bluuebunny/crossref_metadata_2025_split huggingface dataset:
Purified type III secretion system needle proteins are novel TLR agonists that induce NF-κB signaling and stimulate NLRP3-dependent IL-1β production by innate cells in vitro
Authors: Alvine Travis D , Knopick Peter L , Nilles Matthew L , Bradley David S 
Published: January 2023

Abstract
Purified type III secretion (T3S) system needle proteins from a number of Gram-negative bacteria have been identified as protective antigens as well as strong adjuvants in vivo. These proteins have been shown to act as TLR2 and TLR4 agonists, producing robust pro-inflammatory cytokine release in a MyD88-dependant manner from both human and mouse cells in vitro. Additionally, it has been established that TLR agonists alone can stimulate IL-1β through the NLRP3 inflammasome. Interestingly, we have demonstrated that T3S needle proteins induce NF-κB signaling downstream of both TLR2 and TLR4. Given the vaccine potential of T3S needle proteins, it is necessary to further understand the signaling mechanisms underlying their adjuvant properties. Here we characterized the innate signaling pathways engaged by T3S needle proteins. We show T3S needle proteins induce NF-κB signaling and pro-inflammatory cytokine release from mouse macrophages more strongly through TLR4 as compared to TLR2. Utilizing primary cells from inflammasome component knockout mice, we demonstrate that IL-1β secretion from T3S needle protein stimulated cells was dependent on the NLRP3 inflammasome, as well as caspase-1. Interestingly, pre-treatment with cytochalasin D reduced IL-1β secretion and resulted in the accumulation of intracellular pro-IL-1β after T3S needle protein stimulation; suggesting that internalization of T3S needle proteins is critical for inflammasome activation and IL-1β secretion. These findings further identify critical innate signaling pathways engaged by T3S needle proteins. T3S needle proteins have tremendous vaccine potential due to their ability to act as protective antigens and their innate immunity stimulating properties.
Scientific language communication within postgraduate Immunology education
Authors: Sika-Paotonu Dianne , Tait Carolyn 
Published: January 2023

Abstract
Language is the dominant medium through which communication occurs in tertiary education contexts. It is paramount that teachers consider the language of the classroom where learning and teaching activities occur as this is highly relevant to all students and in particular, English as Second Language (ESL) learners. The purpose of this work was to explore scientific language communication in the postgraduate learning and teaching environment for nursing, midwifery and health students undertaking Immunology classes and consider the implications for ESL learners in particular. Participant responses based on formal teaching performance and student satisfaction scores were provided by nursing, midwifery and health students in response to Immunology teaching sessions presented at postgraduate level. Formal teaching feedback from students within these postgraduate classes that included ESL students was analysed and indicated that teaching category measures for “clarity of communication” and “attitude towards students” were highly favorable. Additional feedback also indicated positive responses to in-class activities including peer-to-peer teaching and learning interactions. Student feedback includes responses including that from ESL learners and would suggest that the scientific language communication and the use of group and peer interaction activities being undertaken in this postgraduate education setting are providing support and promoting scientific language learning for all students.
Impact of antigen affinity on T cell dysfunction in solid tumors
Authors: Shakiba Mojdeh , Philip Mary , Horste Ellen , Camara Steven , Schietinger Andrea 
Published: January 2023

Abstract
Although tumor-specific T cells (TST) are found in human solid tumors, cancers progress, indicating that these T cells are dysfunctional. TSTs express high levels of inhibitory receptors and fail to execute effector functions; however, the regulatory mechanisms underlying TST dysfunction remain poorly defined. T cell mediated immune response is triggered by T cell receptor (TCR) binding to peptide-major histocompatibility (pMHC) complex on the surface of cells. The affinity of TCR:pMHC interaction is a critical determinant of T cell expansion and effector function in acute infections, where T cells with high affinity interactions generally show superior function. However, little is known about how TCR:pMHC affinity impacts T cells activation, induction of dysfunction and susceptibility to immunotherapy in progressing tumors. To elucidate this, we generated tumor cell lines expressing altered peptide ligands derived from SV40 large T antigen epitope I (Tag) and recognized by Tag-specific transgenic CD8 T cells (TCRTag) with varying functional avidity. We found that tumor-infiltrating TCRTag encountering low and high affinity tumor antigens were equally activated and expressed similar levels of inhibitory receptors, suggesting that even very weak TCR ligations can induce a typical “exhaustion” phenotype. Strikingly, while high affinity TCR:pMHC interactions led to complete loss of cytokine production, T cells with low affinity interactions remained functional, suggesting that TSTs with high affinity TCR:pMHC interactions enter a profound state of dysfunction. Future experiments will test the impact of tumor antigen affinity on the efficacy of therapeutic reprogramming, with important implications for immunotherapy.
Combinations of resveratrol, curcumin and cisplatin lower the apoptosis threshold in Jurkat cell lines.
Authors: Valenzuela Hector F , Grabauskas Titas , Chen Michelle , Ruiz Thomas , Kwak Yerin 
Published: January 2023

