bluuebunny/crossref_metadata_2025_split huggingface dataset:
B2AR Deletion from T-Cells Enhances Tumor Immunity in a Tumor Metastasis Model
Authors: Massalee Rachel , Mustapha Habeebat , Puppala Eswar , Cao Xuefang 
Published: November 2024

Abstract
Previous studies suggest that Beta-2-adrenergic receptor (β2-AR) signaling plays a role in dampening anti-tumor immune response. Given that B2AR is expressed in innate and adaptive immune cells, , it remains to be determined how B2AR signaling affects the activity of specific types of immune cells in the setting of tumor immunity. Therefore, we have developed T cell-specific deletion of B2AR by crossing LCK-Cre mice with B2AR Floxed mice, and used the resultant T cell-specific B2AR knockout (LCRCre-B2ARFL) mice to study tumor metastasis. We utilized the B16-F10 melanoma model via intravenous injection and examined metastatic tumor nests in the lungs 2-3 weeks after tumor injection. Our findings indicate that (LCRCre-B2ARFL) mice showed significantly lower burden of metastatic tumor nests in the lungs compared to control groups (LCKCre mice and B2ARFL mice). These results indicate that endogenous B2AR signaling in T cells plays an immune checkpoint role, restraining their anti-tumor activity, while selective deletion of β2AR from T cells enhances their anti-tumor function, resulting in significant reduction of tumor metastasis. Therefore, this study provides an important rationale for blocking B2AR signaling to improve tumor immunity and disabling B2AR in adoptive T cell therapy for cancer patients.
Lineage tracing reveals heterogeneity within tumor-reactive CD8 T cells in mismatch repair-proficient (MMR-p) CRC
Authors: Duhen Thomas , Rosales Wesley , Fesneau Olivier , Samson Kimberly , Jones Brett , Rajamanickam Venkatesh 
Published: November 2024

Abstract
While CRC develop in the colon and rectum, little is known about the relationship between tissue resident memory (TRM) CD8 T cells and newly recruited tumor-reactive T cells. We compared the phenotype of CD8 T cells from paired adjacent normal colon (NC) and tumor by flow cytometry and observed a higher T cell infiltration in the tumor with an enrichment in CD8 T cells. Interestingly, a subset of CD103+ CD8 T cells in NC expressed CD39, a phenotype reminiscent of tumor-reactive T cells, but those cells lacked PD-1 and Ki-67. To better understand the relationship between T cells from NC and tumor and to uncover the differentiation path of tumor-reactive CD8 T cells, we performed scRNA-seq and scTCR-seq together with CITE-seq on paired NC and tumor from five patients. We confirmed that DP CD8 T cells from NC were distinct from tumor-infiltrating DP CD8 T cells (DP CD8 TILs). In contrast, the latter represented an heterogenous population with cells at different stages of differentiation as illustrated by the detection of cells sharing the same TCRs in multiple cell clusters. To further appreciate the differentiation path of neoantigen-reactive CD8 TILs, we performed neoantigen discovery on three of the five patients. We are now evaluating whether T cell differentiation and activation are linked to functional avidity and cellular location in the tumor. This work provides essential information regarding the differentiation of tumor-reactive CD8 TILs in MMR-p CRC tumors.
fluorescent tracing unveils the impact of radiation therapy on the migration and plasticity of Tregs in the tumor microenvironment
Authors: Friedman David , Blair Tiffany , Kramer Gwen , Kaur Aanchal Preet , Baird Jason , Alice Alejandro , Potuznik Megan , Crittenden Marka , Gough Michael 
Published: November 2024

