bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kant et la renaissance de la métaphysique
Authors: Römer Inga 
Published: February 2023

Après des décennies durant lesquelles la thèse de la « fin de la métaphysique » semblait aller de soi, on assiste actuellement à une certaine renaissance de la métaphysique dans différents courants de la philosophie contemporaine. Ce regain d’intérêt pour le problème de la métaphysique est également présent dans les interprétations de l’œuvre de Kant. L’article résume les recherches dans ce domaine avant de développer une perspective spécifique basée sur le Preisschrift de Kant sur les progrès de la métaphysique en Allemagne depuis Leibniz et Wolff. Une première section montre comment Kant esquisse une métaphysique spéciale critique qui opère avec des objets posés par l’homme et lui permet de repenser ainsi que de transformer le monde. Une deuxième section traite de la question de savoir si cette conception kantienne peut être comprise comme une « onto-théo-logie » au sens heideggerien du terme. Une conclusion affirme que l’approche de Kant peut difficilement être qualifiée d’« onto-théo-logique », mais qu’elle introduit plutôt un type particulier de métaphysique, inscrit dans l’histoire de la métaphysique spéciale, mais fondé sur la philosophie morale – un type de métaphysique qui pourrait être intéressant dans le cadre des débats contemporains sur le problème de la métaphysique.
Enfermer en « salle détente ».
Authors: Primerano Adrien 
Published: February 2023

Depuis le début des années 2000, évolutions juridiques et recommandations de bonnes pratiques ont produit un ensemble de nouvelles normes visant la « bientraitance » en établissements médico-sociaux. Pour autant, l’usage de la contrainte n’a pas disparu des pratiques professionnelles en institution. Cet article interroge ce paradoxe apparent en cherchant à saisir les discours et usages qui entourent les espaces d’enfermement au sein d’Instituts Médico-Éducatifs (IME) accueillant des adolescent·e·s désigné·e·s autistes. L’« espace d’enfermement » désigne des pièces dont l’un des usages est d’enfermer à clef, seul, un individu. Cet usage est structuré autour de l’idée d’un bénéfice pour la personne enfermée, d’une dimension d’apprentissage et de progrès à travers un cadrage éducatif. Ces dimensions sont regroupées ici sous le vocable d’« objectif éducatif ». Pour autant, le recours à l’enfermement prend également la forme d’une épreuve de professionnalité, mettant en jeu les dimensions éthiques et morales du travail des éducateur·rice·s. Ils et elles cherchent à légitimer leurs pratiques en s’appuyant sur les psychologues et psychiatres, en réclamant une plus grande protocolisation. L’idée de « soupape » émerge enfin, dans l’enfermement, comme un usage pour rendre durable le travail émotionnel des éducateur·rice·s, comme une pratique par défaut au vu du contexte organisationnel.
The development of peripheral intraepithelial lymphocytes in vivo is influenced by microbial metabolites
Authors: Soderholm Amelia T , Beresford-Jones Benjamin , Clare Simon , Pedicord Virginia Ahn 
Published: February 2023

Abstract
Peripheral CD4+CD8αα+TCRαβ+ intraepithelial lymphocytes (pIELs) are a specialised T cell population that require the presence of intestinal microbes for their development, however the microbes and factors involved are not well characterised. pIELs are closely associated with intestinal epithelial cells (IECs) that line the gastrointestinal tract, but the contribution of IECs in shaping pIEL development is also not well defined. We investigated a number of microbial metabolites for their ability to influence pIEL development, and whether this is mediated by microbe-IEC-pIEL interactions.
In this study we utilised flow cytometry to characterise pIEL frequencies in GF mice administered with different microbial metabolites, in SPF mice from different colonies and animal facilities, and in GF mice monocolonised with potential pIEL-inducing commensal species. qPCR of IEC RNA isolated from these mice was performed to identify candidate genes expressed by IECs that may influence pIEL development.
We identified a common bacterial metabolite that partially restores pIEL development in GF mice, and a novel pIEL-inducing bacterial species. pIEL frequency of SPF mice varied between different sources, and qPCR identified IECs expressed several T-cell-influencing cytokines that correlated with pIEL frequency in vivo.
Our results identify a common microbial metabolite that contributes to pIEL development that may mediate IEC expression of T-cell-influencing cytokines. Our work further elucidates the mechanisms of host tolerance triggered by commensal microbes, which will facilitate the development of better strategies to prevent and treat intestinal infections and inflammatory diseases.
Hedgehog signaling interfaces with the Hexoseamine Biosynthetic Pathway to promote M2 polarization of mammary tumor associated macrophages
Authors: Hinshaw Dominique C , Hanna Ann , Samant Rajeev , Shevde-Samant Lalita 
Published: February 2023

