bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resilient CD8+ T cells maintain a high cytotoxic capacity by balancing ROS and energy needs via ME1 upregulation
Authors: Gicobi Joanina K , Mao Zhiming , DeFranco Grace , Li Ying , Liu Xin , Hirdler Jacob H , Vianzon Vianca , Dellacecca Emilia R , Hsu Michelle A , Barham Whitney , Kim Yohan , Abraha Feven , Harmsen William , Yan Yiyi , Dronca Roxana S , Zhu Mojun , Markovic Svetomir , Mansfield Aaron , Lin Yi , Wu Xiaosheng , Owen Dawn , Grams Michael P , Orme Jacob J , Lucien Fabrice , Zeng Hu , Park Sean S , Dong Haidong 
Published: August 2023

Abstract
Cytotoxic T lymphocytes (CTL) are indispensable in anti-tumor immunity. Although CTLs are prone to exhaustion in patients with advanced cancer, T cell resiliency explains the presence of tumor-reactive CTLs that are less exhausted, capable of cytolytic function, expansion, and rebound in response to immunotherapy to reject metastatic malignancies. However, the features of resilient T cells have not been clearly defined. In this report, we demonstrate that peripheral CX3CR1+ CD8+ T cells with low mitochondrial membrane potential rebounded CTL function quickly after radiation therapy in patients with large tumor burden portraying their functional resiliency. Furthermore, CX3CR1+ CD8+ T cell with low, but not high, mitochondrial membrane potential are highly cytotoxic, accumulate less reactive oxygen species (ROS), and express more Malic enzyme 1 (ME1). ME1 overexpression increases ATP production in a glycolysis-independent manner while concurrently curtailing excessive ROS in activated CD8+ T cells; and expands CX3CR1+NKG7+ effector CD8+ T cells with enhanced cytotoxicity. Importantly, transfection of ME1 mRNA promotes tumoricidal activity in CD8+ T cells from patients with advanced cancers. Our study reveals a mechanism used by CTLs to balance excessive ROS via ME1 to maintain a metabolic and functional resiliency. Modification of ME1 expression in CTLs may be a novel method to improve the efficacy of cancer immunotherapy by preventing T cell exhaustion.
Supported by grants from Mayo Clinic Foundation and NIH (R01CA 256927-2)
Investigation of the effect of 5’UTR on immunogenicity in coxsackievirus VP1 mRNA vaccine
Authors: Li Jiali , Liu Longding 
Published: August 2023

Abstract
Hand, foot and mouth disease (HFMD) is a group of common infectious diseases caused by various enteroviruses, which are transmitted through gastrointestinal tract, respiratory tract and contact. The mRNA vaccine is safe, effective, simple to produce and easy to promote, and has attracted much attention in recent years. Starting from the screening modification of the 5’UTR of antigen nucleic acid sequence, the mRNA translation efficiency was improved by introducing the antigen epitope cleavage processing signal through the untranslated region screening modification, and the nucleic acid vaccine design with stable translation characteristics and effective control of inflammation homeostasis was studied to provide a reference for the molecular design of future mRNA vaccines. In this study, 5’UTRs of different lengths of human β-globin origin were successfully constructed in front of the gene sequences of CA6-VP1 and CA10-VP1; the target gene sequences were transcribed in vitro with capping and tailing reactions to obtain structurally complete mRNA sequences; 293T cells were transfected and Western Blot assays were performed to find that the target genes with the modified 5’UTRs attached The mRNA was able to express the protein correctly and stably, and the protein expression was more compared with the original sequence without the modified 5’UTR. The human β-globin 5’UTR is useful for improving the translation efficiency and protein stability of the target gene mRNA. Further experimental evidence is needed to assess its induction of immune responses in vivo.
Reducing PI3Kδ signaling in a dose-dependent manner promotes human T cell stemness
Authors: Li Matthew , Rivera Guillermo Omar Rangel , Paulos Chrystal Mary 
Published: August 2023

