bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+ T cells are critical to the therapeutic efficacy of TAA-based cancer vaccines and control of recurrences (48.11)
Authors: Sharma Rajesh , Srivastava Abhishek , Yolcu Esma , Shirwan Haval 
Published: January 2023

Abstract
The role of CD4+ T cells remains ambiguous in cancer immunotherapy. We herein addressed this issue using a novel form of soluble 4-1BBL (SA-4-1BBL) costimulatory molecule as an effective adjuvant component of HPV E7 and survivin as TAA-based vaccines in E7 expressing TC-1 cervical and survivin over expressing 3LL lung cancer preclinical models, respectively. Vaccination of C57BL/6 mice on day 6 having established tumors with SA-4-1BBL admixed with E7 or survivin TAAs resulted in the eradication of TC-1 and 3LL tumors in 70% and 80% of mice, respectively, along with generation of tumor specific long-term memory that prevented tumor recurrence on second challenge. The in vivo depletion of CD4+ T cells one day before tumor challenge significantly compromised vaccine efficacy in both TC-1 (25%) and 3LL (12.5%) models. In marked contrast, the depletion of CD4+ T cells one day prior to vaccination did not significantly alter the therapeutic efficacy of the vaccines. However, these mice had compromised immunological memory since a second challenge of 3LL on day 60 resulted in tumor development in the majority (85.7%) of mice. Taken together, this study demonstrates an indispensable role of CD4+ T cells in priming immune responses against cancer as well as establishment of long-term memory.
Protective role of T-bet in anti-IL17A treatment of lung cancer (48.13)
Authors: Reppert Sarah , Boross Ildiko , Koch Sonja , Koslowski Michael , Türeci Özlem , Lehr Hans-Anton , Finotto Susetta 
Published: January 2023

Abstract
IL17A is a cytokine mainly produced by Th17 cells. The function of the Th17 cell lineage in lung cancer remains to be elucidated. In our study we found increased expression of the Th17 transcription factors RORα4 and RORγt and the cytokine IL-17A in the lungs of patients with lung adenocarcinoma compared to healthy control tissue. In lung cancer tissues IL-17A inversely correlated with the Th1 specific factor T-bet. Targeting of IL-17A in a murine model of lung adenocarcinoma by intranasal application of anti IL17A antibodies resulted in reduction of lung tumor load and prolonged survival of wild-type mice. Studies in T-bet (-/-) mice revealed up-regulation of lung IL-23/IL-23-R and IL-17A/IL-17A-R in T cells infiltrating the tumor. Local anti-IL-17A antibodies treatment improved (50%) survival in treated T-bet (-/-) mice, reduced the number of IL-17R expressing lung CD4+ T cells, induced the number of natural killer cells and CD8+ T cells producing IFNγ compared to wild type littermates-bearing tumor and treated in the same way. These data might indicate that local anti IL-17A antibody therapy could be successful for the treatment of lung tumor also in the absence of T-bet.
Activation of endogenous CD4 T cells stimulates favorable immunologic changes in the tumor milieu and enhances the antitumor effect of lentivector immunization (48.15)
Authors: He Yukai , Hong Yuan , Peng Yibing , Xiao Haiyan , Mi Michael , Munn David , Wang Gui-Qiang 
Published: January 2023

Abstract
CD4 T cells are known to help the induction, migration, and effector functions of CD8 antitumor responses. Here, we reported an additional layer of CD4 helper function, i.e. activation of endogenous CD4 T cells could modulate the tumor milieu. We engineered a lentivector to express a nominal fusion Ag composed of hepatitis B surface protein (HBsAg) and IgG2a Fc domain (HBS-Fc-lv) that induced potent CD8 as well as robust CD4 response. Remarkably, immunization with this vector caused regression of established tumors. Immunological analysis revealed that functional CD8 and CD4 T effector (Teff) was markedly increased while the Treg ratio was substantially decreased in the regressing tumors. HBS-Fc-lv immunization also shifted the suppressive tumor lesion microenvironment to one that is immune stimulating. Mechanistically, the decrease of tumor Treg ratio and the improvement of antitumor effect of HBS-Fc-lv immunization were dependent on CD4 activation and IFNg production. CD4 Teff cells were preferentially expanded in the vaccine draining lymph nodes and selectively recruited into tumor lesions as the chemokines for Teff recruitment were significantly increased in the tumor lesions after HBS-Fc-lv immunization. These data indicate that immunization strategies capable of activating both CD8 and CD4 T cells can improve the tumor milieu and generate an enhanced antitumor effect.
Transient mTOR blockade augments vaccination induced CD8 memory responses for tumor immunity (48.21)
Authors: Shrikant Protul , Li Qingsheng , Rao Rajesh , Vazzano Joseph , Gibbs John , Odunsi Kunle 
Published: January 2023

