bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deubiquitinase CYLD controls the plasticity of Treg cells by regulation of Scinderin expression
Authors: LEE JEEHO , Wan Qingqing , Han Jihye , el Baghdady Sarah , Geels Shannon , Elly Chris , Liu Yun-Cai 
Published: January 2023

Abstract
Regulatory T (Treg) cells are indispensable for the maintenance of immune tolerance and the prevention of autoimmunity; however, how Treg cells retain their homeostasis with immune suppressive function remains largely unclear. Here we report that deubiquitinase CYLD plays a critical role in the maintenance of Treg cells. Foxp3− specific CYLD knockout mice showed severe pulmonary inflammation due to preferential migration of Treg cells into the lung and increased interleukin-4 (IL-4) production compared to control mice, which was reversed by the deletion of IL-4. Genome-wide microarray analysis unveiled that Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, which contributed to IL-4 production through complex formation with MEK/ERK. Increased IL-4 production by CYLD-deficient Treg cells was significantly rectified by Scinderin ablation. Our findings indicate that CYLD is essential to maintain Treg cell function through regulating Scinderin expression.
An agonist TIGIT mab suppresses regulatory T cell activity via an IL-2-mediated mechanism
Authors: Jones Brian H. , Liu Changbao , Swiecki Melissa , Strake Brandy , Chi Ellen , Bansal-Pakala Pratima 
Published: January 2023

Abstract
The co-inhibitory receptor TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a 26 kDa immunoglobulin domain-containing transmembrane protein that contains both intracellular ITIM (Immunoreceptor Tyrosine-based Inhibitory Motif) and ITT (Immunoreceptor Tail Tyrosine) like domains and is found on the surface of Natural Killer and T cells. CD155 (or the poliovirus receptor) and CD112 (or Nectin-2) are natural ligands for both TIGIT and the activating receptor CD226 (or DNAM-1). In addition to the complexity of the TIGIT/DNAM-1 interplay, TIGIT has been demonstrated to drive both cell intrinsic and extrinsic functions. TIGIT binding to CD155 on Dendritic cells can drive reduction of pro-inflammatory cytokines while inducing tolerogenic cytokine secretion (Yu, 2009). More recently regulatory T cells have been demonstrated to express high levels of TIGIT and upon ligation have been demonstrated to induce effector molecules like FGL2 and reported to promote suppressive function (Joller, 2014).
We’ve identified an agonist anti-TIGIT monoclonal antibody, TGTB227, that inhibits T cell responses in vitro in both cellular reporter assays and primary memory T cell assays. TGTB227 is a human IgG1k mab that reduced the expression of the transcription factor, Foxp3, on Tregs. Moreover, TGTB227, but not the related TGTB277, reduced the functional suppressive ability of both natural and induced Tregs. Finally, these data support a TIGIT driven intrinsic CD25/IL-2-dependent mechanism for the modulation of Treg activity.
Fatty acid transporter 2 regulates the suppressive functions of PMN-MDSC in cancer
Authors: Veglia Filippo , Tyurin Vladimir , Blasi Maria , De Leo Alessandra , Donthireddy Laxminarasimha , DiRusso Concetta , Black Paul , Kagan Valerian , Gabrilovich Dmitry I 
Published: January 2023