Abstract
Adoptive T Cell Therapy (ACT) is a promising type of highly personalized immunotherapy against cancer. However, during the clinical production of T cell products for ACT, the cells experience cues that lead to early senescence and poor quality. Thus, ways to improve T cell quality for ACT is warranted. Previous mouse data indicate that inhibiting the PI3Kδ pathway in T cells using Idelalisib, an FDA-approved selective inhibitor of the δ subunit of PI3K, produces less differentiated T cells with enhanced efficacy against cancer. We hypothesized that Idelalisib treatment in human T cells would recapitulate a dose-dependent acquisition of stemness features. Mouse T cells, bulk donor human peripheral blood mononuclear cells (PBMCs), and isolated human CD3+ T cells were cultured in vitro for seven days with dose escalation of Idelalisib. We counted the number of T cells to track expansion and assessed the phenotype through flow cytometry. Reducing PI3Kδ signaling produced a less differentiated phenotype in both murine and human CD3+ T cells. Human CD3+ T cells had lower expression of TCF-1 and LEF-1, transcription factors regulating stemness, due to Idelalisib. However, other markers (CD62L and CD45RA) still suggested dose escalation up to 25 μM led to less differentiation. PBMCs and CD3+ T cells treated with dosages of Idelalisib above 10 μM had limited expansion and decreased viability compared to mouse T cells. Altogether, our data demonstrate that blocking PI3Kδ with Idelalisib in human T cells supports acquisition of stemness features.
The role of specific IL-27-producing DC subsets on the magnitude of the CD8 T cell response to subunit vaccines
Authors: Moreno Miguel Guerrero , Manalastas John J , Kedl Ross M , Klarquist Jared 
Published: August 2023

Abstract
The generation of long-lasting, adjuvant-elicited cellular immunity is a significant unmet medical need. Specifically, the use of adjuvants to induce clinically relevant CD8 T cells responses would have great utility in chronic infectious diseases and cancer. Our previous data has shown a unique requirement for T cell intrinsic IL-27 signaling in their response to adjuvanted subunit vaccination. Indeed, the magnitude of IL-27p28 production by cDC1s (CD3/B220−, CD11c+, XCR1+) actually predicts the magnitude of the CD8 T cell response generated. cDC1s are also required to present subunit vaccine-derived antigens to responding CD8+ T cells. However, whether IL-27 needs to be produced by the same cDC1s presenting antigen, or whether non-antigen presenting APCs can produce IL-27 in trans, for the maximal CD8+ T cell response to subunit vaccination is as of yet unknown. Here, we confirm that IL-27p28 is required for maximal adjuvant-elicited CD8 T cell responses. Furthermore, in mice with Il-27p28 deleted in only CD11c+ cells (IL-27p28fl/fl x CD11c-cre) the CD8 cell response to vaccination phenocopied the defective response seen in mice fully deficient in IL-27p28, EIB3, and IL-27 receptor. Interestingly, the distribution of MPECs (CD127hi) and SLECs (KLRG1hi, CD127lo) in these mice as compared to WT (C57BL/6) controls did not vary. Numerous myeloid subsets (cDC2, monocytes) as well as B cells also make IL-27. Utilizing cell-specific cre expression transgenes in conjunction with the floxed IL27p28, we have characterized the cellular requirements for IL-27 in the adjuvant elicited CD8+ T cell response.
Elucidation of regulatory mechanisms in the activation of dendritic cells by combined stimuli with PRR ligands and sulfated polysaccharide fucoidan
Authors: Miyazaki Yoshiyuki , Satoyama Toshiya , Nakano Hayato , Takeuchi Shugo , Takeuchi Hideaki , Tachikawa Daisuke 
Published: August 2023

Abstract
Fucoidan, a series of natural high-molecular weight sulfated polysaccharides derived from brown algae, has been reported to have various physiological effects such as antitumor, antiviral, and immunomodulatory activities. In a previous study, we demonstrated that fucoidan from Cladosiphon okamuranus (Okinawamozuku) was effectively activate murine macrophage-like cell line RAW264 in synergistic action with dectin-1-stimulating beta-glucan from Saccharomyces cerevisiae. In this study, we further examined their synergistic mode of action of Okinawamozuku-derived fucoidan in cooperate with pathogen stimulation in terms of dendritic cell activation. After myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC) were differentiated by culturing bone marrow cells isolated from C57BL/6J mice with Flt3 ligand, cytokine production upon stimulation with fucoidan and various pathogen components (pattern recognition receptor, PRR ligands) was measured. As the results, fucoidan alone enhanced the production of interferon (IFN)-gamma by the Flt3-L-induced mixed BMDCs, and besides, fucoidan synergistically augmented IFN-gamma production with Pam3CSK4 (bacterial TLR1/TLR2 ligand) or Poly(I:C)/LyoVec (viral RIG-I ligand). On the other hand, their IFN-alpha productions were reinforced with Poly(I:C) (viral TLR3 ligand), ODN1585 (viral TLR9 ligand) and Poly(I:C)/LyoVec, although no synergic enhancement by fucoidan was observed. These results suggested that fucoidan was extremely effective in activating dendritic cells, which play a central role in the regulation of immune function to eliminate infectious pathogens.
Supported by grants from JSPS KAKENHI (JP21K05423)
Combined IL-12, IL-15 and IL-18 activation induces epigenetic changes in human NK cells during the memory-like state transition
Authors: Tran Jennifer , Wong Pamela , Fan Changxu , Russler-Germain David , Cubitt Celia C , Marin Nancy D , Schappe Timothy , Berrien-Elliott Melissa , Wang Ting , Foltz Jennifer A , Fehniger Todd A 
Published: August 2023

