bluuebunny/crossref_metadata_2025_split huggingface dataset:
A paradoxical role for classical dendritic cells and Flt3 ligand in tumor immune response
Authors: Darrasse-Jeze Guillaume , Régnier Paul , Cagnard Nicolas , Podsypanina Katrina 
Published: January 2023

Abstract
Flt3 ligand (FL) induces differentiation and proliferation of classical dendritic cells (cDCs) and is a promising molecule in therapies of cancer and vaccination, but has mixed effects in clinical trials. The role of cDCs in antitumor response is ambiguous as they may induce priming of anti-tumor lymphocytes, but also may favor recruitment of tumor-protecting regulatory T cells (Tregs).
To better understand the role of FL/DCs axis in cancer, we monitored tumor growth in a mouse model of melanoma in the context of low, normal or high levels of FL. Paradoxically, both genetic FL depletion and overexpression stalled tumor growth and increased animal survival as compared to control. We show that FL-deficient mice tumor growth is predominantly controlled by the adaptive immune system unleashed by a diminution of Tregs, while high FL levels favor the innate anti-tumor response through the recruitment of NK cells. Analysis of human gene expression data confirmed the paradoxical effect of FL as well as cDCs on survival in several types of cancer. Tumor samples from patients in these groups expressed Treg and NK cells signatures in correlation with the levels of cDCs, FL, IL15 and IL15RA expression.
As a proof-of-principle, we showed that the combination of FL overexpression and Tregs depletion resulted in regression of established tumors in mice. We propose that FL is a master regulator of immune control of tumor growth owing to its key role in DCs function.
CD26 enzymatic activity modulates efficient migration of adoptively transferred cancer-specific T cells to solid tumors
Authors: Wyatt Megan M. , Bailey Stefanie , Knochelmann Hannah , Smith Aubrey S , Dwyer Connor , Rivera Guillermo O Rangel , Reyes Amalia Rivera , Nelson Michelle , Paulos Chrystal M 
Published: January 2023

Abstract
The restricted ability of adoptively transferred T cells to eradicate solid tumors limits their use in some patients. Efforts to improve ACT for solid tumors aim to identify strategies that poise T cells for migration. We have previously identified a specific subset of CD4 T cells which express high levels of the ubiquitous ectoenzyme dipeptidyl peptidase-4 (DPP-4), also known as CD26, that produce a tremendous antitumor response in solid tumors. We therefore sought to investigate the functional importance of CD26 on T cells destined for ACT. We transferred tumor specific CD26+ T cells into melanoma-bearing CD26−/− mice and blocked the CD26 enzymatic activity of the donor cells in vivo with sitagliptin, an established competitive inhibitor of CD26. Sitagliptin-treated mice eventually succumbed to tumor burden, while tumors in untreated mice were ablated, eliciting long-term cures exceeding 4 months. Additional analysis determined that tumor infiltrating donor and host T cells diminished with sitagliptin treatment. A 32-plex cytokine array of peripheral blood plasma from these mice revealed a global diminishment of cytokines and chemokines, signifying that the inflammatory response of the T cells was dampened with sitagliptin treatment. Further experiments examined how CD26+ T cells responded to tumor trafficking signals using a transwell migration assay and found that sitagliptin treatment significantly impaired their migratory capacity. However, sitagliptin did not impair the ability of T cells to mount a functional response to tumor antigen. These data reveal that the enzymatic activity of CD26 is important for the ability of T cells to migrate to malignant sites and supports an effective antitumor response.
Microbiota-derived butyrate promotes metabolism and memory potential of effector CD8+T cells
Authors: Bachem Annabell , Makhlouf Christina , Binger Katrina J , de Souza David P , Tull Dedreia , Lew Andrew M , Perdomo Carolina , Kupz Andreas , Figgett William , Mackay Fabienne , Oleshansky Moshe , Russ Brendan E , Parish Ian A , Kallies Axel , McConville Malcolm , Turner Stephen J , Gebhardt Thomas , Bedoui Sammy 
Published: January 2023