Abstract
The Hedgehog (Hh) signaling pathway is aberrantly activated in breast cancer, and contributes to tumor cell survival, proliferation, and migration. The success of these events is heavily influenced by the surrounding immune microenvironment. One such cell type, macrophages (MΦ) can make up to 50% of the tumor mass. MΦs can be polarized to M1 (tumor-eradicating) or M2 (tumor-promoting), and a high M2/M1 ratio within the tumor microenvironment (TME) is correlated with worse prognosis.
We have uncovered a novel role for Hh signaling in promoting M2 polarization. We propose that the mechanism underlying this phenomenon is due to changes in the Hexoseamine Biosynthetic Pathway and consequently cellular O-GlcNAcylation. M2 MΦs have considerably higher levels of UDP-GlcNAc, the substrate for O-GlcNAcylation, compared to M1s, but the consequences of this are unknown. We hypothesize that O-GlcNAc modifications on key M2-specific proteins contribute to enhanced M2 phenotype and function within the TME, and that this phenomenon can be reversed with Hh blockade.
Methodology: mouse model of mammary carcinoma, flow cytometry, RNA-seq, metabolomics, IP.
This study is the first to elucidate Hh signaling’s role in recalibrating the metabolism of tumor-supporting MΦs. Inhibition of Hh signaling reduces MΦ O-GlcNAcylation resulting in weakened suppressive properties of M2 MΦs through the reduced activity of STAT6. Moreover, mitigating O-GlcNAcylation through Hh blockade pivots M2 MΦs to resemble M1s.
Our work provides evidence for modulating Hh activity, and consequently MΦ metabolism, to sculpt the plasticity of MΦs. This knowledge will help us to better understand how to target and diminish the pro-tumorigenic phenotypes of MΦs in the TME.
Mature neutrophils acquire a T cell suppressor phenotype in the ovarian cancer microenvironment characterized by disruption of key T cell signaling and metabolic responses
Authors: Giridharan Thejaswini , Emmons Tiffany R , Khan ANM Nazmul , Suzuki Sora , Varghese Aaron , Sullivan Meagan , Odunsi Kunle , Zsiros Emese , Yaffe Michael B , Segal Brahm H 
Published: February 2023

Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Despite being an immunogenic tumor, single-agent checkpoint inhibitor therapy in the recurrent setting has been disappointing, raising the notion of suppressive factors in the tumor microenvironment (TME) as obstacles to immunotherapy. We previously observed that neutrophils acquire a complement dependent T cell suppressor phenotype in the TME, characterized by inhibition of T cell proliferation and activation through mechanisms distinct from myeloid-derived suppressor cells. Using ascites fluid supernatants (ASC) from patients with EOC as an authentic component of the TME, we identified ASC-activated neutrophils require multiple neutrophil effector functions including NADPH oxidase activation, SNARE-mediated exocytosis and degranulation. ASC-activated neutrophils also adhered to T cells and caused trogocytosis of T cell membranes. These injury and signaling cues resulted in T cell immunoparalysis, characterized by impaired CD3/CD28 stimulated Zap70 phosphorylation, NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. We also observed that in anti-CD3/CD28 pre-activated T cells, addition of neutrophils + ASC resulted significant reduction in Zap70 phosphorylation. Our results demonstrate complement-dependent priming of neutrophils in the TME inducing a T cell non-responsiveness distinct from established checkpoint pathways and identify targets for immunotherapy. Further studies will focus on the effects of neutrophil suppressors on the TCR signaling cascade and cell stress response pathways that may enable T cell survival in response to neutrophil damage at the expense of activation.
Elucidating the role of CD91 on dendritic cells during immunosurveillance of emerging tumors
Authors: Nayak Devanshi A , Binder Robert J 
Published: February 2023