Abstract
Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are critically important for the regulation of immune responses in cancer, promotion of tumor progression, and metastases. PMN-MDSC contribute to the failure of cancer therapies and their presence in cancer patients correlates with a poor prognosis. However, despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for their suppressive functions are not well defined. The understanding of these mechanisms is critical important for the development of therapeutic strategies for the specific targeting of PMN-MDSC in cancer. Here, we report a massive accumulation of lipids in PMN-MDSC from tumor bearing mice and from cancer patients, compared to normal neutrophils from tumor free mice and healthy donors, respectively. The content of lipids was much higher in PMN-MDSC infiltrating the tumor. The accumulation of lipids was mediated by the exclusive up-regulation of the fatty acid transporter 2 (FATP2) in PMN-MDSC. The deletion of FATP2 abrogated the suppressive activity of PMN-MDSC in spleens and tumors. The selective pharmacological inhibition of FATP2 altered the activity of PMN-MSC and delayed tumor progression in mice. Importantly, FATP2 inhibition in PMN-MDSC favored tumor regression in mice when combined with checkpoint inhibitors. In conclusion, we show that FATP2 regulates the immune suppressive activity of PMN-MDSC and may represent a new target to selectively inhibit the functions of PMN-MDSC and to improve the effect of immunotherapy.
Rapid Isolation of untouched mouse MDSCs
Authors: Antignano Frann , Messing Melina , Hughes Michael R , McNagny Kelly , Kokaji Andy I , Woodside Steven M. , Eaves Allen C. , Thomas Terry E. 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that regulate immune responses in cancer, chronic infections and inflammatory conditions. In an individual with a tumor burden, MDSCs accumulate in peripheral lymphoid organs and within the tumor microenvironment. In several human cancers, and in mouse tumor models, the presence of high numbers of MDSCs correlates with tumor growth, metastasis and an overall poor prognosis. Approaches that impair the activity or deplete MDSCs have shown promise in animal models. Thus, MDSCs are an attractive target for therapeutic intervention.
We have developed an immunomagnetic method for the isolation of untouched mouse MDSCs. Using CyTOF analysis of cell surface antigens on spleen cells from tumor bearing mice, we developed a cocktail of antibodies that targets non-MDSCs for removal using a column-free, negative selection protocol. Our method isolates CD45+CD11b+Gr1+ cells with the following purity and recovery from spleen, BM and blood:
MDSCs (CD11b+Gr1+) from tumor-bearing miceTissuePurity (±SD)Recovery (±SD)Spleen94 ± 2.1%50 ± 12%Blood99 ± 0.6%55 ± 7.0%Bone marrow96 ± 1.0%68 ± 5.6% (naïve)
As a functional test, naïve mouse splenocytes were labeled with a proliferation dye and the T cells were activated with anti-CD3 and anti-CD28 antibodies. MDSCs isolated from tumor-bearing mice were added at different ratios and after 3 days of culture proliferation of CD4+ and CD8+ T cells was assessed by flow cytometry. This assay showed a dose-dependent suppression of both CD4+ and CD8+ T cells by the isolated MDSCs.
Our new EasySep™ Mouse MDSC (CD11b+Gr1+) Isolation Kit offers a fast and easy method that could facilitate MDSC discoveries that impact a wide range of diseases.
TRPV4 Mediates the Macrophage Phagocytic and Cytokine Response to Leptin
Authors: Scheraga Rachel Greenberg , Perelas Apostolos , Abraham Susamma , Grove Lisa , Southern Brian D , Crish James , Olman Mitchell 
Published: January 2023

Abstract
Obesity is characterized by chronic activation of the innate immune system. Leptin is an adipokine upregulated in obesity that has been shown to stimulate macrophage function through an unidentified signal. Our lab recently showed that the mechanosensitive calcium channel, transient receptor potential vanilloid 4 (TRPV4) mediates macrophage phagocytosis in response to infection. This study seeks to determine if TRPV4 also mediates the macrophage response to leptin. Bone marrow derived macrophages were isolated from 7–10 week old WT and TRPV4 KO mice and incubated in the presence of pathophysiological range leptin concentrations (0.1–1μg/mL; 24 hr) ± LPS (E coli 0111:B4 as a positive control) ± TRPV4 inhibitor. Macrophage phagocytosis was measured as uptake of fluorescently-labeled E coli particles. Intracellular calcium was measured using the FLIPR Calcium 5 Assay in the presence of a selective TRPV4 agonist (GSK). MIP-2 and IL-8 secretion was measured by ELISA. Leptin increases phagocytosis of E coli particles by 17% (59% of the LPS response) and TRPV4 activity by 24% (51% of the LPS response). The phagocytic response and calcium influx are abrogated by either pharmacologic inhibition or deletion of TRPV4. Secretion of MIP-2 and IL-8 in response to leptin increases by 8-fold after pharmacologic inhibition of TRPV4. Our data show that TRPV4 mediates macrophage phagocytosis of E coli particles, and suppresses proinflammatory cytokine release, in response to leptin. In addition, we show that TRPV4 function is increased by leptin. In vitro results predict that TRPV4 enhances host defense and suppresses inflammation in the setting of obesity-induced hyperleptinemia, thus potentially modulating pneumonia severity in obese patients.
Dietary Soluble Fiber Induces HCC in Dysbiotic Mice Through a Spectrum of Immunosuppressive Mediators
Authors: Vijay-Kumar Matam , Yeoh Beng San , Singh Vishal , Golonka Rachel M , Saha Piu 
Published: January 2023