Abstract
Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation and function. Here we examined the impact of microbiota on one of the key functions of CD8+T cells, the transition to long-lived and protective memory. Antigen-activated CD8+T cells transferred into germ-free mice failed to transition into long-lived memory cells with enhanced recall capacity and had transcriptional impairments in oxidative metabolism. To the contrary, the microbiota-derived short-chain fatty acid (SCFA) butyrate promoted cellular metabolism, enhanced memory potential of activated CD8+T cells and was required for optimal recall responses upon antigen re-encounter. Mechanistic experiments revealed that the SCFA butyrate increased turnover of glycolysis and oxidative phosphorylation (OXPHOS) of effector CD8+T cells but led to a partial uncoupling of the tricarboxylic acid cycle from glycolytic input. This allowed preferential fueling of oxidative phosphorylation through short-chain fatty acids. Our findings reveal a role for the microbiota in promoting CD8+T cell long-term survival as memory cells and suggest that microbial metabolites potentially guide the metabolic rewiring of activated CD8+T cells that enables this transition.
Mechanistic mathematical representation of CD8+ T cell mediated drug-induced liver injury (DILI) Part 3: translation from mouse to human amodiaquine (AQ) response
Authors: Shoda Lisl , Battista Christina , Kenz Zackary 
Published: January 2023

AbstractIdiosyncratic DILI (iDILI) is poorly understood and costly to patients and drug developers. Some iDILI events appear immune-mediated. This work builds on DILIsym mouse modeling of CD8+ T cell mediated killing of OVA or AQ-expressing hepatocytes1,2 to develop a human representation of AQ DILI.The representation was adapted to account for human AQ exposure and endogenous T cell numbers3,4.Simulation results indicate an adult human treated with 200–700 mg AQ weekly is unlikely to present with liver injury, even if liver tolerance is broken. Simulations reflect alternate mechanisms of non-response depending on antigen levels. With low antigen, few responsive T cells of low affinity and avidity result in low level expansion without effective cytotoxicity. At high antigen levels, the emergent T cell response is dominated by dysfunctional T cells (exhaustion). However, when regulatory pathways (co-inhibition, exhaustion) are perturbed, simulated human liver injury manifests over weeks to months consistent with case reports5. Halting treatment led to simulated recovery provided sufficient liver mass remained; subsequent AQ re-challenge resulted in a more rapid ALT response, consistent with data5, mechanistically mediated by re-activation of memory T cells.Simulation results provide proof-of-concept that CD8+ T cell mediated cytotoxicity can explain human AQ DILI. Evaluation of additional compounds and the identification of testable experimental hypotheses are needed to demonstrate model utility in understanding iDILI.
PD-L1 on macrophages protects from severe collagen induced arthritis
Authors: Wood Megan Kay , Talor Monica V , Won Taejoon , Čiháková Daniela 
Published: January 2023

Abstract
Immune related adverse events linked to severe inflammatory arthritis have been identified in 10–43% of patients receiving immune checkpoint inhibitor therapy, aCTLA-4, aPD-1 and aPD-L1, indicating the importance of immune inhibitory pathways in maintaining homeostasis in the synovium. We found that immune checkpoint, PD-L1, is primarily expressed in the joint compared to other immune checkpoints. Furthermore, blocking of PD-L1 during collagen induced arthritis (CIA) resulted in more severe arthritis. Mice synovial macrophages have the highest PD-L1 expression level at homeostasis and macrophage PD-L1 expression is further increased during CIA. Similarly, in human synovial fluid, macrophages have the highest frequency of PD-L1 expression. We hypothesize that the expression of PD-L1 by macrophages is essential for synovial homeostasis and regulation of joint inflammation. We selectively deleted PD-L1 in macrophages using the cre/flox system and induced CIA analyzing disease severity using flow cytometry. LyzcrePD-L1fl/fl showed more severe CIA with a greater change in paw thickness, higher disease and histology score and a higher frequency of CD4 and CD8 T cells in the synovium. Interestingly, female LyzcrePD-L1fl/fl mice have higher arthritis severity to LyzcrePD-L1fl/fl males. This indicates the importance of sex specific PD-L1 expression by synovial macrophages during CIA. Our project has high translational potential since joint specific PD-L1 expression could be modulated for therapeutic purposes in humans with rheumatoid arthritis or check point inhibitors induced arthritis.
A novel human milk protein-derived peptide BCCY-1 exerts immunomodulatory effects on monocytes through NF-κB and MAPK signaling pathways
Authors: Cao Yan , Cai Jinyang , Li Xin , Ji Chenbo 
Published: January 2023