Abstract
The premise of immunosurveillance is that the immune system, particularly T cells, can detect and eliminate emerging tumor cells. However, the mechanisms that allow efficient T cell priming during nascent tumor immunosurveillance despite limited antigen availability remain unclear. Immunogenic heat shock proteins (HSPs) such as gp96 can efficiently chaperone minute levels of peptides available in nascent tumors to elicit antigen-specific immunity. In immune-competent hosts, the receptor CD91 which is expressed on antigen presenting cells (APCs) facilitates uptake and cross-presentation of these chaperoned tumor antigens. Further, engagement of CD91 on dendritic cells (DCs) initiates signals for co-stimulation and cytokine production to prime anti-tumor responses. Recent studies from our lab indicate that mice deficient in CD91 expression in DCs are more susceptible to chemically induced tumors compared to wild type mice. DCs are critical in CD91-mediated immune responses, yet the CD91+ DC subset(s) that prime robust anti-tumor T cell responses have not been elucidated. This study seeks to define the DC subset(s) necessary for CD91-mediated immune responses using mice with DC-specific CD91 deficiency. Given the dual role of CD91 on DCs in antigen transfer and co-stimulation, we examine the mechanism and consequences of CD91-mediated immunosurveillance during cancer induction. Advancing our understanding of this mechanism of immunosurveillance and the role of CD91+ DCs will have significant implications for predicting cancer incidence and therapy.
The responder/nonresponder phenomena: The immune system’s role in determining the outcome of radiation therapy in rectal cancer
Authors: Uccello Taylor Paige , Mills Bradley N. , Kintzel Sarah , Lord Edith M. , Linehan David C. , Gerber Scott A. 
Published: February 2023

Abstract
While surgical resection is a viable option to treat patients with rectal cancer (RC), it is not without significantly reducing patients’ quality of life. In an effort to delay or even prevent surgery, patients are often administered pre-operative radiation therapy (RT). Although RT can significantly reduce tumor burden in a subset of patients, there are many patients whose tumors do not respond to RT. To study this, we developed an orthotopic model of RC that recapitulates human disease in which administration of clinically relevant RT results in mice bearing tumors that demonstrate a reduction of tumor burden (responders), and a group of animals whose tumors respond poorly (nonresponders). RNA-sequencing of intratumoral immune populations identified a unique gene signature associated with each group. Tumor-associated macrophages (TAMs) from nonresponding tumors were more similar to TAMs from untreated tumors when compared to TAMs from responding tumors. Interestingly, TAMs in responding tumors upregulate pathways associated with pattern recognition receptor signaling and damage associated molecular patterns. These data suggest that TAMs from responding tumors may be polarized to respond to the immunostimulatory damage induced by RT. While TAM polarization plays a large role in promoting either an immunostimulatory or immunosuppressive microenvironment, CD8+ T cells are directly responsible for killing tumor cells. We sequenced intratumoral CD8+ T cells as well and determined that T cells from responding tumors induced pathways consistent with enhanced effector function. These data suggest that a targeted therapy aimed at the TAM:CD8+ T cell interaction may promote a stronger RT response in the nonresponding tumors.
CaMKK2 deletion increases antitumor potential through enhanced MHC-II expression in Macrophages
Authors: Perera Jonathan J , Tomaszewski William H , Polania Jessica Waibl , Racioppi Luigi , Sanchez-Perez Luis A , Gunn Michael D. , Sampson John H 
Published: February 2023

Abstract

Objective:
Glioblastoma is the most common and aggressive primary brain tumor with a 5 year prognosis of less than 5% survival. Efforts to extend this survival through therapeutic advancement have only led to modest improvements. Immunotherapy has shown promise in other cancers but only has limited effect in GBM, partially due to the dense infiltration of pro-tumor myeloid cells. Calmodulin-dependent Kinase Kinase 2 (CaMKK2) is highly expressed in myeloid cells and high expression is associated with a more severe tumor grade and worse survival in GBM. Preliminary studies show that CaMKK2 KO mice display extended median survival and tumor clearance. We hypothesize that CaMKK2 may drive myeloid cells’ pro-tumor function.

Methods:
To investigate this, immune cells were isolated from tumor-bearing CaMKK2 KO, LysMcre x CaMKK2fl/fl and CaMKK2-eGFP reporter mice. Multi-parameter flow was used to detect CaMKK2 and phenotype the tumor microenvironment (TME). The presence of CaMKK2 expressing myeloid cells in the TME was confirmed by confocal microscopy.