Abstract
NK cells exhibit memory properties after activation with haptens, viral infection, or cytokines with each stimulus having distinct biology. Memory-like (ML) NK cells differentiate over one week after brief activation with combined IL-12/15/18, and have augmented responses upon restimulation by cytokines, activating receptor, or tumor targets. While much is known about their functional characteristics, there are large gaps in our understanding of the molecular mechanisms involved in programming conventional (c)NK cells into ML NK cells. As ML NK cells have enhanced ability to produce IFN-γ after multiple cell divisions, this suggests that the IFNG gene, and others, may be epigenetically poised. Therefore, we hypothesize that activation with IL-12/15/18 triggers epigenetic remodeling of cNK cells to ML NK cells that drives enhanced functionality. To test this, we performed ATAC-seq on baseline cNK cells, IL-12/15/18 activated NK cells, and in vitro differentiated cNK and ML NK cells after one week. Activation with IL-12/15/18 induces dramatic early epigenetic remodeling with &gt;10,000 differentially accessible regions (DARs) compared to cNK cells. Moreover, ML differentiation generates epigenetically distinct ML NK cells (&gt;1,000 DARs) compared to in vitro differentiated cNK cells, including increased IFNG locus accessibility, suggesting epigenetic mechanisms regulate their enhanced functionality. Also, ML NK cells are markedly different from IL-12/15/18 activated NK cells (&gt;15,000 DARs) suggesting not all epigenetic changes are immediately induced, and time is required for full implementation of the memory-like state. Together, this supports that ML NK cells rely on epigenetic programming for enhanced function.
Supported by grants from NIH (P50CA171963, R01CA205239, P30CA91842, 1F31GM146361-01).
Targeting S100A9 to prevent Streptococcus pneumoniae-induced allergic asthma exacerbation
Authors: Boko Mèdéton Mahoussi Michaël , de Campos Fraga-Silva Thais Fernanda , Martins Núbia Sabrina , Cipriano Ualter Guilherme , Veras Flávio Protásio , Melo Bruno Marcel Silva , Ramalho Leandra Naira Zambelli , Cunha Fernando Queiroz , Alves-Filho José Carlos , Bonato Vânia Luiza Deperon 
Published: August 2023

Abstract
The alarmin S100 calcium-binding protein A9 (S100A9) plays a role in the immunopathology of lung diseases such as asthma and pneumonia. We hypothesized that acute pneumonia induced by S. pneumoniae exacerbates asthma through S100A9 induction that increase neutrophilic inflammation and NET production. C57BL/6 Wild Type (WT) animals and mice deficient for the expression of S100A9 (S100A9−/−) were sensitized and challenged with ovalbumin (OVA) and infected or not with S. pneumoniae during the challenge. In WT mice, the comorbidity resulted in a significant increase in neutrophil recruitment in the bronchoalveolar lavage fluid (BALF) accompanied by an increased perivascular and peribronchial leukocyte infiltration, S100A9 secretion and NET production in the lungs compared to the WT mice exposed only to the allergen. During the comorbidity, S100A9−/− mice exhibited significant reduction in the levels of neutrophil chemoattractant CXCL1 and neutrophilic inflammation in the BALF as well as perivascular and peribronchial leukocyte infiltration into the lungs compared to their WT counterpart. Moreover, during the comorbidity, S100A9−/− mice showed an increase in neutrophil death. Pharmacological intervention with tasquinimod, an inhibitor of S100A9 signaling, or BB Cl-amidine, an inhibitor of NET, protected mice from neutrophilic inflammation and NET production and reduced lung inflammation during the asthma and acute pneumonia comorbidity.Our results provided evidence that S100A9 might be a therapeutic target in severe asthma triggered by S. pneumoniae infection.
Financial support: The Sao Paulo Research Foundation (FAPESP), grants 2017/21629­5 (VLDB) and 2019/09881-6 (TFCF-S), and the Brazilian National Council for Scientific and Technological Development (CNPq), grant 142139/2019-0 (MMMB).
Role of mechanosensitive Piezo1 receptor expressed on macrophage in Periodontitis
Authors: Shindo Satoru , Kumagai Tomoki , Nakamura Shin , Pastore Maria Rita , Leon Elizabeth , Huang Shengyuan , Han Xiaozhe , Kawai Toshihisa 
Published: August 2023