Abstract
Resveratrol and curcumin are natural compounds consumed for both nutritional and medicinal reasons. Resveratrol and curcumin (and corresponding analog compounds) possess potent anti-inflammatory and anti-oxidative properties. In addition, both compounds also have potent anti-proliferative effects against a number of cancer cell lines, including lymphomas. Cisplatin is a chemotherapy medication used to treat a number of cancers including lymphomas. However, cisplatin, unlike resveratrol and curcumin, have a number of harmful side effects such as neurotoxicity, nephrotoxicity, nausea and vomiting that can limit its use. The purpose of our research was to compare different combinations of resveratrol, curcumin and cisplatin as a strategy to lower the dosages of cisplatin while still inducing apoptosis on human Jurkat cells. In this study we show that inhibition of Jurkat cells is due to both inhibition of proliferation and induction of apoptosis. We used RT-PCR to also show that the down-regulation of COX-2 is also involved. These experiments support the notion that combinatory therapy is an effective strategy to treat lymphomas.
C/EBPd enables the efficient extravasation of human CCR2+ MAIT cells
Authors: Zhang Howard H , Lee Chang Hoon , Too Lily , Singh Satya , Tsang Hsinyi , Kabat Juraj , Singh Tej Pratap , Farber Joshua M 
Published: January 2023

Abstract
Early responses to pathogen challenge depend in part on recruitment of effector-capable T cells from blood. Human mucosal-associated invariant T (MAIT) cells are abundant, mostly CD8+, MR1-restricted, anti-bacterial T cells that could contribute to this response. However, little is known about these cells’ ability to traffic in inflammation. We found that, as compared with non-MAIT CD8+ T cells, human MAIT cells excelled at entering inflamed skin in mice. In flow chamber assays, MAIT cells were efficient at trafficking across activated human umbilical vein endothelial cells (HUVEC) due to high levels of selectin ligands, and chemokine receptors CCR6, and CCR2, which we showed were important for rolling, arrest, and transendothelial migration, respectively. We found that MAIT cells express high levels of the mRNAs for FUT7 and ST3GAL4, which are critical for synthesizing selectin ligands. We also found that expression of FUT7, ST3GAL4, and CCR6 depends on C/EBPd, a bZIP transcription factor that we discovered is expressed preferentially in MAIT cells and that binds to the FUT7, ST3GAL4, and CCR6 promoters. For MAIT cells, knockdown of C/EBPd decreased rolling and arrest on HUVEC and extravasation into inflamed mouse skin. Thus, CCR2+ MAIT cells display trafficking abilities that depend on chemokine receptors with non-redundant roles and the cooperative activities of C/EBPd-regulated genes - and exemplify effector-ready T cells that express a coordinated program enabling rapid entry into sites of inflammation.
The highly pathogenic Ebola and Nipah viruses hijack the host antiviral E3-ubiquitin ligase TRIM6 to enhance their own replication
Authors: Rajsbaum Ricardo , Bharaj Preeti , Atkins Colm , Luthra Priya , Wang Yao E , Dawes Brian E , Giraldo Maria Isabel , Park Arnold , Yen Benjamin C , Lee Benhur , Basler Christopher F , Freiberg Alexander N 
Published: January 2023

