bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secondary damage or viral infection following mild traumatic brain injury impedes tissue repair induced by distinct myeloid cell subsets
Authors: Russo Matthew V. , McGavern Dorian B. 
Published: January 2023

Abstract
Mild traumatic brain injury (mTBI) causes severe meningeal cell death and vascular injury, leading to a robust peripheral immune response featuring neutrophils and monocytes/macrophages. Complications such as repetitive head injuries or viral infections following mTBI have the potential to significantly alter the immune response and impact wound repair. Using a closed-skull compression model of mTBI, we found that meningeal vasculature can regenerate within 7 days of injury, coinciding with a dynamic, bifurcated myeloid cell response. Macrophages derived from inflammatory monocytes scavenged dead cells while non-classical monocyte-derived macrophages promoted angiogenesis. The CD206+ angiogenic macrophages were positioned around the lesion perimeter where they aided in fibrinogen clearance and matrix remodeling. A peripheral infection by lymphocytic choriomeningitis virus (LCMV) during peak vascular damage delayed wound repair and promoted a significant meningeal CD8+ T cell response. The infected environment also shifted the myeloid cells to a more inflammatory state, reducing the amount of CD206+ macrophages around the lesion. Interestingly, we found that a secondary injury also interrupted wound repair only when experienced during the acute “inflammatory” but not the “wound-healing” phase. In fact, the mTBI lesion and infiltrating macrophages were resistant to further damage when reinjured during the wound-healing phase. Our findings demonstrate that meningeal vasculature can undergo robust regeneration following mTBI orchestrated by distinct myeloid cell populations. However, this wound repair process can be significantly disrupted by both sterile and viral insults following the initial injury.
CD5 expression influences T cell metabolism and mice behavior
Authors: Freitas Claudia T. , Cox Tyler , Johnson Deborah , Weber K. Scott 
Published: January 2023

Abstract
T cells are key players in the adaptive immune response and undergo metabolic changes upon activation. CD5 is a co-receptor found on T cells and plays a significant role in regulating T cell thymic development, intracellular signaling and cytokine production. Previous studies have found that naïve T cells with high CD5 expression (CD5hi) have increased TCR signal strength and enhances immune response to foreign peptide in the periphery. Additionally, we have reported that CD5hi naïve T cells have higher calcium mobilization and improved T cell activation compared to CD5lo T cells. Calcium influx levels can modulate and influence metabolic changes in T cells. Thus, we hypothesized that CD5hi, CD5lo and CD5 deficient T cells have different bioenergetic demands that affect metabolic pathways and T cell activation. We evaluated the effects of CD5 levels on metabolism using CD5 deficient mice vs wild type controls and found CD5 deficient T cells had significant differences in metabolic function. Recently published work has described a connection between increased T cell metabolism and altered cognitive function in PD-1 deficient mice. We have also found significant differences between CD5 deficient and wild type mice in marble burying rates, elevated plus and water maze behavior and open field activity. These behavioral test results suggest CD5 deficient mice have altered cognitive function and higher levels of anxiety. Thus, CD5 deficiency alters T cell metabolic and cognitive function.
The Mechanosensitive Ion Channel, Transient Receptor Potential Vanilloid 4 (TRPV4) in Macrophages Regulates the Host Defense Response to Bacterial Pneumonia
Authors: Scheraga Rachel Greenberg , Abraham Susamma , Grove Lisa M. , Southern Brian D. , Crish James , Lumpkin Timothy Brian , Hamilton Thomas A. , McDonald Christine , Olman Mitchell A. 
Published: January 2023