Abstract
Dietary fermentable, soluble fibers (e.g. inulin) are known for promoting health; yet, ~40% of Toll-like receptor 5 deficient (T5KO) mice fed inulin-containing diet (ICD) develop icteric hepatocellular carcinoma (HCC) (Cell, 2018). Specifically, the disease progresses starting with hepatic cholestasis and neutrophilic inflammation at one month, followed by HCC at 6 months of ICD feeding. This diet-driven HCC was dependent on the gut microbiota and was mediated, largely in part, via surfeit production of immunosuppressive short-chain fatty acids (SCFA) and secondary bile acids, presumably as compensatory mechanisms against inflammation in the 40% pre-HCC T5KO mice. What was most striking was the upregulation of systemic bilirubin (a host immunosuppressive metabolite) within one week of ICD feeding. The hyperbilirubinemia was accompanied with an increase in IgA by ~50 and ~10-fold in the serum and liver, respectively, compared to the 60% non-HCC T5KO mice. Markers for anti-tumor T cell exhaustion, i.e. hepatic PD-L1 and layilin, were also upregulated, where the former was elevated within a week of feeding and persisted, while the latter was observed at 6 months. Hepatic immune cell phenotyping after the onset of HCC revealed substantial increase in CD4+FOXP3+PD-L1+T cells and IgA+IL10+PD-L1+Bcells, with the latter denoting a recently identified subset of highly immunosuppressive B cells. Our unprecedented findings collectively demonstrate that dietary fibers and SCFA —which are widely-held to be anti-inflammatory— could potentiate immunosuppression and impede anti-tumor immune surveillance in the tumor microenvironment in mice with gut microbiota dysbiosis.
BHLHE40 programs mitochondrial regulation of resident CD8+ T cell fitness and functionality
Authors: Li Chaofan , ZHU BIBO , Son YoungMin , Wang Zheng , Edelson Brian T , Hitosugi Taro , Rathmell Jeffrey C , Dong Haidong , Sun Jie 
Published: January 2023

Abstract
Tissue-resident memory CD8+ T cells (TRM) share characteristics and core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic and epigenetic regulation of TRM and TIL differentiation, maintenance and function are largely undefined. Furthermore, it is unknown whether metabolic and epigenetic manipulations can be employed to promote TRM/TIL functional programs for cancer immunotherapy. Here we report a critical mechanism programming the mitochondrial and epigenetic regulation of TRM/TIL functionality in situ. We find that mouse and human TRM/TIL express the transcription factor BHLHE40 and the BHLHE40-associated gene signature. Bhlhe40 is specifically required for TRM and TIL development and poly-functionality. Local PD-1 signaling inhibits TIL Bhlhe40 expression, and Bhlhe40 is critical for TIL reinvigoration following anti-PD therapy. Mechanistically, Bhlhe40 sustains TRM/TIL mitochondrial fitness for the promotion of a functional epigenetic state. Building on these findings, we also identify an epigenetic and metabolic regimen that promotes TRM/TIL gene signatures associated with tissue residency and poly-functionality through in vitro T cell screening. Strikingly, this regimen empowers the anti-tumor activity of CD8+ T cells and possesses therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights on the local regulation of TRM and TIL function, and offer a viable strategy for developing novel immunotherapeutic means for cancer.
Novel expression of Bone Morphogenic Protein 10 (BMP10) in lymphocytes
Authors: Tsiagbe Vincent K , Avina Samantha , Mills Steven , Patel Sehrish , Li Yu 
Published: January 2023