Abstract
Protective effects of breastfeeding in reducing childhood infection have been reported. Human breast milk contains diverse bioactive compounds with direct and indirect antimicrobial activities as well as molecules that modulate the immune system. Although some of the molecules involved in human milk’s beneficial effects on development of immune function have been studied, the role of specific milk component in immunomodulation is not yet clear. Milk protein-derived bioactive peptides have been identified with various health-promoting functions icluding immunoregulation. In the present study, we found that a peptide derived from human milk protein β-casein (BCCY-1) enhance the migration of monocytes without affecting cell proliferation and apoptosis. In addition, BCCY-1 induced the chemokine production via activition of NF-κB and MAPK signaling pathways, which could be blocked by specific inhibitors of NF-κB and MAPK. Moreover, the relative intensity of peptide BCCY-1 as well as a cluster of β-casein derived peptides comprising a fragment of BCCY-1 were decreased in the preterm breast milk compared with the term breast milk, indicating a potential role of BCCY-1 and the similar sequences under physiological condition. Identification of those peptides and their physiological functions are necessary to transfer their potent functional properties into food or potential applications in health-care. This study highlight the important role of β-casein derived peptides in the immunomodulatory effects of human breast milk and suggest a promising way to develop novel dietary supplements, foods and even pharmaceutical agents.
Trem2 Supports the Metabolic Program of Alternative Activated Macrophages
Authors: Gonzalez-Cotto Marieli , Palmieri Erika M , Baseler Walter A , Rice Christopher M , McVicar Daniel W 
Published: January 2023

Abstract
Metabolism is a key modulator of macrophage differentiation, polarization and effector responses. While M1 favors a glycolytic configuration resembling the “Warburg effect”, M2 is fueled by oxidative metabolism. Here we describe a previously unappreciated metabolic phenotype controlled by The Triggering Receptor Expressed on Myeloid Cells (TREM)-2, a key player in inflammation and innate immunity. Trem2−/− macrophages show lower TCA cycle metabolites compared to wild type, but maintenance of glycolytic intermediates. Interestingly, while we show Trem2 abrogation is beneficial in M1 and protective against MCSF withdrawal, we find Trem2−/− cells to have disrupted lipid utilization as they accumulate both long chain free fatty acids (FFA) and carnitine-conjugated lipids. Because lipid metabolism is key for M2 responses, we hypothesized that Trem2 supports a metabolic program to maintain M2 activation. Indeed, in M2 cell, Trem2 sustains mitochondrial respiratory capacity, CD36 expression and lipoprotein and FFA uptake. Lipidomics confirmed Trem2−/− M2 cells had decreased FFA and enhanced triglycerides. Moreover, Trem2−/− M2 cells show a distinct metabolic profile with enhanced glutamine utilization, suggesting compensatory mechanisms in lieu of FFA for mitochondrial respiration. Transcriptome profiling decisively shows dysregulated genes related to defense response and glycerolipid metabolism, linking the metabolic findings to effector responses. Finally, in a model of in vivo Th2 response, Trem2−/− mice failed to control infection and exhibit metabolic dysregulation. Our findings suggest Trem2 is required for reprograming of macrophages by supporting the energetic requirements for M2 function.
Lymphocyte metabolism in the islet microenvironment
Authors: Felton Jamie Lynn , Bonami Rachel , Hulbert Chrys , Conway Holly , Nelson Jen , Thomas James W 
Published: January 2023

Abstract
Type 1 diabetes (T1D) results in immune-mediated destruction of insulin-producing beta cells in the pancreas. Immune intervention to prevent or reverse T1D is an appealing therapeutic approach; however, selective targeting of autoreactive lymphocytes remains an elusive goal. Recently, cellular metabolism has emerged as a potent modulator of immune cell function. The metabolic state of lymphocytic infiltrate within the highly vascularized islet, termed insulitis, is not known. To test the hypothesis that pathogenic, islet-infiltrating lymphocytes have a distinct metabolic phenotype that has the potential to be selectively targeted, we compared the metabolic signatures of islet infiltrating lymphocytes in two transgenic mouse models. VH125SD.NOD mice develop accelerated diabetes and robust insulitis. BDC2.5.NOD develop insulitis but are protected from T1D. These models were used as examples of pathogenic and protective insulitis, respectively. Mitochondrial polarity was significantly increased in VH125SD.NOD islet-infiltrating B cells compared to BDC2.5.NOD islet-infiltrating B cells. Mitochondrial polarity was also increased in insulin-binding B cells compared to non-insulin-binding B cells in the pancreas, but not in the spleen or pancreatic lymph nodes. Assessment of hypoxia in islet-infiltrating lymphocytes revealed that the oxygen-sensing transcription factor, hypoxia-inducible factor 1α was increased in islet-infiltrating B cells specifically. Together, these findings suggest that tissue specific changes drive metabolic reprogramming at the site of autoimmune attack in the islet and that these metabolic pathways have the potential to be targeted for selective therapeutic interventions in T1D.
Thrombin fine tunes innate immune cell function
Authors: Wilkinson Hannah , Chen Daxin , Dorling Anthony 
Published: January 2023