Abstract
Vaccination aims to generate functional CD8+ T cell responses for tumor immunity. However, the CD8+ T cell functions that empower tumor efficacy have not been clearly established. In this study, we demonstrate that a vaccination strategy that generates memory rather then effector CD8+ T cells shows enhanced tumor efficacy. A short-course of rapamycin treatment transiently blocks viral vaccination induced mTOR in CD8+ T cells for reduced early clonal expansion; due to dampened proliferation, and transitions T-bet induced type 1 effector cells to memory precursors. Strikingly, longer-course of rapamycin treatment abrogated the enhanced viral vaccination induced CD8+ memory generation; persistence and antigen-recall, generated by transient mTOR blockade. Although, the phenotype of day 40 antigen-specific CD8+ memory responses produced by vaccination alone or vaccination plus rapamycin appeared to be identical, they were quantitatively and qualitatively distinct and demonstrated greater tumor efficacy. These findings identify the use of rapamycin in vaccination strategies to enhance CD8+ T cell memory and demonstrate the augmented tumor efficacy of memory rather than effector CD8+ T cells.
Role of MDA5 in triggering of potent antiviral responses in the absence of type I IFN positive feedback (49.1)
Authors: Kim Won-keun , Tapia Karla , Barria Maria , Moran Thomas , Lopez Carolina 
Published: January 2023

Abstract
Viral recognition by specialized cellular sensors is critical for the innate immune response to virus infection. Detection of viral components by these sensors triggers the production of type I interferon (IFN), the earliest hallmark of viral infection, which plays an essential role in inducing an antiviral state in both infected and non-infected cells. Highly pathogenic respiratory viruses replicate in the lungs to high titers before a detectable anti-viral response begins, indicating that the viruses have devised effective mechanisms to avoid the innate anti-viral response. We have shown that dendritic cells can be potently activated in response to Sendai virus that contains a high dose of defective viral genomes (SeV HD) even in the absence of type I IFN signaling. The induction of anti-viral cytokines is driven by a quick and potent activation of IRF3 and NF-κB independently of IRF7. This response depends on the presence of MAVS that is essential for the signaling of the viral RNA sensors RIG-I and MDA5. Interestingly, our study indicates that infection with SeV HD triggers MDA5, but not RIG-I, in a type I IFN independent manner. This supports the hypothesis that the type I IFN-independent up-regulation of MDA5 is involved in the recognition of viral RNA and the subsequent induction of antiviral genes. In conclusion, this study suggests a previously unappreciated type I IFN independent function of MDA5 in the innate immune response to respiratory viruses.
Parasite induced IFN-γ treats severe H5N1 influenza infection (49.11)
Authors: O'Brien Kevin , Knoll Laura , Schultz-Cherry Stacey 
Published: January 2023

Abstract
Outbreaks of influenza A viruses are a continued burden to society in terms of both human health and economic costs. Given the continuous evolution of the virus away from our limited antiviral therapies, new treatments are desperately needed. An alternative approach is through the identification of immune enhancement treatments. We show that mice chronically infected with the immune modulating protistian parasite Toxoplasma gondii survive lethal influenza infection. Because a non-infectious fraction of parasite extract elicits an immunologic response similar to live parasites, it was tested as a post-infection treatment for severe influenza virus. Extract administration two days post- lethal influenza infection enhanced survival, lowered viral titers, and reduced clinical disease. Examination of treated, influenza virus infected mice lacking lymphocytes showed that while the adaptive immune response is not absolutely required for enhanced survival, it is necessary for extract-mediated viral clearance. Mechanistic analysis of the extract induced-innate immune responses showed that interferon gamma (IFNγ) production is both necessary and sufficient for survival. These studies demonstrate that T. gondii may have beneficial properties for its warm-blooded host and a non-infectious component from one microbe can be used to enhance the immune response to a second microbe.
Augmentation of immunity to influenza A virus by manipulating a host counter inflammatory pathway (49.5)
Authors: Sharma Shalini , Sundararajan Aarthi , Rouse Barry 
Published: January 2023