Abstract
The bone morphogenic protein family (~20 BMPs in humans), are members of the transforming growth factor-β (TGF-β) superfamily. BMPs have been shown to exert important roles during development and organogenesis by delivering positional information in both vertebrates and invertebrates. We had previously observed early induction of mRNA for BMP10 in rat B cells soon after Aggregatibacter actinomycetemcomitans (Aa) bacterial infection, in studies conducted in a rat model for human periodontal disease. However, prior to the onset of bone resorption, BMP10 mRNA precipitously declined. Being the first demonstration that mRNA for BMP10 is expressed by lymphocytes, we examined the expression of BMP10, at the protein level. Peripheral blood lymphocytes from humans, rats and mice were purified, by micro-immunomagnetic bead separation, into B cell, CD4, and CD8 T cell fractions. Flow cytometry analysis conducted with anti-BMP10 antibody revealed cellular expression of BMP10 in all the fractions examined. Interestingly, activation of CD4 T cells by Con A, rodent B cells by LPS, or human B cells by S. Aureus, resulted in drastic shut-down of BMP10 expression at mRNA and protein levels. In conclusion, our studies demonstrate, for the first time, that lymphocytes express BMP10 protein. Furthermore, while activation of B cells by bacterial antigen induced early BMP10 expression, further chronic stimulation resulted in decline in BMP10 expression. Intriguingly, mitogen stimulation of B cells and CD4 T cells, led to a drastic reduction in BMP10 expression at mRNA and protein levels, suggesting that BMP10 might be a novel marker for naïve lymphocytes.
High Spare Respiratory Capacity is a Canonical Feature of Virtual Memory, but not Conventional Memory CD8 T Cells, and is Driven by IL-15 Signalling
Authors: La Gruta Nicole L , Quinn Kylie M , Kraus Felix , Formosa Luke , Dagley Michael , Saunders Eleanor , Hussain Tabinda , Assmus Lisa , Costin Adam , Clark Joan , Ramm Georg , Good-Jacobson Kim , McConville Malcolm , Ryan Michael 
Published: January 2023

Abstract
Virtual memory T (TVM) cells are antigen-naïve CD8 T cell cells that exist in a semi-differentiated state. They exhibit some characteristics that are classically associated with conventional memory T cells (TMEM), including elevated expression of CD44, accelerated TCR-driven proliferation, and enhanced cytokine responsiveness. Despite rapid and robust proliferation of young TVM cells after TCR-mediated stimulation, aged TVM cells exhibit marked proliferative dysfunction. Recently, high spare respiratory capacity (SRC) was proposed as a defining metabolic characteristic of antigen-experienced memory T cells (TMEM) cells, thought to promote both their longevity and rapid functionality. Given the semi-differentated state of TVM cells, we sought to determine whether the SRC of TVM cells also corresponded to their longevity and functionality. Surprisingly, we found that elevated SRC was a feature of TVM cells, but not TMEM cells, and that SRC increased substantially with age in both subsets, repudiating a link between SRC and functionality. We further showed that SRC was closely linked with responsiveness to IL-15, since TVM cells alone were dependent on IL-15 for survival/accumulation, and showed increased receptor (CD122) expression, and IL-15 mediated STAT5 phosphorylation. Moreover, recent infection caused an increase in SRC in TVM cells but inhibition of IL-15 during infection was sufficient to prevent this increase. Collectively, these findings indicate that elevated SRC is a feature of TVM and not TMEM cells and is a consequence of their heightened IL-15 sensitivity. Moreover, elevated SRC is not associated with T cell functionality in young or aged cells, but may be associated with survival of TVM cells.
TIM-3-dependent regulation of restimulation-induced cell death sensitivity flips changes in early versus late-stage human effector T cells
Authors: Lake Camille , Jiang Timothy , Bauman Bradley , Voss Kelsey , Snow Andrew L 
Published: January 2023

Abstract
In healthy individuals, the balance between immune-mediated pathogen clearance and tissue damage is tightly regulated through multiple processes. One such mechanism is restimulation-induced cell death (RICD), a propriocidal apoptotic mechanism that constrains T cell responses. Activated T cells must surpass a high threshold of TCR signal strength to induce pro-apoptotic genes responsible for executing RICD. Because co-receptors such as TIM-3 are thought to modulate TCR signal strength, we hypothesized that TIM-3 can shape the T cell response by tuning RICD sensitivity. We utilized siRNA knockdowns and transfection of wild-type and mutant TIM-3 expression constructs to assay for changes in RICD sensitivity in both immortalized and primary human T cells in vitro. Strikingly, we observed that the effect of altering TIM-3 expression varied temporally during the effector T cell response. Whereas TIM-3 promoted RICD resistance in newly activated T cells, TIM-3 enhanced RICD sensitivity in late-stage effector T cells by boosting TCR-induced FASL and BIM expression in a ligand-independent fashion. Preliminary evidence suggests that this dichotomy may relate to substantial temporal changes in the expression, cellular localization, and glycosylation of TIM-3 in early versus late-stage effector T cells. Overall, these results indicate that TIM-3 influences apoptosis sensitivity differently at distinct phases of the human T cell response, with important implications for the use of checkpoint blockade immunotherapies targeting TIM-3. Our findings may also help to clarify discrepancies in the literature regarding TIM-3 signaling and function in T cells.
Maximizing engagement and critical thinking with stories – case studies of all shapes and sizes
Authors: Lukin Kara R , Aviszus Katja 
Published: January 2023