Abstract
Thrombin is the main effector protease in the coagulation cascade. It can also signal via protease activating receptors (PAR). The presence of these receptors on the surface of innate immune cells has been well reported but the functional consequence of activation has yet to be fully defined. This study aims to investigate the role thrombin has on innate immune cell function using murine bone marrow macrophages (BMM).
In Vitro, stimulating mature MCSF-cultured BMM with thrombin did not affect gross markers of macrophage polarisation (iNOS or CD206). The stimulated cell supernatants contained increased amounts of Interferon gamma (IFNγ) but reduced IL10. Thrombin increased IFNγ receptor expression at the cell surface. Thrombin-treated cells had increased lipid rich microdomains by Cholera Toxin B staining and increased co-localisation of the LPS receptor within the lipid rafts. Compared to untreated cells, thrombin stimulated cells were highly sensitive to low dose M1 polarising stimuli, as evidenced by iNOS expression. The thrombin treated cells down regulated surface ABCA1 expression, but this was prevented by transfecting cells with siRNA against Cullin 3. This preserved ABCA1 expression and prevented the increase in lipid rich microdomains after thrombin stimulation and was associated with the loss of heightened sensitivity to low dose M1 stimuli.
Taken together this shows a clear pro inflammatory signal on the thrombin treated cells and to date the first description of ABCA1’s key role in thrombin mediated inflammatory signalling.
Subsets of thymic resident NKT cells show differential requirements for CD28 co-stimulation during antigen activation
Authors: Shissler Susannah Claire , Singh Nevil J , Webb Tonya J 
Published: January 2023

Abstract
Natural killer T (NKT) cells rapidly respond to antigenic stimulation with cytokine production and direct cytotoxicity. These innate-like characteristics arise from their differentiation into mature effector cells during thymic development. A subset of mature NKT cells remain thymic resident, but their activation and function remain poorly understood. We examined the roles of CD28 and CTLA-4 in driving activation of these thymic resident NKT cells. Unlike previous studies with peripheral NKT cells, the proliferation of thymic NKT cells was significantly impaired when CD28 engagement was blocked - but unaffected with CTLA-4 activation or blockade. Within NKT cell subsets, however, stage 3 NKT cells marked by higher NK1.1 expression were significantly more sensitive to the loss of CD28 signals compared to NK1.1 negative stage 2 NKT cells. In concordance with this, CD28 blockade suppressed all NKT cell cytokines, lowering the ratio of IFN-γ:IL-4 production by NK1.1 positive NKT cells. Intriguingly, the activation-dependent upregulation of the master transcription factor PLZF did not require CD28 co-stimulation in either NK1.1 positive or negative thymic NKT subsets – underlining a dichotomy between requirements for early activation and the subsequent proliferation and effector function of these cells. Collectively, our studies demonstrate the ability of CD28 co-stimulation to fine tune subset-specific responses by thymic resident NKT cells and contextually shape the milieu in this primary lymphoid organ.
Regulatory T cells in skin coordinate responses to epidermal injury by initiating anti-microbial immunity while delaying tissue repair
Authors: Moreau Joshua Michael , Boda Devi P , Rosenblum Michael D 
Published: January 2023