Results/Conclusions:
CaMKK2 is preferentially expressed in myeloid cells in naïve and tumorous mice. CaMKK2 deletion upregulated MHC-II in macrophages which is expected to promote an antitumor response. Upregulation was not seen in naive CaMKK2 KO mice suggesting it is a product of tumor-exposure. Conditional deletion of CaMKK2 in bone-marrow derived macrophages (BMDM) did not lead to this MHC-II upregulation suggesting that it is not a BMDM-intrinsic phenotype but results from CaMKK2 deletion in another cell-type. In summary, CaMKK2 deletion induced macrophages to a more immunostimulatory phenotype with expected anti-tumor effect, making CaMKK2 a promising therapeutic target for GBM.
Vaccine-elicited T cells adopt an early memory-like transcriptional phenotype distinct from infection-elicited T cells
Authors: Thompson Scott Beckett , Ivanova Daria Leonidovna , Klarquist Jared , Kedl Ross 
Published: February 2023

Abstract
Protection from pathogens relies on both humoral (antibody-mediated) and cellular (T cell-mediated) responses. While infections robustly elicit both of these types of immunity, currently approved vaccine adjuvants largely fail to induce significant T cell responses. However, recent work by our lab and others suggests that the mechanisms governing vaccine-elicited T cells (Tvac) may be substantially different than those governing infection-elicited T cells (Tinf). We have recently demonstrated that optimal subunit vaccine-elicited T cell responses rely on different cytokine signals (IL-27 and 15) and metabolic function (oxidative phosphorylation vs. aerobic glycolysis) leading to phenotypically and functionally different outcomes (memory vs. effector). Our goal was to investigate the transcriptional programming that drives Tvac formation and function from immunization to memory timepoints. Using a single-cell RNA-seq approach along with functional assays, we compared Tvac and Tinf at various time points post-immunization or infectious challenge. Our data indicate that the gene expression of Tvac markedly diverges from Tinf at early and peak time points. Remarkably, while capable of being highly proliferative, Tvac adopt a distinct transcriptional phenotype with similarities to recently identified self-renewing stem cell memory T cells, such as TCF1 expression. This transcriptional program likely enables the persistence of Tvac in substantially greater abundance at memory time points conferring overall greater protection. Taken together, our data have identified a novel transcriptional program that supports a robust vaccine-elicited T cell response with implications for future therapeutic vaccine design.
The transcription factor T cell factor 1 (TCF1) expression is elevated in vaccine-elicited CD8+ T cells and negatively regulated by T-bet
Authors: Ivanova Daria Leonidovna , Kilgore Augustus , Klarquist Jared , Kedl Ross 
Published: February 2023

Abstract
T cells that express high levels of TCF1 display stem cell-like properties and give rise to effector-like cells that protect during chronic infections and cancer. Due to their increased responsiveness to checkpoint blockade, TCF1hi T cells are now recognized as promising targets for immunotherapies. We found that adjuvanted subunit vaccine-elicited T cells (Tvac) express significantly higher levels of TCF1 than T cells responding to infections (Tinf). In exploring the underlying causes for such high expression of TCF1 in Tvac, we examined the role of sustained TCR and inflammatory mediators in Tvac TCF1 regulation. Using Nr4a3-Tocky reporter mice and pMHCI antibody blockade, we found that TCR mediated signals regulate Tvac TCF1 to a limited degree. In line with previous reports, TCF1 expression in Tvac inversely correlated with adjuvant-elicited pro-inflammatory signals, increasing concomitantly with the rapid decline of cytokines after adjuvant administration. Further, the addition of TLR9 ligand CpG increased inflammatory cytokine production as it reduced TCF1 expression. However, in contrast to previous work, anti-IL-12 or anti-IFNγ treatment failed to reverse the lower TCF1 expression induced by CpG. More surprisingly, we found that Tvac TCF1 is regulated independently of Foxo1 even while Foxo1 plays its canonical role in facilitating TCF1 expression under inflammatory conditions. Inflammation does however negatively regulate TCF1 in a T-bet dependent manner, such that T-bet KO Tvac maintained high TCF1 expression even when inflammation was increased. Our data highlight differences in the transcriptional regulation of vaccine- and infection-elicited T cells and provide insights into the mechanism of TCF1 regulation.
Co-delivery of antigens with TLR7/8 agonists leads to an improved Th1-mediated immune response to subunit vaccines.
Authors: Lathrop Stephanie K , Massena Casey J. , Davison Clara J. , Schoener Roman , Burkhart David J. , Evans Jay T. 
Published: February 2023

