bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel kynurenine-dependent circuit in DC1 promote IDO1 expression in DC2 leading to experimental autoimmune encephalomyelitis suppression
Authors: Gargaro Marco , Scalisi Giulia , Briseño Carlos G. , Manni Giorgia , Durai Vivek , Bagadia Prachi , Puccetti Paolo , Murphy Theresa L. , Murphy Kenneth M. , Fallarino Francesca 
Published: January 2023

Abstract
Classical dendritic cells (cDCs) are professional antigen-presenting cells that play a key role in shaping appropriate immune responses. DCs are a potent T cell activators but they are also involved in maintaining immune homeostasis and self-tolerance. DCs can be classified into three major types: pDC, DC1 and DC2. One mechanism by which DCs regulate tolerance involves indoleamine 2,3-dioxygenase 1 (IDO1) a tryptophan (Trp) metabolizing enzyme. In this study, we analyzed the ability of L-Kyn to induce tolerogenic IDO1 pathway in different DCs subsets in vitro and in vivo model of experimental autoimmune encephalomyelitis (EAE). We show that inflammatory stimuli, like LPS, was able to induce IDO1 only in DC1, but not in DC2 or pDC, when DCs were treated as isolated cultures. In contrast, when LPS was added to cultures containing all three DC subsets, LPS could also induce IDO1 expression in DC2, which acquired tolerogenic function. Induction of IDO1 in DC2 involved a novel DC1-DC2 communication pathway mediated by a Kyn-AhR-RelB axis. Kynurenine produced by DC1 activates AhR in DC2 inducing IDO1 in a RelB-dependent manner. In vitro L-Kyn treatment impaired DC2 T cells priming ability causing suppression of MOG-specific reactivity with an increment of Foxp3+ CD4+ T cells. In vivo, oral administration of L-Kyn induces functional Treg cells that suppress EAE and this effect is completely abrogated in Ahrflox/floxCD11C Cre+ mice. These data suggest that in specific microenvironments, small numbers of IDO1-expressing DC1 may spread tolerogenic activity to DC2 cells through a kynurenine-AhR axis and L-Kyn could constituting a unique endogenous molecule for therapeutic immunomodulation of inflammatory and autoimmune diseases.
Regulation of necroptotic factors in gastric cancer cells through miR-93-5p and EBV-miR-BART 18-3p.
Authors: Kim Seon Hyun , CHOI DABIN , HUR DAEYOUNG , KIM YEONGSEOK 
Published: January 2023

Abstract
Epstein-Barr virus (EBV), as well as Helicobacter pylori, has recently been admitted as an infective agent causing gastric carcinoma(GC). EBV encodes multiple non-coding RNAs during all types of latency, 44 mature miRNAs have been identified. EBV-encoded microRNAs showed that these small molecules function as post-transcriptional gene regulators and may play a role in the carcinogenesis process. MiR-BARTs produced by EBV can regulate cellular genes for preventing apoptosis and escaping the host immune system. We examined interactions of microRNAs with necroptosis factors in EBV positive/negative gastric cancer cells. RIPKs(receptor-interacting serine/threonine-protein kinase) were little expressed in EBV positive cells. Incubation of EBV negative gastric cells with EBV particles or exosome purified from EBV positive cells revealed that MLKL as a regulator of necroptosis were decreased. We investigated expression profiles for viral and cellular miRNAs in EBV positive/negative gastric cancer cells. To identify possible miRNAs targeting necrotic factors, we searched miRNA candidates that could bind to sequence in the 3′UTR of necrosis factors using an online miRNA database. We found the putative target binding sites of EBV-miR-BART18-3p (BART18-3p) within MLKL 3′UTR and miR-93-5p within RIPK3 3′UTR. Expectedly, we observed that EBV negative KATOIII transfected with mimics for BART18-3p diminished expression of p-MLKL, inhibitor for BART18-3p increased p-MLKL in EBV positive SNU719. However, mimics for miR-93-5p decreased RIPK1 rather than RIPK3 in EBV negative KATOIII. Taken together, we suggested that EBV might regulate necroptosis in gastric cancer cells through miRNAs including BART18-3p and miR-93-5p.
Non-canonical autophagy mediates immunosuppression during challenge
Authors: Martinez Jennifer 
Published: January 2023