Abstract
When barrier tissues are breached, two coordinate responses need to occur: 1) clearance of pathogens and 2) repair of damaged epithelium. Regulatory T cells (Tregs) play a major role in skin barrier repair; however, the mechanisms by which they modulate local tissue are unclear. To identify molecular pathways underpinning Treg interactions with their tissue environment, we performed single cell RNA sequencing on Tregs isolated from the skin. Our analysis revealed elevated TGFβ and integrin signaling. Specifically, we found high expression of the latent TGFβ activating integrin, αvβ8. To ascertain the physiological significance of this expression we crossed Foxp3CreERT2 and Itgb8f/fmice to generate an inducible and lineage specific system for deleting Itgb8 in Tregs. Deletion of Itgb8 led to improved epidermal healing following sterile injury. Mechanistically, Treg activation of TGFβ directly induced keratinocytes to produce the myeloid chemoattractant CXCL5, leading to neutrophilic inflammation and delayed epidermal healing. We hypothesized that during barrier injury Tregs harness integrin αvβ8 to initiate innate immune responses that temporarily override tissue reparative signals. To interrogate this hypothesis we epicutaneously infected Treg Itgb8 deleted mice with the bacterial pathogen Staphylococcus aureus. Deleted mice developed an uncontrolled infection consistent with impaired immune responses. These data indicate that activation of TGFβ by skin Tregs in response to tissue injury initiates local anti-microbial immunity. Altogether, our study uncovers a unique ability of skin Tregs to leverage TGFβ signaling to coordinate epithelial repair and innate immunity for optimized tissue healing.
Cellular dynamics of immune evasion during Leishmania major infection
Authors: Zayats Romaniya , Mou Zhirong , Yazdanpanah Atta , Koh Wan , Lopez Paul , Uzonna Jude E , Murooka Thomas 
Published: January 2023

Abstract
Concomitant immunity against intracellular parasites is dictated by the immune response and parasite escape mechanisms that prevent clearance. Infection by Leishmania major generates a strong T cell response, yet parasite clearance is incomplete and leaves a small pool of persistently infected cells. T cell behaviours are augmented by the biochemical and spatial conditions of their immediate environments, and a gap in knowledge is the cellular and molecular mechanisms that prevent complete clearance of pathogen-infected cells in the skin.
We combined MP-IVM with a novel T-cell receptor transgenic mouse model, where T cells recognize the immunodominant Leishmania-glycosomal phosphoenolpyruvate carboxykinase (PEPCK) peptide, to provide insights into the spatiotemporal dynamics of anti-Leishmania T cell responses during active disease and persistent infection. We show that monocyte-derived macrophage:T cell interaction dynamics were transient at steady-state, but prolonged upon antigen recognition. PEPCK-specific T cells produced high levels of IFNg in response to peptide or infection. We also show that in vitro expanded Treg cells can suppress effector T cell functions, and that greater suppression was observed by PEPCK-specific Treg cells. Ongoing studies that address the cellular and molecular mechanisms of Treg-mediated response blunting will be presented. Intravital microscopy studies characterizing PEPCK-specific T cell migration dynamics and tissue localization within skin lesions directly in live mice will also be presented. The goal of our study is to identify barriers to overcome in order to achieve complete parasite clearance and to better describe the dynamic aspects of concomitant immunity generation.
B7H3 modulate tumor micro-environment via Th1 subset response
Authors: Lee Jun Sik , Kim Mi Eun 
Published: January 2023

Abstract
B7H3 is a new molecule that can regulate T cells-mediated immune responses. Several studies suggested a costimulatory function for B7-H3 in murine models of cancer. In contrast, clinical association of B7-H3 expression suggested a coinhibitory role. The physiological role of B7-H3 is still unclear. To investigate the B7-H3 functions on T cell activation, we used the B7-H3 peptide, B7-H3 negative and overexpressed tumor cells. To establish the T cell inhibitory gene database by B7-H3, we performed the microarray. In the results, B7-H3 inhibited the T cell proliferation and production of cytokines including IL-2 and IFN-γ. We identified the 12 significant effective genes, and confirm the mRNA expression by real-time PCR. These results suggest that B7-H3 showed the co-inhibitory role on T cell functions. And further study is needed to identify the receptor and mechanism of B7-H3 on T cell function.
IL-23 Regulates TH17 Cell Function through Activation of the Unfolded Protein Response Pathway
Authors: Yang Xuexian O , Wu Dandan , Zhang Xing , Liu Meilian 
Published: January 2023

Abstract
IL-23 plays an essential role in TH17 cell-mediated cellular immunity and inflammation. However, the detailed mechanism remains elusive. In the current study, we found IL-23 activated the unfolded protein response (UPR) and promoted TH17 cell function. IL-23 induced UPR factor XBP1s and promotes its downstream genes in TH17 cells, leading to increased expression of TH17 cell cytokines. Induction of XBP1s required IRE1 activation by IL-23; pharmaceutical blockade of IRE1 largely diminished the effects of IL-23 on induction of TH17 cell effector cytokines. Taken together, our results suggest that IL-23 promotes TH17 cell function through activation of the UPR pathway. Targeting the IL-23-UPR axis may provide therapeutic benefit for TH17 cell-driven inflammatory and autoimmune diseases.