Abstract
The antiviral function of type-I interferons (IFN-I) requires activation of multiple signaling components, including the IκB kinase epsilon (IKKɛ). We recently reported that the E3-ubiquitin ligase TRIM6 catalyzes the synthesis of unanchored K48-linked polyubiquitin chains, which are not covalently attached to any protein, and activate IKKɛ for induction of IFN-I mediated antiviral responses. The importance of TRIM6 as an antiviral factor is highlighted by our findings that the highly pathogenic Nipah virus (NiV; Paramyxoviridae family) can inhibit IFN-I responses by targeting TRIM6. To overcome this antiviral pathway, the matrix protein of NiV promotes TRIM6 degradation, resulting in reduced levels of unanchored K48-linked polyubiquitin chains associated with IKKɛ, which in turn leads to impaired IKKɛ activation. In contrast, Ebola virus (EBOV; Filoviridae family), which antagonizes IFN-I responses via its VP35 protein, also hijacks TRIM6 to enhance its own replication, but does it primarily by directly promoting virus replication. Our data show that EBOV-VP35 is ubiquitinated by TRIM6 and promotes VP35-dependent polymerase activity. In line with these results, TRIM6-knockout cell lines and cells derived from our newly generated TRIM6−/− mouse exhibit reduced EBOV replication, even in the absence of IFN-I production. This is the first evidence indicating that TRIM6 represents a major antiviral host factor that is targeted by different viruses to promote their own replication.
Macrophage Krüppel-like factor 4 regulates response to Mycobacterium tuberculosis infection
Authors: Mazahery Claire , Chirieleison Steven , Shukla Supriya , Onwuzulike Sophia , Jain Mukesh , Boom W Henry , Abbott Derek W , Harding Clifford V 
Published: January 2023

Abstract
Krüppel-like factor 4 (KLF4) is a transcription factor that polarizes macrophages towards an anti-inflammatory (M2) phenotype, which suggests that it may regulate immune responses to Mycobacterium tuberculosis (Mtb), as immune evasion by Mtb may be due to an overabundance of anti-inflammatory mediators in response to infection. We hypothesize that myeloid KLF4 is permissive of immune evasion by Mtb, causing decreased control of Mtb infection. There are no prior in vivo data on the role of KLF4 in infection. Using mice with myeloid-specific knockout of KLF4 (LysMCre/CreKLF4fl/fl, abbreviated Mye-KO) we observed decreased Mtb CFU in macrophage cultures in vitro and in lungs of Mye-KO mice early in infection (day 14) relative to wild-type controls. However, these experiments also revealed complexities to the KLF4-Mtb relationship. Despite their improved control of early infection, at later time points Mye-KO mice developed worsened clinical disease features, such as wasting, which suggests that the loss of KLF4 results in pathologic immune state. In addition, we found discrepancy between KLF4 RNA and protein expression during Mtb infection, suggesting that KLF4 is regulated at a posttranslational level during infection. We are designing an in vitro system in which to study the molecular mechanisms of KLF4 regulation and activity in macrophages. Our data indicate that KLF4 plays an important role is regulating immune responses to Mtb with the potential to both diminish host defense mechanisms and repress host-damaging immune mechanisms.
Vaccinia virus host-range factor C7 has dual inhibitory functions in type I IFN production and signaling
Authors: YANG NING , Shuman Stewart , Deng Liang 
Published: January 2023

Abstract
Vaccinia virus C7 protein is an important host-range factor for vaccinia virus life cycle in mammalian cells. C7L homologs are present in almost all of the poxviruses that infect mammalian hosts. Type I IFN plays an important role in host defense of viral infection, and yet, the role of C7 in immune modulation of the IFN pathway is unclear. We have previously reported that the highly attenuated modified vaccinia virus Ankara (MVA) infection of conventional dendritic cells (cDCs) induces type I IFN via the cGAS/STING/TBK1/IRF3 pathway. In this study, we find that ectopic C7 expression blocks STING, TBK1, or IRF3-induced IFNB and ISRE (interferon stimulated response element) promoter activation. Murine or human macrophage cell lines that overexpress C7 have blunted innate immune responses to DNA or RNA stimuli, or the infection of DNA or RNA viruses. Overexpression of C7 also attenuates ISG gene expression induced by IFN-b treatment. MVA with deletion of C7L (MVAΔC7L) infection of cDCs induces higher levels of type I IFN than MVA. C7 blocks IFN-b-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway via preventing Stat2 phosphorylation. C7 directly interacts with stat2 as demonstrated by co-immunoprecipitation studies. Taken together, our results provide evidence that C7 has dual inhibitory roles in type I IFN production and signaling.
mMGL receptor plays an important role to macrophage activation during Trypanosoma cruzi infection
Authors: Rodriguez-Sosa Miriam , Juarez-Avelar Imelda , Vazquez-Mendoza Alicia , Rodriguez-Hernandez Mario Alberto Tonathiu 
Published: January 2023