Abstract
Autophagy is an evolutionarily conserved, catabolic pathway that lies at the intersection of homeostasis and host immune response. The autophagy machinery functions in a multitude of biological pathways, including the recycling of intracellular nutrients during starvation or stress (macroautophagy), the quality control removal of damaged proteins or organelles (aggrephagy, mitophagy), or the degradation of and host defense to extracellular threats, such as pathogens or dying cells. However, the non-canonical roles of the autophagy machinery are a critical node in the immune response to invasive pathogens, as well as prevention of autoimmunity. We have identified a form of non-canonical autophagy termed LC3-associated phagocytosis (LAP), a phenomenon in which phagosomes containing engulfed particles, including pathogens and dying cells, recruit certain elements of the autophagy pathway to facilitate phagosome maturation, digestion of cargo, and modulation of innate immunity. Importantly we have characterized Rubicon as a LAP-specific, autophagy-independent molecule, allowing the study of the unique role of LAP. We recently demonstrated that defects in LAP, but not canonical autophagy, result in a lupus-like disease with age. Using Rubicon−/− mice, we are now investigating the role of LAP in other autoimmune disease onset and progression. Our evidence clearly indicates that LAP is critical in the maintenance of immunotolerance in a variety of inflammatory diseases, including type 1 diabetes, allergic asthma, and atopic dermatitis. Mechanistically, we have begun to dissect the molecular pathways, such as metabolism, that LAP modulates in order to achieve immunosuppression.
This research was supported by the NIEHS.
The Effect of Exogenously added and Endogenously Produced Cytokines on the Regulation of Inflammatory Mediators and SOCS Proteins in Mouse Macrophages Exposed to Chlamydia muridarum Major Outer Membrane Protein
Authors: Duncan Skyla A. , Sahu Rajnish , Singh Shree R. , Dennis Vida 
Published: January 2023

Abstract
The major outer membrane protein (MOMP) of Chlamydia is a candidate for vaccine developmental efforts due to its high immunogenic potential. We previously reported that IL-10 can regulate Chlamydia inflammation by inhibiting its associated-induced inflammatory mediators possibly via induction of the Suppressor of Cytokine Signaling (SOCS) proteins. In this study, we determined the effect of exogenously added and endogenously produced cytokines on the regulation of inflammatory mediators and SOCS proteins as induced in mouse J774 macrophages exposed to C. muridarum (Cm) recombinant MOMP. Macrophages were stimulated with rMOMP (10 ug/mL) in the presence and absence of exogenous IL-10, TNF and IL-6 (each at 10 ng/mL). Cytokine and chemokine specific ELISAs revealed that exogenously added IL-6 and TNF did not alter the levels of inflammatory mediators (CCL5, CXCL10, IL-12) induced by rMOMP; whereas IL-10 downregulated all mediators. Neutralization of endogenously produced IL-6 and TNF, respectively by anti-IL-6 or anti-TNF antibodies (each at 25 μg/mL) did not significantly perturb the expression of rMOMP-induced inflammatory mediators. On the contrary, neutralization of IL-10 by an anti-IL-10 antibody increased the production of all mediators, thus confirming that IL-10 regulates Cm-induced inflammation. Removal of endogenously produced IL-10 increased SOCS1 expression, which suggest an important role of IL-10 in the regulation of SOCS1 expression to potentially control Cm-induced inflammatory responses. Collectively, our data sheds more light on the potential roles of these cytokines implicated during chlamydial infections, but more importantly, how IL-10 regulates Chlamydia inflammation via SOCS proteins.
Hrd1 protects regulatory T cells from ER stress-induced instability and dysfunction
Authors: Xu Yuanming , Cardenas Sindey Johanna Melo , Jin Hongjian , voss Jessica heinrichs , Gau Isabella , Wei Juncheng , Montauti Elena , Zhang Yusi , Gao Beixue , Mathew James , Fang Deyu 
Published: January 2023

