector cells. DC-Treg contact significantly enhanced IL-2 uptake by Tregs and resulted in up-regulation of CD25 on Tregs. In contrast, Teffs did not acquire IL-2 from DCs in culture. Altogether, these data suggest that 1) DCs are an important source of IL-2 for Tregs, and 2) delivery of IL-2 from DCs to Tregs is Treg-specific and facilitated by close cell-cell contact. These novel findings may further our understanding of requirements for Treg biology during the homeostatic maintenance and immune response.
T cell-intrinsic IL-10 signaling negatively regulates Th1 immunity by restraining IL-12 responsiveness of effector T cells. (49.20)
Authors: Yap George , Wilson Douglas , Marple Andrew , Kamanaka Masahito , Flavell Richard 
Published: January 2023

Abstract
The principal mechanism by which IL-10 mediates downregulation of T cell immunity is through its action on antigen presenting cells, including dendritic cells and macrophages. Whether or not T cells themselves are important physiologic targets of IL-10 regulation has remained unclear. Here we report that transgenic mice expressing a dominant-negative acting, truncated form of the IL-10 R alpha chain in T cells (CD4-IL-10DNR transgenic mice) exhibit enhanced Th1 responses to the parasite, Toxoplasma gondii. CD4-IL-10DNR transgenic mice were considerably more susceptible to peroral T. gondii infection and exhibited enhanced production of IFN-gamma, but not IL-17 or IL-12, indicating that T cells are important targets of IL-10 downregulation in a Th1 response in vivo. To investigate the mechanism of IL-10’s negative effect on Th1 cytokine, we interrogated the ability of Th1 effector cells from the peritoneal cavity of T. gondii-primed mice to respond to IL-12. Our analysis showed that normally, effector cells are highly responsive to IL-12, but rapidly lose signaling competence 12 hrs following the challenge with parasites in vivo. Remarkably, effectors from CD4-IL-10DNR transgenic mice retain their IL-12 responsiveness under the same circumstances. Our results clearly establish the importance of T-cell intrinsic IL-10 signaling for the control of Th1 responses in vivo and shed light on a new mechanism for the antagonistic interactions between IL-10 and IL-12.