Abstract
The C-type lectin receptor (MGL) is exclusively expressed on macrophages (MΦs) and dendritic cells (DCs), recognizes glycosylated antigens, particularly galactose (Gal) and N-acetylgalactosamine (GalNAc), that are present in tumors, fungi and viruses. However, little is known the role of MGL in the interaction with parasites. We evaluated the role of murine MGL (mMGL) in the activation and functionality of MΦs in Trypanosoma cruzi (T. cruzi) infection, a parasite that has molecules glycosylated rich in Gal and GalNAc in its membrane.
Peritoneal MΦs from C57BL/6 WT and mMGL nockout (mMGL−/−) mice were infected in vitro with epimastigotes of T. cruz,i Qro strain (10000 parasites). The percentage of infected MΦs and the number of internalized parasites/MΦs was analyzed by microcopy. Cytokines TNF-α, IL-12 and IL-10 were determine in supernatants by ELISA. The trypanocidal capacity of MΦs was determined by the incorporation of tritiated thymidine ([3H] TdR). Expression of TLR-4, TLR-2 and mannose receptor (MR) in MΦs stimulated in vitro with T. cruzi antigen was analyzed by flow cytometry.
mMGL−/− MΦs were higher infected with more parasites per MΦ and had a reduced capacity to eliminate the T. cruzi, these were associated to lower levels of TNF-α, TLR-4 and MR expression compared to WT MΦs. These results demonstrate that absence of mMGL favors susceptibility to infection with T. cruzi, suggesting a regulatory role of mMGL on the expression of other important receptors in the immune response to T. cruzi infection.
Myeloid and plasmacytoid dendritic cell subsets are differentially regulated by the pregnancy hormone human Chorionic Gonadotropin
Authors: Schumacher Anne , Sauss Karoline , Ehrentraut Stefanie , Zenclussen Ana 
Published: January 2023

Abstract
Dendritic cells (DCs) are critically involved in the establishment and maintenance of fetal tolerance. However, the precise mechanisms underlying their regulation during pregnancy are still not defined. The placenta-derived hormone human Chorionic Gonadotropin (hCG) possesses immune modulatory properties and is commonly used in artificial reproductive techniques (ART). Here, we analyzed the effect of placenta-derived hCG and two hCG preparations on different DC subsets.
After isolation from peripheral blood of non pregnant women, DCs were stimulated with LPS to induce maturation. In parallel, DCs were co-cultured with placenta-derived hCG (JEG-3 cells), with urine-derived hCG or recombinant hCG. The total number and maturation state of two myeloid DC (MDC1; MDC2) and one plasmacytoid DC subset (PDC) was evaluated. Additionally, the levels of IL-6, IL-8, IL-10, IL-12 and TNF were determined in co-culture supernatants. In all experiments, unstimulated DCs and stimulated DCs cultured alone served as controls.
JEG-3 impaired the LPS-induced increase of total MDC1 while both hCG preparations hindered the increment of total MDC1 and MDC2. Moreover, JEG-3 interfered with PDC and MDC1 maturation while both hCG preparations hampered maturation of all DC subsets. However, significant effects could only be observed on the MDC1 subset. Cytokine assays revealed that JEG-3 and both hCG preparations impaired LPS-induced secretion of all analyzed cytokines.
Our results suggest that hCG from distinct sources regulates DC subsets in a different manner. This information does not only contribute to our understanding of a differential regulation of various DC subsets during pregnancy but is also relevant for the use of hCG preparations in ART.
Simultaneous ablation of natural killer cells and mast cells leads to poor uterine vascularization that compromises fetal-well being.
Authors: Zenclussen Ana , Meyer Nicole , Schumacher Anne , Pollheimer Jürgen 
Published: January 2023