Abstract
When done purposely, case studies blend desires of modern students for relevance and social engagement with educators needs to convey detailed content and develop critical thinking skills. By selecting or creating cases that include both local and international settings as well as characters from broad socio-economic and cultural backgrounds, we elevate discussions of diversity and students’ feelings of inclusivity. In addition, even terse mini-scenarios can require students to analyze situations and apply their knowledge instead of memorize facts. For many, finding or writing exciting narratives and integrating case study strategies can seem daunting. However, barriers to adopting this pedagogical tool are reduced when educators recognize that cases are 1) highly variable in depth (from a few sentences to several pages), and 2) can be used very flexibly. Here, we explain examples of how we have integrated cases of various lengths throughout an undergraduate immunology course. Two examples of how a single, well selected case can address topics through an entire term will be detailed. We will explain a simple strategy for converting standard exam or practice questions into mini-cases, leveraging summaries of primary literature and the course text.
All classroom ready resources will be available for immediate access through AAI’s preferred method.
Role modelling Immunology to support STEM education outreach efforts for Pacific College students
Authors: Sika-Paotonu Dianne 
Published: January 2023

Abstract
Educators are important role models for their students. Specialists and professionals working within STEM related areas can support outreach related education activities as role models for children and young people. To support improved education and health outcomes for Māori and Pacific young people in New Zealand (NZ), various strategies and interventions have been proposed. The importance of role modelling in this context is recognised. The purpose of this work was to support a STEM-related outreach education event organised by an external organisation, with a teaching contribution delivered by a Pacific Biomedical Scientist that was Immunologically based. The female Pacific Biomedical Scientist was invited to contribute to this work as a role model specifically to support improved interest and participation with STEM related learning in a workshop classroom environment. Given that context relevant science related learning was a primary focus, clinical research work was presented to the Pacific College students aged 14–16 years. The research work in part related to the autoimmune condition known as Acute Rheumatic Fever (ARF) that can trigger permanent heart damage known as Rheumatic Heart Disease (RHD) if left untreated. It is recognised that Māori and Pacific Peoples in NZ and in the Pacific Region are affected disproportionately by ARF and RHD. Verbal and written feedback from the College students highlighted the Immunology teaching session was well-received and enjoyed by the students. This work also demonstrated the importance of role modelling in the classroom blended with scientific knowledge communication in supporting positive interactions in the classroom for Pacific College students.
Crosstalk between lung epithelial cells and myeloid cells in innate immune defense
Authors: Liu Xin , Boyer Mark A , Shin Sunny 
Published: January 2023

Abstract
Pathogens have evolved a wide range of strategies to allow survival and subsequently cause disease in humans. However, it is still poorly understood how the immune system successfully overcomes pathogen-induced disturbance and enable robust immune responses against infection. The intracellular bacterium Legionella pneumophila has the ability to block global protein synthesis in target macrophages, but the host can still strongly evoke an IL-1-dependent inflammatory response that clears infection. Here, we show that IL-1 signals directly to alveolar epithelial cells, which potently drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by these cells. Importantly, GM-CSF-mediated JAK2/STAT5 signaling promotes inflammatory gene expression in myeloid cells. We found that STAT5 was enriched at the 5′ upstream regions of inflammatory cytokine genes. In addition, GM-CSF metabolically reprogrammed myeloid cells to undergo aerobic glycolysis, which was required for maximal inflammatory cytokine production. Our findings reveal that lung epithelial cells act as a key intermediary to facilitate communication between infected and bystander myeloid cells and orchestrate antimicrobial defense.