Abstract
T regulatory cells (Treg)differentiation, maintenance, and function are controlled by the transcription factor FoxP3, which can be destabilized under inflammatory or other pathological conditions. However, the microenvironmental factors that compromise Treg identity and the underlying mechanisms remain unclear. Here, we show that ER stress destabilizes both human and mouse Treg by suppressing FoxP3 expression, suggesting a critical role of the ER stress response in maintaining Treg properties. We found that genetic deletion of Hrd1, an E3 ligase critical in suppressing the ER stress response, leads to elevated expression of ER stress-responsive genes in Treg. Importantly, mice with Treg-specific ablation of Hrd1 displayed massive multi-organ lymphocyte infiltration, body weight loss, and the development of severe small intestine inflammation with aging. At the molecular level, the deletion of Hrd1 led to upregulation of the ER stress response, in particular, the activation of the ER stress sensor IRE1. Impaired FoxP3 expression caused by Hrd1 deletion was largely rescued by an IRE1 kinase inhibitor. Taken together, these findings indicate that Hrd1 is crucial for maintaining the expression and suppressive function of Treg through suppression of the IRE1-mediated ER stress response. The study is significant because it will help to fill fundamental gaps in our knowledge of the role of Hrd1 in T regulatory cells, which will inform the design of future immunotherapies for cancer patients or immune dysregulated diseases.
Fetal naive T cells are primed for preferential regulatory T cell differentiation through increased chromatin accessibility and expression at the Helios locus.
Authors: Ng Melissa , Burt Trevor D. 
Published: January 2023

Abstract
Human fetal CD4+ naïve T cells are primed to differentiate into CD25hiFOXP3hi regulatory T (Treg) cells upon T cell receptor (TCR) stimulation without TGFβ supplementation, thus contributing to the generation of immunotolerance in the developing human fetus. In addition to expression of the lineage-determining factor FOXP3, commitment to the Treg cell fate is preceded by the acquisition of permissive epigenetic modifications at Treg-specific enhancers associated with the transcriptional control of Treg signature genes. Through ATACseq (Assay for Transposase-Accessible Chromatin Sequencing) and H3K27ac ChIPseq (Chromatin Immunoprecipitation Sequencing), we reveal that this intrinsic predisposition for Treg differentiation in fetal naïve T cells is correlated with increased chromatin accessibility and H3K27ac enrichment at 906 and 109 Treg-specific enhancers respectively. We show by RNA sequencing that fetal naïve T cells subsequently have increased transcription of the underlying Treg-associated genes such as Helios (IKZF2). Using flow cytometry, we confirmed that Helios expression is higher in fetal naïve T cells relative to adult naïve T cells. CRISPR (clustered regular interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) mediated knockdown of Helios expression in primary human fetal naïve T cells reduced induction of CD25hiFOXP3hi Treg cells in response to TCR stimulation alone, indicating that high baseline Helios expression contributes to the priming of Treg differentiation in fetal naïve T cells. Overall, a novel Treg-associated epigenome and transcriptome within fetal naïve T cells establishes preferential Treg differentiation as a mechanism to maintain immunotolerance in utero.
GDF15 and BMP4 co-regulate stress erythropoiesis cmaintain erythroid homeostasis and resolve inflammation during infection.
Authors: Fraser James William , Dey Adwitia , Nettleford Shaneice K. , Zhao Luming , Hankey-Giblin Pamela A. , Prabhu K. Sandeep , Xiong Na , Paulson Robert F. 
Published: January 2023

Abstract
Bone marrow steady state erythropoiesis maintains erythrocyte homeostasis. However, during inflammation it is unable to generate sufficient erythrocytes as pro-inflammatory cytokines inhibit medullary output. At these times extra-medullary stress erythropoiesis (SE) predominates. SE utilizes progenitors and signals that are distinct from the steady state. Using a model of sterile inflammation, we have recently shown that the inflammatory signals that suppress steady state erythropoiesis activate SE. While we have demonstrated an important role for SE in maintaining erythroid homeostasis during inflammation, the potential for SE to directly influence inflammation remains largely unexplored. We report the first study to demonstrate the importance of SE in the context of a bona fide infection using the model pathogen Citrobacter rodentium. We observed that infection rapidly induces SE in the spleen, however mice mutant for either of the two key signals (BMP4 and GDF15) that regulate SE exhibited compromised recovery following infection. Inflammation was significantly increased while FoxP3+ regulatory T-cells (Tregs) were decreased in these mice. In vitro, induction of Tregs was defective when naïve CD4+ T cells from mutant mice were used. The addition of BMP4 or GDF15 into these cultures rescued Treg induction. These data suggest a new model that includes a more extensive interplay between erythroid homeostasis and the immune response. In this model Treg induction, like the activation of SE, depends on the action of both BMP4 and GDF15. Thus, BMP4 and GDF15 may function together during the critical period immediately following inflammation to synchronously maintain both erythroid homeostasis and regulate inflammation in vivo.
Tregs orchestrate antigen specific suppression via stripping cognate peptide-MHCII from the DC surface
Authors: Akkaya Billur , Akkaya Munir , Oya Yoshihiro , Al Souz Jafar A. , Holstein Amanda H. , Kamenyeva Olena , Kabat Juraj , Dorward Dave , Glass Deborah D. , Shevach Ethan M. 
Published: January 2023