Abstract

Objectives
The mechanosensitive Ca2+ ion channels, Piezo1, converts the mechanical stimulus into cell signals in a variety of immune cells. However, the pathophysiological property of Piezo1 in the oral polymicrobial infectious disease of periodontitis is largely unknown. This study investigated the role of Piezo1 in the inflammatory and phagocytic reactions by RAW264.7 macrophages in response to the exposures to periodontal pathogen, P.gingivalis.

Experimental methods
Short hairpin RNA (shRNA) vector for Piezo1 or control scrambled sequence was transfected to RAW264.7 cells. Then, RAW264.7 cells were incubated for 24 hours in the presence or absence of whole P.gingivalis (MOI; 10) or outer membrane vesicles (OMVs, 1 μg/ml) isolated from P.gingivalis, w or w/o Yoda1 (synthetic Piezo1 activator), or shear stress. qPCR was used to monitor the mRNA expressions of Piezo1, TNF-α, TLR-2, and TLR-4, whereas TNF-α protein was detected by ELISA. RAW264.7’s phagocytic ability was evaluated by cytoplasm-internalization of pHrodo-labeled whole P.gingivalis or OMVs using a flow cytometer.

Results
OMVs induced more TNF-α production and phagocytosis by RAW264.7 cells than whole P.gingivalis, both of which were further upregulated by Yoda1 as well as shear stress (p&lt;0.05, ANOVA). Shear stress combined with OMV-stimulation upregulated the gene expression of TLR-4, while downregulating TLR-2 gene in RAW264.7 cells. The shRNA-targeting Piezo1 significantly suppressed the TNF-α production and internalization of OMVs by RAW264.7 cells compared control scramble shRNA (p&lt;0.05, ANOVA).

Conclusion
The present study indicated that mechanical stress may dysregulate the macrophage-mediated innate immune responses in periodontitis.

NIH NIDCR grants, DE-027851, DE-028715 and DE-029709
The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8 T cells in chronic viral infection
Authors: Marx Anna-Friederike , Pinschewer Daniel David 
Published: August 2023

Abstract
T-cell factor 1 (Tcf-1) expressing CD8 T cells exhibit stem-like self-renewing capacity rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8 T cell (CD8SL) remain poorly defined.
Studying CD8 T cell differentiation in mice with chronic viral infection we identify the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8SL as well as for virus control. IL-33 receptor-(ST2-) deficient CD8 T cells exhibit biased end-differentiation and premature loss of Tcf-1. Intriguingly, ST2-deficient CD8SL responses are restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8SL formation in chronic infection. IL-33 signals broadly augment chromatin accessibility in CD8SL and determine these cells’ re-expansion potential.
Our study identifies the IL-33 – ST2 axis as an important CD8SL-promoting pathway in the context of chronic viral infection.
Swiss National Science Foundation (grant No. 310030_185318/1) Swiss National Science Foundation (grant No. 310030_200898) Swiss National Science Foundation (grant No. 310030_185226/1) Swiss National Science Foundation (grant No. CRSII3_160772/1) DFG grant LO 1542/5-1 Willy Robert Pitzer Foundation Dr. Rolf M. Schwiete Foundation
Indol-3-Carbinol ameliorates colitis in mice by AhR-mediated production of antimicrobial peptides and mucins
Authors: Palrasu Manikandan , Kakar Khadija , Aladhami Ahmed , Carter Tayler , Wilson Kiesha Maria , Zhong Yin , Yang Xiaoming , Singh Narendra P , Busbee Philip Brandon , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: August 2023