Abstract
Macrophage phagocytosis and cytokine production are sensitive to the surrounding matrix and thereby mediate host defense and lung tissue injury. The consequences and mechanism of this matrix sensitivity are unknown. We have determined that the mechanosensitive channel, TRPV4, responds to extracellular matrix biophysical properties and thereby modulates the macrophage response to pathogens. We undertook this study to determine the in vivo consequences and the intracellular signaling pathway by which TRPV4 modulates macrophage responses. In order to evaluate the role of TRPV4 in chronic pneumonia/lung injury, WT and TRPV4 KO mice were administered agarose bead embedded-Pseudomonas aeruginosa. Loss of TRPV4 led to decreased phagocytosis by macrophages (6-fold), and increased lung injury as measured by inflammatory cell infiltration (≥ 80 ± 3%), vascular permeability (total protein ≥ 63 ± 6%), and cytokine secretion (IL-1β ≥ 71 ± 4%). In vivo, lung alveolar macrophages predominantly expressed TRPV4 and were the key phagocytic cell, as assessed by FACS and immunofluorescence. Known LPS signaling pathways were investigated in vitro. Loss of TRPV4 abrogates LPS-induced p38 activation and phagocytosis of E. coli particles. Additionally, loss of TRPV4 increased basal pro-/active IL-1β expression (2-fold), thereby enhancing IL-1β secretion independent of caspase 1 cleavage and blockade. These findings demonstrate that TRPV4 is important for bacterial clearance, lung injury and cytokine production in macrophages. TRPV4 mediates these effects through p38 and through upregulation of IL-1β protein expression in an inflammasome-independent manner. The results implicate macrophage TRPV4 as a key component of the host defense.
Heatr9 is upregulated during influenza virus infection in lung alveolar epithelial cells
Authors: Stairiker Christopher , Mueller Yvonne , van Meurs Marjan , Brouwers-Haspels Inge , Erkeland Stefan , Katsikis Peter D. 
Published: January 2023

Abstract
Influenza virus infection poses a serious threat to public health. Influenza virus infects lung alveolar epithelial cells in the respiratory tract and utilizes them to produce more virus, spreading the infection. Understanding genes that are dynamically regulated during influenza virus infection may help elucidate essential genes and pathways that affect influenza virus infection. We examined by RNAseq the in vivo gene expression profiles of alveolar epithelial cells sorted from A/Puerto Rico/8/1934-GFP (PR8-GFP) expressing influenza virus infected mice. We identified a novel influenza virus-induced gene, Heatr9 (also known as Gm11435), that was upregulated by &gt;200-fold in vivo in mouse alveolar epithelial cells. The upregulation of Heatr9 by influenza virus was further confirmed in vitro in PR8-GFP influenza virus infected human lung A549 cells. In vivo Heatr9 upregulation was found to be an indirect effect of influenza virus infection as bystander alveolar epithelial cells in lungs exhibited similar levels of Heatr9 induction as directly infected cells. Furthermore, supernatants of influenza virus infected A549 cells were capable of potently inducing Heatr9 mRNA even in the absence of infection. To identify factors that upregulate Heatr9 we examined the effect of cytokines on Heatr9 expression in vitro. Heatr9 expression was not induced by type I IFN, TNFα, and IL-1β alone in A549 cell, however when used in combination IFNβ and TNFα or IFNβ and IL-1β potently induced Heatr9 mRNA. Currently, we are generating Heatr9 deficient cell lines to examine the function of this gene in infection. In summary, we have identified Heatr9 as a cytokine-induced gene during influenza virus infection, the function of which has a yet to be determined.
Effect of the blocking by monoclonal antibodies of TLR2 and CD14 receptors on the expression of intracellular signaling molecules and the production of cytokines in THP-1 macrophages infected with Mycobacterium tuberculosis
Authors: Mendoca Alma Yolanda Arce , Rosas-Taraco Adrian Geovanni , Rodriguez Victor Garcia , Zapata Edgar Ivan Montes , Flores Alberto Yairh Limon 
Published: January 2023

Abstract

INTRODUCTION
There are several reports that indicate the importance of TLR2 and CD14 in the response against Mycobacterium tuberculosis since they activate the cascade of intracellular signaling and the production of inflammatory cytokines necessary for the infiltration of neutrophils and macrophages in the focus of the infection, however it can remain the live bacillus inside the granuloma.

MATERIAL AND METHODS
In this study, monoclonal antibodies (mAbs) against TLR2 and CD14 were used to block these receptors in the macrophages of the THP-1 cell line infected with Mycobacterium tuberculosis. Molecules of the intracellular signaling cascade were measured: MYD88 and TRAF6 and the transcription factor NFKB by RT-PCR, preinflammatory and anti-inflammatory cytosines by ELISA, also CFU and nitric oxide were measured.

RESULTS
An increase in the expression of Myd88, TRAF6 and NFKB was found; a decrease in CFU, increased production of TNF-α and INF-γ and low production of nitric oxide.