Abstract
Reactions to pathogens are usually tuned to effect immunity and limit tissue damage.With chronic infections, where immunity is unsuccessful, tissue damage would be more severe were it not for the operation of numerous host counter inflammatory events. One such event is the inhibitory effects of some galectins binding to their receptors on effector T cells. A potential downside of counter inflammatory events is that they may constrain the effectiveness of immunity to acute infections. We present evidence for this situation in mice acutely infected with Influenza A virus (IAV). We show that virus specific CD8+T cells in both bronchoalveolar lavage (BAL) and spleen up regulate Tim-3 following IAV infection. In an ex-vivo apoptosis assay, addition of Galectin-9 (Gal-9) to the splenocytes (d10pi) caused apoptosis of both Tim-3+and DbNPtet+ CD8+T cells. Furthermore, Galectin-9 knockout (G9KO) mice mounted more robust acute phase virus-specific CD8+T cell response and cleared virus more rapidly than WT mice. G9KO mice also generated higher virus specific serum IgM, IgG and a more rapid IgA response than WT. When IAV immune mice were challenged with a heterologous IAV, G9KO mice mounted a 4 fold stronger IAV specific CD8+T cell response than WT mice. Tim-3 fusion protein infusion into infected WT mice enhanced CD8+T cell responses to IAV. Our results could indicate that manipulating galectin signals may represent a convenient approach to improve immune responses to some vaccines.
Differential role of UVB-induced photolesions in skin and immune response. (50.10)
Authors: Bombardieri Cíntia , Quayle Carolina , Rebel Heggert , Rijksen Yvonne , de Gruijl Frank , Hoeijmakers Jan , Menck Carlos Frederico Martins , van der Horst Gilbertus 
Published: January 2023

Abstract
UV-induced DNA damage is an essential step in the process by which UVB can alter host resistance to infections diseases. UV-light induces two types of photolesion on DNA that are repaired by photolyases (absent in placental mammals) or Nucleotide Excision Repair. Photolyases are capable of repair these lesions using a photon of light as source of energy. Although the deleterious effects of UV are widely known, the specific role of each photolesion in the induction of changes in the immune response remains unknown. It has been shown in vivo that CPDs are responsible for the majority of the effects after UVB skin irradiation of DNA repair proficient mice, such as erythema, apoptosis, hyperplasia, tumorigenesis and immunosuppression. However the role of 6-4PP is still unknown. We show that the removal of CPD lesions prevents hyperplasia and induces dark skin pigmentation. When 6-4PPs were removed, UVB promoted hyperplasia and tanning. Also, unlike 6-4PP removal, CPD removal is capable of preventing the development of p53 epidermal patches, which have a direct correlation with carcinoma development. Furthermore, the CPD removal is sufficient to suppress the induction of Treg (CD4+CD25+Foxp3) in draining lymph nodes and spleen indicating a minor state of immunosuppression. This study can provide new information as how immune responses are regulated depending of the lesion that is repaired and improve our understanding the immune system role in skin cancer induction.
TLR2 stimulation drives human CD4+CD25+CD127negFOXP3+ Tregs into a Th17-like phenotype with reduced suppressive function. (50.4)
Authors: Gran Bruno , Sanvito Lara , Darlington Peter , Constantinescu Cris , Bar-Or Amit , Nyirenda Mukanthu 
Published: January 2023