Abstract
Tregs are professional suppressors of the immune response, yet their mechanism of action in vivo remains unclear. We compared the morphology and stoichiometry of the interactions of activated 5CC7 T cells and 5CC7 iTregs with MCC88–103 pulsed splenic DCs by electron and confocal microscopy. Image analyses revealed that Tregs interacting with DC displayed a distinct morphology with finger like membrane projections at the DC binding site and uropods at the rear end within three hours of in vitro culture. In contrast, activated T cells maintained their round morphology. Tregs occupied a greater extent of the DC surface than activated T cells consistent with a higher binding avidity. Dynamic intravital two-photon microscopy of adoptively transferred OTII iTregs and activated OTII cells demonstrated that Treg displayed a greater volume and duration of contact with OVA323–339 pulsed DC compared to that of activated OTII cells. Subsequent to their high avidity interactions with DC, 5CC7 iTregs captured MCC88–103-I-Ek complexes from DC surface reducing the amount of MCC presented on DC. Reduced antigen presentation was not due to global suppression of the DC’s ability to present antigen as 5CC7 and 3A9 iTregs only captured their cognate peptide-MHCII from MCC/HEL double pulsed DC, reducing the DC presentation in an antigen specific manner. When double pulsed DCs were cultured with iTregs specific for one peptide, separated from the iTregs, the DC failed to prime T cells specific for the antigen seen by the iTreg, but primed T cells specific for the second antigen. Altogether, we propose antigen specific depletion of peptide-MHCII complexes as a new mechanism for Treg-mediated suppression.
Subset-specific neurotransmitter receptor expression tunes T cell activation
Authors: Rosenberg Kenneth M. , Singh Nevil J. 
Published: January 2023

Abstract
T cells continually patrol and invade other tissues and are exposed to varying tissue-specific cues. Different tissues are typically innervated by neurons using characteristic neurotransmitters. Therefore, encounter with particular neurotransmitters has the potential to influence the tissue-specific behavior of T cells. Although neurons utilize a complex array of over 180 neurotransmitter receptor (NR) genes, we find that murine T cells in total express only a limited set (26 detected) of them. Furthermore, the expression is T cell subset-specific suggesting distinct functional roles. Several receptors, including Adrb2, Gabrr2, and Chrnb2, are most highly expressed in naïve CD4 T cells while CD8 T cells specifically express the glutamate receptor Gria3 and have high expression of the cannabinoid receptor Cnr2. Within the CD4 population, memory T cells upregulate Hrh4 and P2ry1 while the VIP receptor Vipr1 is uniquely absent from regulatory T cells. In order to understand how these distinct patterns affect immune responses, we are analyzing the functional impact of signaling T cells through them. Importantly, NR signaling pathways considerably overlap with T cell receptor (TCR) signaling pathways. Accordingly, preliminary data shows that a competing signal from NR receptors such as the β2 adrenergic, histamine H2, and VPAC1 (VIP) receptors dampens direct T cell activation through the CD3 complex. Determining how T cells integrate the complex contextual information they encounter in vivo guides our understanding of T cell decision making and will allow for the development of more targeted therapeutics.
CD11bhigh CD11clow Ialow DCs regulate T-cells activation in the experimental autoimmune uveitis
Authors: Lin Wei , Wang Xin , Fan Zhichao 
Published: January 2023