Abstract
Once pregnancy is established, uterine spiral arteries (SA) need to undergo dramatic remodeling to ensure a consistent blood supply to the fetus.
Here, we studied the single and joint participation of natural killer cells (NKs) and mast cells (MCs) in SA remodeling and pregnancy outcome and investigated the underlying mechanisms. We show that NK deficiency or their depletion arrested SA remodeling without affecting pregnancy. MC absence resulted in abnormally remodeled SAs and intrauterine growth restriction (IUGR). Combined absence of NKs and MCs dramatically affected SA remodeling, and impaired fetal growth. Despite abnormal Doppler measurements and dramatic IUGR, maternal maternal blood pressure was not affected. We found that a-chymase mast cell protease (Mcpt) 5 mediates apoptosis of uterine smooth muscle cells, a key feature of SA remodeling. Additionally, we report a previously unknown source for Mcpt5: uterine (u) NKs. We confirmed the importance of Mcpt5 by employing mice with selective deletion of Mcpt5+ cells: pregnant females presented un-remodeled SAs and growth-restricted progeny. The human a-chymase CMA1, phylogenetic homolog of Mcpt5, stimulated the ex vivo migration of human trophoblasts, a pre-requisite for SA remodeling.
Our results show that chymases secreted by uMCs and uNKs are pivotal to the vascular changes required to support pregnancy. Understanding the mechanisms underlying pregnancy-induced vascular changes is essential for developing therapeutic options against pregnancy complications associated with poor vascular remodeling.
Cutaneous commensal bacteria drive an unconventional T cell response that accelerates wound healing
Authors: Linehan Jonathan L , Belkaid Yasmine 
Published: January 2023

Abstract
Our laboratory recently demonstrated that skin-resident commensals control steady state immunity and host protective responses to cutaneous infection. However, little is known about the mechanisms by which this occurs, including which arms of the immune system are involved. S. epidermidis (S.epi), a common human skin commensal, promotes a robust Interleukin-17A+ (IL-17A+) CD8+ T cell response when applied to the skin of mice. We investigated whether these cells were restricted to MHCIa or MHCIb molecules. Surprisingly, S.epi evoked CD8+ T cells produced IL-17A in the presence of S.epi loaded KbDb−/− dendritic cells (DCs), but not H2-M3−/− DCs, indicating that these cells are restricted to the MHCIb molecule H2-M3. We previously showed that S.epi induced CD8+ T cells share many traits with skin resident memory T (TRM) cells. Strikingly, RNA-seq analysis identified a profile for IL-17A+ CD8+ T cells distinct from TRM cells, including upregulated transcripts typically associated with tissue repair. Supporting the idea that these cells may control skin physiology, we found that pre-exposure of mice with S.epi led to significant differences in the early events of wound healing, including accelerated wound closure. We believe these data are the first formal demonstration that MHCIb molecules can function to present commensal derived antigens to T cells and are direct mediators in the interaction between host and microbiota. Additionally, these results reveal a T cell response that couples antimicrobial function with tissue repair, a form of immunity not previously appreciated. These findings have important implications for our understanding of tissue immunity, wound healing, and tissue specific immune responses to the microbiota.
Differential localization of distinct CD4 T cell subsets in the female genital tract during the menstrual cycle is regulated by CCR5
Authors: Kohlmeier Alison , McMaster Sean , Li Zheng-Rong , Radzio-Basu Jessica , Haddad Lisa B , Sheth Anandi N , Cong Mian-er , Dinh Chuong , Martin Amy , Hayward Sarah L , Ofotokun Igho , Antia Rustom , Garcia-Lerma J. Gerardo , Kohlmeier Jacob E 
Published: January 2023

Abstract
CD4 T cells are essential for optimal immune responses against sexually transmitted infections, yet the composition of the CD4 T cell pool localized in the female genital tract (FGT), and the impact of the menstrual cycle on the CD4 T cell population dynamics in the FGT, remains poorly defined. Here we show the FGT CD4 T cell pool is comprised of distinct subsets of memory CD4 T cells based upon trafficking profile, anatomic regionalization, and effector responses. Based on expression of trafficking and tissue retention markers, FGT CD4 T cells are comprised of both migratory memory (TMM) and resident memory (TRM), with TMM expressing a broad array of trafficking markers that would enable their ability to perform immune surveillance in diverse tissues. Furthermore, these subsets differ in both their regionalization throughout the FGT and in their cytokine responses, notably IL-2 production. The frequency of TMM in the FGT increased during the luteal phase of the menstrual cycle and correlated with increased CCR5 expression on circulating memory CD4 T cells. Using a dual adoptive transfer mouse model, we observed that CCR5-mediated trafficking was required for the localization of memory CD4 T cells to the luminal surface of the FGT. In addition, to test cycle influence on T cell trafficking into the FGT, we administered a CCR5 antagonist to pigtail macaques at different stages of the menstrual cycle and found that inhibition of CCR5 signaling selectively reduced TMM numbers solely at luteal time points. Together, these data provide broader insight into role that distinct tissue resident CD4 T cell subsets play in barrier defenses at the FGT and also demonstrate a role for the menstrual cycle in modulating immune protection through CCR5 signaling.