Abstract
Naturally occurring CD4+CD25hiFOXP3+ Tregs suppress the activity of pathogenic T cells and prevent development of autoimmunity. TLRs are involved in modulating Treg functions both directly and indirectly. Specifically, TLR2 stimulation can reduce the suppressive function of Tregs by mechanisms that are incompletely understood. The developmental pathways of Tregs and Th17 cells are considered divergent and mutually inhibitory, and IL-17 production has been associated with reduced Treg function. We examined the effect of different TLR2 ligands on the suppressive functions of human CD4+CD25hiCD127negFOXP3+ Tregs and found that activation of TLR1/2 heterodimers reduces the suppressive activity of Tregs on CD4+CD25- responder T cell (Tresp) proliferation while at the same time enhancing the expression of IL-17, increasing RORC, and decreasing FOXP3 expression. Neutralisation of either IL-17 or IL-6 abrogated Pam3Cys-mediated reduction of Treg suppressive function. We also found that TLR2 stimulation in combination with TCR activation drives naïve human T helper precursors to Th17 differentiation. We conclude that TLR2 stimulation can induce human Tregs to a Th17 phenotype skewing and identify this plasticity as a new mechanism of regulation of Treg function by TLRs, which could enhance microbial clearance by releasing T effector functions.
TLR agonist, R848, induces further differentiation of myeloid-derived suppressor cells (50.5)
Authors: Im Sun-A , Lee Moon-Kyu , Kim Ki-Hyang , Hwang Hyun-Jee , Kim Ae-Ran , Lee Chong-kil 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patient and tumor-bearing mice and potently suppress T-cell activation. MDSCs represent a group of immature myeloid cells expressing CD11b and Gr-1. Here we show that TLR agonist R848, which binds to TLR7/8, induces further differentiation of MDSCs into mature myeloid cells. MDSCs were isolated from the spleens of mice bearing mammary carcinoma 4T1 cells, and then cultured in the presence of R848. Phenotypic analysis of the MDSCs showed that they differentiate into cells expressing higher levels of F4/80, CD11c and class II MHC molecules. Consequently, the MDSCs cultured in the presence of R848 induced anti-CD3/anti-CD28-induced T cell proliferation strongly. The differentiation-inducing activity of R848, however, was abrogated in the presence of high concentration of GM-CSF. The differentiation-inducing activity of R848 on immature myeloid cells was also confirmed using immature bone marrow-derived dendritic cells and peritoneal macrophages. These results show that R848 could be useful in the induction of further differentiation of MDSCs into mature myeloid cells, and further suggest that neutralization of GM-CSF activity might be necessary in developing therapeutics inducing further differentiation of MDSCs.
NKG2D signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses (52.12)
Authors: Guevara-Patino Jose-Alejandro , Zloza Andrew , Lyons Gretchen , Kohlhapp Frederick , A. O'Sullivan Jeremy , Lacek Andrew , Bellavance Emily , Zafirova Biljana , Polić Bojan 
Published: January 2023

Abstract
In the absence of CD4+ T cell help, primed CD8+ T cells mount defective responses. However, the description of priming cues capable of rescuing these defective functions is lacking. Here, we show that concurrent delivery of DNA plasmids encoding antigen and NKG2D ligand, Rae-1ϵ, to antigen presenting cells rescues CD4-unhelped CD8+ T cell memory recall but not effector phase responses. NKG2D-mediated rescue of CD4-unhelped CD8+ T cell memory recall responses is characterized by reversal of elevated T-bet expression, recovery of granzyme B, IL-2, and IFNγ production and recovery of CTL function. NKG2D-mediated rescue requires NKG2D expression on CD8+ T cells and is dependent on IL-15. These findings have the potential to address limitations of current CD8+ T cell regiments used in the absence of CD4 help against intracellular pathogens and cancer, by generating effective CD8+ T cell memory recall responses.
Extracellular matrix from porcine small intestinal submucosa as immune adjuvants (52.21)
Authors: Aachoui Youssef , Ghosh Swapan 
Published: January 2023

Abstract
Porcine small intestinal submucosa (SIS) of Cook Biotech is widely used in tissue remodeling. It also proved safe and effective in enhancing efficacy of a prostate cancer vaccine. In this study, we compared SIS-adjuvanticity with alum’s in mobilizing innate immunity via inflammasomes, and in boosting antibody response to soluble proteins, ovalbumin, and a hapten-protein conjugate, phthalate-KLH. This evaluation carried out in BALB/c, C57Bl/6 and lupus-prone NZB/WF1 mice was done by both Intraperitoneal and subcutaneous routes of immunization. Methods involved determination of antibody titer, isotyping, microarray profiling of cytokines and chemokines and qPCR of inflammasomes-related genes. Results clearly highlighted the difference between SIS and alum. SIS provoked neither pro-inflammatory cytokines (IL-6, IL-1β, and TNFα) nor NLRP3 inflammasomes as alum did, but it did up-regulate IL4 and CD30-ligand. SIS also activated chemotactic factors LIX and KC (neutrophil chemotactic factors), MCP 1 (monocyte chemotactic factors), MCSF and MIP 1-α (macrophage chemotactic factor) and Lympotactin, albeit a little less than Alum. SIS, however, was as effective as alum in engendering lasting and specific antibody responses, primarily of IgG1 type, but proved inconsequential in induction of anti-DNA response or renal pathology. In conclusion, although both alum and SIS induced Th2 type immune response, SIS was much less inflammatory than alum.
Display of conserved Human Immunodeficiency Virus Type 1 gp41 membrane-proximal external region epitopes on bovine papilloma virus-like particles (53.19)
Authors: Zhai Yougang , Zhong Zhenyu , Zariffard Reza , Spear Gregory , Qiao Liang 
Published: January 2023