Abstract
Uveitis is a serious inflammatory disease that can cause visual disability and blindness. Uveitogenic antigen-specific CD4+ T cells which secrete IFN-γ or IL-17, are believed to be crucial effector cells to infiltrate in the sites of inflammatory eyes to drive inflammation and tissue damage. Recently, dendritic cells (DCs) act as unique antigen presenting cells, are reported to involve into the pathogenic process of uveitis. Regulating the status of DCs could prevent the generation of Ag-specific Th1 and Th17 cells to attenuated EAU. Herein, in a mouse model of experimental autoimmune uveitis (EAU), we found CD11bhighCD11chighIahigh DCs increased at the inflammation stage of EAU, while CD11bhighCD11clowIalowDCs, a regulatory DCs subset, increased at the recovery stage. CD11bhighCD11chighIahigh DCs expressed high level of CD80, CD86 and CD54 to promote T cells secreting IFN-γ, While CD11bhighCD11clowIalowDCs promote T cells to express high level of CTLA-4 and to be CD4+CD25+FoxP3+ T cells. Furthermore, CD11bhighCD11clowIalowDCs were found to form a regulatory immunological synapse with T cells, and CTLA-4 localized at the contact of DC-T to prevent the localization of TCR signaling molecules and the localization of calcium microdomains at the contact of DC-T to inhibit T-cell activation. However, CD11bhighCD11chighIahigh DCs promote the accumulation of TCR signaling molecules in the IS and calcium releasing in T cells. Transferring CD11bhighCD11clowIalowDCs into EAU could relive the symptom of EAU and decrease Ag-specific T cells in EAU. Overall, CD11bhighCD11clowIalowDCs could suppress T-cells activation by forming a regulatory synapse to decrease calcium releasing in T cells to prevent the development of EAU.
Glutamate receptors provide costimulatory signals to improve T cell immune response.
Authors: Shanker Anil , de Aquino Maria Teresa P. , Hodo Thomas , Uzhachenko Roman 
Published: January 2023

Abstract
The interaction between the nervous system and immune system has sparked interest in recent years. Emerging evidence shows an intricate neuro-immune network. Studies revealed that neurotransmitters can trigger immune cell responses such as cytokine secretion, integrin expression, and chemotaxis. We were intrigued by the expression of various neurotransmitter receptors on mouse T lymphocytes. Specifically, following TCR stimulation, glutamate receptors (GluR) were significantly upregulated on both CD4+ and CD8+T cells, with a peak at 48 h. Concomitant with the upregulation of activation molecules CD69, CD25 and CD44, proliferating CD8+T cells presented higher levels of GluR3 and GluR1 when compared with non-proliferating cells, as well as a higher production of IFN-g and granzyme B. Based on the augmentation of GluR expression upon T cell activation, we evaluated the role of GluR signaling in modulating T cells in orthotopic mammary tumors that express a low avidity epitope of a model antigen hemagglutinin (4T1HA). We found that HA-reactive CD8+ T cells in the tumor-infiltrate had an upregulated expression of GluR3 and GluR1 when compared with control group. The blockade of GluR signaling down-regulated expression of CD69 and CD25, impaired T cell proliferation, and interfered with their cytolytic activity. Early TCR-activation pathways such as Lck/Akt as well as calcium signaling were affected by GluR antagonists, suggesting their signaling interaction. Overall, data suggest that glutamate receptors may have costimulatory effects on T cell activation and glutamate agonists may boost T cell response in an immunosuppressive setting such as cancer.
Role of the CD27/CD70 pathway in regulatory T cell function
Authors: Bowakim Natalia , Acolty Valérie , Dhainaut Maxime , Yagita Hideo , Oldenhove Guillaume , Leo Oberdan , Moser Muriel 
Published: January 2023

Abstract
There is evidence that the CD27/CD70 pathway plays a major role in the regulation of immunity versus tolerance in vivo. In particular, the transgenic expression of CD70 by dendritic cells breaks tolerance and induces a lethal autoimmune disorder.
Although CD27 engagement on conventional T cells (Tconv) has been shown to induce Th1-type responses, the role of CD27, expressed at higher levels on regulatory T cells (Treg), remains elusive. Recent data from our laboratory have shown that CD27 expressed on Tregs was involved in the inhibition of CD70, suggesting that CD27 may display opposite functions, i.e. pro- or anti-inflammatory when expressed on Tconv and Treg, respectively.
The objective of this work was therefore to decipher the role of CD27 on Treg function.
Our data show that (i) injection of agonistic anti-CD27 mAb increased the development and function of Tregs, as assessed by increased proliferation and upregulation of hallmarks of Treg activation such as ICOS, GATA-3, Helios, and inhibitory molecules such as CTLA-4, PD-1 ; (ii) similarly, Tregs were activated in mice expressing CD70 in a constitutive manner (WT x CD70tg mice); (iii) CD27+ Tregs from WT mice were more activated and displayed higher suppressive capacity than CD27− Tregs.
These observations suggest that the CD27/CD70 pathway potentiates the homeostasis and inhibitory function of Tregs. Experiments are under way to identify the transcriptomic profile induced by CD27 engagement in Tregs and to analyze their function in various settings in vivo, using a CD27fl/fl mouse to selectively delete CD27 in Tregs.