CONCLUSION
The results suggest that the mechanisms of intracellular signaling were modified by helping macrophages kill the intracellular bacillus, so we suggest that the use of these mAbs as an immunotherapy that together with the antimicrobial can help to resolve the infection in the patients with tuberculosis. Blockade of TLR2 and CD14 favored the expression of MyD88, TRAF6 and NFkB. Cytosine was also produced, such as TNF-α, which helps the confinement of bacilli in the granuloma and INF-γ, which probably also helped the intracellular death of Mycobacterium tuberculosis.
FOXP3 protects human T cells from restimulation-induced cell death via CD48 upregulation and autophagy
Authors: Voss Kelsey , Dalgard Clifton , Arjunaraja Swadhinya , Dorjbal Batsukh , Snow Andrew L. 
Published: January 2023

Abstract
The adaptive immune response relies on specific apoptosis programs to regulate effector T cell expansion and maintain homeostasis. Restimulation-induced cell death (RICD) is an apoptotic pathway triggered by repeated stimulation through the T cell receptor (TCR), which ensures that effector T cell proliferation remains in check. Constitutive fork head box P3 (FOXP3) expression renders regulatory T cells (Tregs) resistant to RICD. Although FOXP3 is also expressed transiently in human conventional T cells (Tcons) during initial rounds of activation-induced proliferation, its function in this context remains unclear. Here we describe a novel role for FOXP3 in protecting both CD4+ and CD8+ human Tcons from premature RICD during the expansion phase. SiRNA-mediated silencing of FOXP3 sensitized early effector Tcons to RICD, and was dependent on de novo transcription. RNA-Seq analysis revealed FOXP3-dependent effects on genes involved in metabolic pathways, autophagy, and cell surface receptors. FOXP3 silencing increased glycolysis and reduced autophagy in Tcons, which has been linked to changes in apoptosis sensitivity. Indeed, blocking autophagy increased RICD in control Tcons without augmenting death of FOXP3-silenced cells, suggesting FOXP3 reduces RICD sensitivity through an autophagy-dependent mechanism. Additionally, FOXP3 knockdown markedly reduced expression of CD48, a SLAM-family receptor. We now show that CD48 protects expanding Tcons from RICD. Surprisingly, CD48 also promoted protective autophagy, illuminating a novel connection between SLAM receptor signaling, autophagy regulation, and RICD sensitivity that is governed by FOXP3 expression in early Tcons.
The cytoplasmic domain of CTLA-4 inhibits effector T cell responses and autoimmunity via increasing regulatory T cells in mice
Authors: Lim Sangho , Lee Hong-Gyun , Kim Gil-Ran , Choi Je-Min 
Published: January 2023

Abstract
Recently, a critical role of CTLA-4 in a regulatory T cell (Treg) function has been highlighted both in peripheral and follicular regulatory T cells. However, the importance of cytoplasmic domain CTLA-4 signaling in Treg function and differentiation is not clearly understood. In this study, we utilized a recombinant extracellular domain (CTLA-4-Ig) and cytoplasmic domain of CTLA-4 (dNP2-ctCTLA-4) to elucidate the mechanism of CTLA-4 in Tregs. We found dNP2-ctCTLA-4 increased follicular regulatory T (Tfr) cells in draining lymph node (dLN), accompanying by decreased level of follicular helper T (Tfh) cells and germinal center (GC) B cells, while CTLA-4-Ig only reduced Tfh cells and GC B cells without affects on Tfr cells. In addition, dNP2-ctCTLA-4 induces Foxp3 positive regulatory T cells in Th17 and Th1 conditions with TGF-β, while CTLA-4-Ig inhibited effector cytokine productions without affecting Foxp3 levels. One of the molecular mechanism of dNP2-ctCTLA-4 in Foxp3 expression would be inhibition of Jak2/STAT3 pathway via binding to Jak2 which inhibits Th17. In addition, TGF-β signaling was enhanced by it via inhibition of phosphorylation on Erk and Smad2 linker region to results increasing Foxp3 expression in T cells. These results suggest that the cytoplasmic domain CTLA-4 signaling would be critical to support immune homeostatic environments in dLN via enhancing Foxp3 expression in T cells.
TRAF6-TAK1 signaling drives Th9 differentiation
Authors: Park Sang A. , Nakatsukasa Hiroko , Chen WanJun 
Published: January 2023