Abstract
Indole-3-carbinol (I3C) is a dietary compound that acts as a ligand for the aryl hydrocarbon receptor (AhR), an important sensor for environmental polyaromatic chemicals and a regulator of the immune response. The pathogenesis of colitis involves multiple interactions between microbial dysbiosis, dysregulation of the host immune response, environmental factors, and host genetic profile. Indeed, studies have shown defective expression of AhR and antimicrobial peptides (AMPs) particularly defensins in inflammatory bowel disease (IBD) patients. Here, we investigated how I3C influences the production of AMPs, particularly b-defensins, through AhR and colonic microbiota composition in Anti-CD40 or dextran sulfate sodium (DSS)-induced colitis. Our analysis found that I3C attenuates colitis through AhR activation leading to increased expression of murine b-defensins (mBDs) by Colonic Epithelial Cells, resulting in the restoration of healthy gut microbiota and prevention of colonic inflammation. We analyzed the colonic expression of AMPs and mucins. Our analysis found that I3C significantly increased the mRNA expression of AhR, AMPs such as mBDs, Reg4, and mucins, when compared to vehicle-treated mice with colitis. Similarly, the mRNA levels of AhR, AMPs, and mucins were significantly increased in DSS+I3C-treated colon adenocarcinoma cells MC-38 (murine) and Caco2 (human) when compared to DSS-treated cells. To conclude, our findings demonstrate that I3C inhibits colitis primarily through AhR-mediated induction of AMPs and protective mucins, resulting in the enrichment of healthy gut microbiota (This work was supported in part by NIH grants R01ES030144, P01AT003961, P20GM103641, and R01AI123947, R01AI160896).
This work was supported in part by NIH grants R01ES030144, P01AT003961, P20GM103641, and R01AI123947, R01AI160896
Immunoresponsive Gene 1: an important regulator of autoreactive CD4+ T Cells in mouse model of multiple sclerosis
Authors: Nematullah Mohammad , Ahmed Mohammad Ejaz , Zahoor Insha , Rashid Faraz , Waters Jeffery , Ayasolla Kameshwar , Mir Sajad , Hoda Nasrul , Rattan Ramandeep , Giri Shailendra 
Published: August 2023

Abstract
Th17 and Th1 CD4 T cells play important roles in the pathophysiology of human MS and the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). As per our findings, metabolic changes in MS alter the phenotypic and functionality of immune cells, which may influence their effector activities as disease progresses. IRG1 (Immuno response gene 1), encodes for cis-aconitic acid decarboxylase in TCA cycle & enhances the manufacture of mitochondria-selective metabolite, itaconic acid from cis-aconitate, is one such gene linking metabolism to immune effector function. It modulates inflammation in myeloid cells in addition to its antibacterial activity. The relevance of IRG1 in CNS autoimmunity, however, is still unknown. We used IRG1 KO mice to know what role it plays in EAE. We observed that global IRG1 KO showed significantly worsened clinical disease severity compared to their WT at the peak of the disease (3.3+0.50 vs. 2.1+0.50, p&lt; 0.05). We found an evident early onset of disease induction & severity in the IRG1 KO as compared to the Wt (D9 vs. D13). Furthermore, to examine the mechanism of EAE pathogenesis, found a significantly higher infiltration of CD45hi cells (mainly Th17/Th1 cells) in the CNS of IRG1 KO mice compared to Wt mice. Adoptive transfer of CD45+ cells from immunized IRG1 KO augmented the disease progression in RAG1 deficient mice suggesting a possible role of IRG1 in a hyperactivated Th17 response. Also, itaconate treatment at the dose of 15mg/kg bw attenuated EAE disease relapse in SJL mice. Our findings suggest that IRG1/itaconate negatively regulates the Th17 immune response & moDCs’ function to attenuate the EAE disease progression, which may open a novel therapeutic avenue in the development of MS-related therapies.
The effect of tolerogenic PLG nanoparticles on transgenic CD8+ T cells
Authors: Neef Tobias , Miller Stephen D 
Published: August 2023

Abstract
Antigen-loaded, biodegradable PLG nanoparticles have demonstrated tolerance induction in models of autoimmune disease. Here we report on the effect of these particles on transgenic CD8+ T cells. Wild-type mice received transgenic cells, were treated with nanoparticles, and then had their spleens and/or pancreases removed for flow cytometric analysis. Relative to controls, mice treated with these particles exhibited a larger percentage of transgenic CD8+ T cells in spleens, suggesting that a sequestration of autoreactive T cells prevents their trafficking to inflamed tissues. Furthermore, nanoparticle treatment led to a higher percentage of cells with surface markers indicative of a regulatory phenotype. These results imply that altered trafficking and an expansion of regulatory T cells are two mechanisms by which PLG nanoparticles induce tolerance in CD8+ T cell - mediated autoimmune disease.
Supported by a grant from the JDRF