Abstract
When designing an effective and safe vaccine, the induction of a protective immune response to a pathogen without unacceptable levels of immunopathology is critical. The use of purified or recombinant antigens in combination with adjuvants that elicit a defined immune response is a promising strategy for eliciting a productive immune response while minimizing toxicity. Our group has developed libraries of novel toll-like receptor (TLR)7 and 8 ligands with a range of activity. Previous clinical trials have shown that the high potency of TLR7/8 adjuvants can lead to unacceptable toxicity. We hypothesized that direct conjugation of the adjuvant to the antigen will limit systemic distribution of the adjuvant, while boosting the immune response by ensuring co-delivery of antigen and adjuvant to antigen presenting cells. We demonstrate that covalent conjugation of TLR7/8 agonists to antigens results in greatly improved humoral and cell-mediated responses, without apparent systemic or local inflammation. This likely improves safety by preventing off-target immune responses from the engagement of PAMPs in the absence of appropriate antigens. When mice were immunized with an antigen/adjuvant conjugate we observed a switch towards IgG2a and away from IgG1 antigen-specific antibodies, plus greater Th1 cytokine production after restimulation of immune cells ex vivo. We hypothesize that co-delivery of a TLR7/8 agonist with antigen leads to activation of CD4+ T cells in the presence of Th1-skewing cytokines. The TLR7/8 agonist also appears to improve cross-presentation, inducing CD8+ T cells. We find this approach has great potential to enhance vaccine efficacy, while reducing potential immunopathology by TLR7/8 adjuvants.
Priming of Long-Lived Memory CD8+ T cell Responses in the Spleen During Influenza Virus Infection
Authors: Jenkins Meagan M , Bachus Holly , Botta Davide , Schultz Michael , Rosenberg Alexander , León Beatriz , Ballesteros-Tato André 
Published: February 2023

Abstract
CD8+ T cell responses to influenza virus infection are canonically known to be activated solely in the lung draining, mediastinal lymph node (mLN). Mechanistically, migratory dendritic cells (mDCs) are activated in the lungs and traffic to the mLN where they encounter cognate CD8+ T cells, initiating the heterogeneous response to influenza virus. As such, when mDCs are absent or when migration is inhibited, CD8+ T cell responses are compromised and the viral burden in the lungs increases. In contrast to the current paradigm, local priming of CD8+ T cells has been hypothesized to occur in the spleen, and mDCs are thought to die in the mLN shortly after trafficking. Therefore, how CD8+ T cells could be primed locally in the spleen has remained an unpopular hypothesis. Here we show using a mouse model of influenza infection, that mDCs not only prime CD8+ T cells in the mLN, but can also prime CD8+ T cell responses locally in the spleen. Mechanistically, we show that a portion of the mDCs trafficking to the mLN can egress the mLN, enter the blood via an S1P/S1PR dependent mechanism, and enter the spleen. CD8+ T cell responses initiated in the spleen are longer lived than mLN primed responses. Collectively, our results demonstrate a novel DC trafficking pathway and support a new paradigm for how heterogeneous T cell responses to influenza are initiated.
Cell-intrinsic MAVS promotes antigen specific CD8+ T cell proliferation and mitochondrial metabolism
Authors: Vanderheiden Abigail , Valenzuela Renan Aguliar , Verkerke Hans , Jin Fengzhi , Price Madeline , Boss Jeremy M , Grakoui Arash , Suthar Mehul S 
Published: February 2023

Abstract
Mitochondrial antiviral signaling protein (MAVS), the central adaptor protein for RIG-I like receptor (RLR) signaling, is essential for promoting innate immunity against RNA virus infections. MAVS is ubiquitously expressed, however its function in T cells is less clear. Using a mouse model of West Nile virus (WNV) infection, we find that MAVS is required in a cell-intrinsic manner for promoting antigen-specific CD8+ T cell accumulation. Through adoptive transfer experiments, we find that MAVS positively regulates cell cycle genes and promotes entry into proliferation in antigen-specific CD8+ T cells. Mechanistically, knockout of MAVS leads to dysregulated metabolic transcriptional profiles and decreased mitochondrial potential in vivo. Furthermore, we determined that CD8+ T cell receptor stimulation promotes oxidative phosphorylation in a MAVS-dependent manner to facilitate entry into proliferation. Our findings identify a non-canonical role for MAVS as a positive regulator of mitochondrial respiration and proliferation in CD8+ T cells during viral infection.