Abstract
Naive CD4+ T cells differentiate into different subsets depending upon milieu of cytokine exposure. Interleukin-9 (IL-9)-producing CD4+ helper T cells (Th9 cells) are induced from naive CD4+ T cells by transforming growth factor-β (TGF-β) together with interleukin-4 (IL-4) during stimulation of the T cell antigen receptor (TCR) in vitro. The master regulator of Th9 cells as well as the molecular mechanisms by which TGF-β signals and IL-4 signals co-operatively drive the differentiation of Th9 cells are not fully understood.
Previously, our group has reported that inhibitor of DNA-binding 3 (Id3), a transcription factor which inhibits DNA-binding of basic helix-loop-helix protein, such as E2A, controls the TGF-β-mediated differentiation of Th9 cells. We found that this process required activation of the kinase transforming growth factor beta-activated kinase 1 (TAK1). In addition, RNA-seq revealed that tumor necrosis factor receptor-associated factor 6 (TRAF6) was highly up-regulated by TGF-β together with IL-4 in CD4+ T cells. Since TRAF6 is one of the TAK-1 activator, we hypothesized TRAF6 is also involved in the differentiation of Th9 cells. We found that the expression and ubiquitination of TRAF6 was upregulated under the Th9 differentiation condition and it resulted in activation of TAK1. These regulations were attenuated both in TGF-β and Smad3 deficient mice, suggesting TRAF6-TAK1 signaling is involved in TGF-β-mediated Th9 differentiation.
Bcl6 interacting corepressor contributes to CD4+ T helper 17 cell formation by repressing CD27 and Foxo1 signaling
Authors: Kotov Jessica Amy , Gearhart Micah D. , Bardwell Vivian J. , Jenkins Marc K. 
Published: January 2023

Abstract
CD4+ T helper 17 (Th17) cells protect against pathogens at mucosal barriers by secreting cytokines that drive clearance of the pathogen by neutrophils. We found that Bcl6 interacting corepressor (BCOR) drives Th17 cell formation after Streptococcus pyogenes infection and was required for optimal expression of IL-17A and CCR6. RNA and chromatin immunoprecipitation sequencing revealed that BCOR enhances Th17 differentiation by directly repressing genes that negatively regulate Th17 cells, including genes related to the CD27 and Foxo1 signaling pathways. We have also found that Streptococcus infection generates a novel BCOR-driven Tfh-Th17 hybrid population, which may provide unique B cell help during mucosal infections. This work provides insight into a novel mechanism that enhances Th17 differentiation and function, which may be informative for the design of T cell based vaccines against extracellular pathogens at mucosal barriers.
STAYING ALIVE! SIGNAL PROCESSING BY NF-κB PROTECTS NKT CELLS FROM TNFR1-TRIGGERED DEATH
Authors: Kumar Amrendra , Gordy Laura E. , Bezbradica Jelena S. , Stanic Aleksandar K. , Hill Timothy M. , Boothby Mark R. , Van Kaer Luc , Joyce Sebastian 
Published: January 2023

Abstract
A unique ontogenetic program controls the thymic development of type I nature killer T (NKT) cells. For example, signal integration by NF-κB plays a critical role in NKT cell development such that RelA and RelB play cell intrinsic and cell extrinsic roles, respectively. The key cell extrinsic role played by NF-κB seems to be the induction of IL-15 production that is required for the development and homeostasis of NKT cells. On the other hand, cell intrinsic NF-κB activity is essential for the development of both NK1.1neg and NK1.1pos NKT cells. We have demonstrated that NKT cells in mice expressing a dominant negative mutant IκBDNtg that prevents NF-κB activation were arrested at a very early stage of their development. Importantly, introgression of Bcl-xL-coding Bcl2l1 transgene into IκBDNtg mice lead to the development of NK1.1pos NKT cells. Further investigations revealed that NKT cell intrinsic NF-κB activation was required to protect developing NKT cells from tumor necrosis factor (TNF) receptor 1-induced cell death and not from Fas/FasL- or NKT T cell receptor-induced apoptosis. Consistent with this finding, we found that TNF-α induces the activation of caspase 8- and 9-mediated apoptosis in NKT cells in which NF-κB activation was blocked. Thus, akin to hepatocytes and some cancer cells, TNF-α induces both cell intrinsic (caspase 8-mediated) and cell extrinsic (caspase 9-mediated) apototic pathways in developing NKT cells that are offset by the activation of NF-κB and the expression of one of its target gene, Bcl2l1.
LSD1 regulates PD-1 expression through interactions with Blimp-1 during acute viral infection
Authors: Neeld Dennis Kyle , Bally Alexander , Majumder Parimal , Barwick Benjamin , Boss Jeremy M. 
Published: January 2023