Abstract
Human immunodeficiency virus type 1 (HIV-1) is mainly transmitted via mucosa; an effective vaccine must induce appropriate mucosal immunity to contain virus transmission. To induce 2F5/4E10-like broadly neutralizing antibody at mucosa sites, the HIV-1 epitopes ELLELDKWASLWN and NWFDITNWLWYIK, recognized by broadly neutralizing antibodies 2F5 and 4E10, respectively, and a short membrane-proximal external region (MPER) (LELDKWASLWNWFDITNW) of HIV gp41 (containing both epitopes) were displayed on three surface loops of bovine papillomavirus (BPV) 1 L1 protein. BPV L1 can form virus-like particles which are mucosa-tropic. Chimeric virus-like particles (CVLPs) were assembled when the fusion proteins were expressed in sf9 cells. CVLPs had sizes similar to those of BPV particles and could be recognized by HIV broadly neutralizing antibodies 2F5 and 4E10. By competition ELISA, CVLP showed strong abilities for competitively binding to 2F5 in the presence of competitors, the peptide ELLELDKWASLWN or to 4E10 in the presence of peptide NWFDITNWLWYIK. Epitope-specific serum IgG and intestinal secretory IgA responses were elicited after oral immunization of mice with the CVLPs. The antibodies specifically recognized HIV-1 gp160 envelope glycoprotein expressed on the cell surface. These findings provide valuable information for an HIV vaccine immunogen design to induce 2F5/4E10-like broadly neutralizing antibody via presenting HIV-1 gp41MPER epitope on BPV VLPs.
IL-15/IL-15Rα improves immune cell survival but does not reduce disease severity following pulmonary infection with the intracellular bacterium Francisella tularensis (56.27)
Authors: Schmitt Deanna , O'Dee Dawn , Brown Matthew , Horzempa Jospeh , Russo Brian , Nau Gerard 
Published: January 2023

Abstract
The potent anti-apoptotic cytokine IL-15 regulates the development and function of a wide range of innate and adaptive immune cells. Treatment with IL-15 in combination with IL-15Rα prevents apoptosis and immunosuppression in mouse models of sepsis. Inhalation of Francisella tularensis results in an acute pneumonia that demonstrates many of the hallmarks of sepsis including bacteremia and hypercytokinemia. We and others have observed widespread cell death in the lung following infection with virulent F. tularensis strain Schu S4. The predominant cell populations depleted are lymphocytes and neutrophils. Cell numbers declined in Schu S4-infected mice despite high levels of chemokines in the lung and correlated with an increase in TUNEL-positive cells. This supports the conclusion that immune cell depletion was due to cell death, and not a lack of recruitment. To determine whether this cell depletion was contributing to Schu S4 pathogenesis, mice were treated with IL-15/IL-15Rα prior to infection. IL-15/IL-15Rα treatment significantly increased the number of viable lung cells in Schu S4-infected mice compared to mock-treated controls, however, no difference in bacterial burden or disease severity was observed. These data suggest that depletion of immune cells by F. tularensis does not contribute to the morbidity and mortality associated with pneumonic tularemia. Moreover, IL-15/IL-15Rα may not be generally applicable to treat sepsis of different etiologies.
A JAK3 pathway may be involved in the production of IL-6 by human monocytes stimulated with BAFF. (57.16)
Authors: Yoshimoto Keiko , Tanaka Maiko , Ogata Hideko , Kojima Masako , Abe Tohru , Takeuchi Tsutomu 
Published: January 2023

Abstract
Background and Purpose: It is known that BAFF plays an important role in the pathogenesis of Sjögren’s syndrome (SS). In our previous study, we found that soluble BAFF (sBAFF) remarkably induced the production of IL-6 by peripheral SS monocytes. In the present study, we investigated a possible pathway which is involved in the transduction of signals triggered by BAFF for the production of IL-6 by monocytes. Materials and Methods: Peripheral monocytes were prepared from SS patients and normal individuals and stimulated in vitro with sBAFF in the presence of several kinase inhibitors. The production of IL-6 by the cells was measured by ELISA. Results and Discussion: The production of IL-6 by monocytes was strongly suppressed by a JAK3 inhibitor in a dose dependent manner. On the other hand, inhibitors for JAK2, JNK and p38MAPK had only marginal effects. In addition, real-time PCR analysis indicated that the expression level of JAK3 in SS monocytes was abnormally elevated upon stimulation with sBAFF as compared with normal monocytes. These data strongly suggest that JAK3 plays a pivotal role in the production of IL-6 by monocytes, and the expression of JAK3 is dysregulated in SS monocytes. Taken together, aberrant production of IL-6 by SS monocytes upon stimulation by sBAFF may be attributed to the abnormal expression of JAK3 in the cells.