Abstract
During prolonged exposure to antigens, such as during chronic viral infections, sustained T cell receptor (TCR) signaling via cognate peptide: MHC interactions results in T cell exhaustion mediated in part by the expression of Programmed cell death protein 1 (PD-1). PD-1 blockade has been implemented in the clinical setting as a promising treatment for several different forms of cancer and therefore obtaining a complete understanding of the epigenetic mechanisms that regulate PD-1 is of great value to improving existing therapies. Here, we demonstrate that CD8 positive T cells lacking lysine-specific histone demethylase 1A (LSD1) expressed approximately 2-fold higher levels of PD-1 mRNA following TCR stimulation. Antigen specific CD8 T cells lacking LSD1 also showed increased surface levels of PD-1 during acute infection with LCMV but not during chronic infection. Molecular analysis revealed that Blimp-1, a known repressor of PD-1, recruits LSD1 for silencing. Although Blimp-1 is able to bind the PD-1 locus during both acute and chronic LCMV infection, it fails to recruit LSD1 in the chronic setting. LSD1 is responsible for removing activating histone modifications H3K4me1 and H3K4me2 and our results show that these marks are removed from the PD-1 locus only during acute infection. During viral infection, loss of DNA methylation is associated with with PD-1 expression. Examination of the PD-1 locus during acute infection revealed that LSD1 null CD8 T cells had less methylation compared to cells expressing LSD1 further demonstrating the role of LSD1 in regulating PD-1 expression. Taken together, these results demonstrate LSD1 downregulates PD-1 by interactions with Blimp-1.
A transient Malt1 aggresome sustains T cell receptor signaling to NF-κB
Authors: Traver Maria K. , Campanello Leonard , Huaman Celeste , Paul Suman , Shroff Hari , Losert Wolfgang , Schaefer Brian C. 
Published: January 2023

Abstract
The T cell receptor (TCR) to NF-κB signaling pathway is crucial for T cell activation and differentiation. Upon engagement of the TCR with cognate antigen, a series of events leads to the formation of the Carma1-Bcl10-Malt1 (CBM) complex, increasingly recognized as vital to a properly functioning immune response. We have demonstrated that in effector T cells, the CBM complex gives rise to a polymeric, filamentous signalosome called POLKADOTS that directs terminal activation of NF-κB. POLKADOTS consist of the core protein Bcl10, its constitutive binding partner Malt1, and their recruited signaling partners. We have previously shown that Bcl10 is degraded via selective autophagy following T cell activation. Here, we show that Malt1, which serves both as an adaptor transmitting signals to NF-κB and as a protease which cleaves a variety of substrates, is not concurrently degraded. Instead, Malt1-containing POLKADOTS coalesce via microtubule transport to a canonical aggresome. Aggresomes are thought to be depots of misfolded protein destined for degradation via macroautophagy; however, the Malt1 aggresome promotes late stage NF-κB activation through prolonging pIKK-Malt1 interactions. Additionally, this aggresome enhances the proteolysis of a subset of Malt1 targets. These results establish a mechanism for sustaining cytoplasmic signals from the TCR. More broadly, our findings demonstrate that aggresomes can serve as a stable platform for signal transduction.
The utilization of scientific language communication techniques to enhance Immunology Education for Postgraduate Clinical Health Science students
Authors: Sika-Paotonu Dianne , Tait Carolyn 
Published: January 2023

Abstract
Classroom discourse describes the spoken face-to-face interactions which happen in the classroom, with language being the dominant communication medium. It has been reported that teachers can easily talk for more than two thirds of a classroom lesson. To facilitate and support effective learning for students within the postgraduate setting where in-class time can be restricted, it is important that teachers carefully consider the language utilized particularly when introducing scientific material to students for the first time. The purpose of this work was to analyse the scientific language communication occurring within the Immunological content delivery for postgraduate Clinical Health Science students during in-class time. Verbal feedback from postgraduate Clinical Health Science nursing, midwifery and health students was obtained after Immunology based in-class learning and teaching sessions. Formal teaching evaluation of the Immunology teaching sessions was also undertaken. The in-class scientific language utilization was also considered within the literature context. Positive student feedback and favorable evaluation responses within specific teaching categories indicate the scientific language communication being utilized in the postgraduate setting for clinical health science students are providing support and promoting scientific language learning for students. The in-class scientific language utilization within this Immunology teaching content and was considered consistent when compared with the literature context. These results reinforce the importance of appropriate scientific language communication for effective of Immunological course content.