Abstract
Radiation therapy (RT) is a pivotal component of cancer treatment, yet its impact on the immune system is not fully understood. RT induces DNA damage in cancer cells, promoting cancer cell death and RT-induced immune responses with the potential to clear surviving cancer cells. However, RT can also recruit suppressive T regulatory cells (Tregs), that hinder adaptive immunity. Following RT-mediated death of tumor Tregs, we hypothesize that immature Tregs are recruited to the post-RT tumor and converted into suppressive phenotypes. Using the Kaede mouse model, we tracked photoconverted cells from either the tumor or TdLN after RT. In photoconverted tumors, Tregs in the TdLN constituted a higher proportion of photoconverted cells compared to non-Treg CD4 or CD8 T cells. When RT was applied to tumors, photoconverted Tregs and non-Treg CD4 T cells decreased in the TdLN. When photoconverting the TdLN we observed selective migration of Tregs to the tumor rather than to NdLN. Analyzing these newly arrived photoconverted Tregs in the tumor post-RT revealed increased expression of CD69, KLRG1, and Ly6C compared to non-photoconverted Tregs, indicating limited suppressive capacity. Ongoing studies are examining the impact of the irradiated tumor environment on newly-entered Treg plasticity. These findings unveil intricate dynamics between RT, Tregs, and the use of site-specific photoconversion for tracking immune cell movement over time.
Critical role of 4-1BB:4-1BBL axis in anti-malaria immune response
Authors: Caloba Carolina , Sturtz Alexandria , John Lijo , Ramachandran Akshaya , Malkina Kateryna , Minns Allen , Lindner Scott , Vijay Rahul 
Published: November 2024

Abstract
Malaria is a deadly disease caused by Plasmodium and remains as a major public health threat. The effective elimination of the parasite and protection against reinfections depend on the generation of high-affinity plasma cells (PCs) and memory B cells (MBCs). Due to the emergence of drug-resistant strains and difficulty of developing an efficacious vaccine, host-directed therapies have been gaining more attention as promising approaches. The co-stimulatory receptor 4-1BB is required for an optimal humoral immune response against Plasmodium. Here, we show that exogenous stimulation of 4-1BB by 3H3 improved memory B cell response against Plasmodium. Despite having fewer polyclonal and antigen-specific MBCs, 3H3-treated mice showed enhanced protection upon heterologous reinfection. Adoptive transfer of MBCs from 3H3-treated mice was more protective than control MBCs and generated a higher number of IgM+ PCs in the bone marrow, suggestive of an extrafollicular memory response. Collectively, our data show that upon 3H3 treatment, B cells are reprogrammed to differentiate into a superior MBC population that provides enhanced protection against repeat infections.
Altered T cell phenotypes in M. tuberculosis ‘resisters’ correlated with bacterial control.
Authors: Sun Meng , Phan Jolie , Kieswetter Nathan , Yu Krystle , Smith Malisa , Huang Huang , Liu Yiran , Gupta Sanjana , Obermoser Gerlinde , Maecker Holden , Krishnan Akshaya , Suresh Sundari , Rieck Mary , Acs Peter , Khatri Purvesh , Boom W Henry , Hawn Thomas 
Published: November 2024

Abstract
A subset of individuals with a high probability of exposure to M. tuberculosis (M.tb) appears to exhibit ‘resist’ infection, as demonstrated by serially negative tuberculin skin test or IFN-γ release assay results. While these ‘resisters’ (RSTR) display IFN-γ-independent T-cell responses to the M.tb-specific antigens ESAT-6 and CFP-10 (PP1), it is currently unknown whether specific T-cell functions are associated with this clinical outcome. We used multi-modal scRNA- and TCR-seq to compare the phenotypes and functions of PP1- and M.tb lysate-specific CD4 T-cells between RSTRs and matched controls with ‘latent’ M.tb infection (LTBI). M.tb-specific CD4s were clonally expanded in both RSTRs and LTBIs, confirming the priming of adaptive immune responses after M.tb exposure. However, RSTR CD4s showed an early differentiation phenotype as well as enrichment of Th17-like transcriptional programs compared to LTBIs, which were characterized by Th1*-like effector programs. These results were validated in an independent set of RSTRs and LTBIs using flow cytometry and Luminex. We found that these IFN-γ-independent CD4 T-cell phenotypes correlated with bacteria control in both published human and non-human primate cohorts. Together, these data suggest that ‘resisters’ may successfully control M.tb after exposure and immune priming, establishing a set of T-cell biomarkers to facilitate further study of this important clinical phenotype.
Enteral Supplementation with Bovine Lactoferrin or Glutamine Alters Neonatal Iron Status, Intestinal Permeability and Sepsis-related Mortality in a Mouse Model
Authors: Watral Kyra , Bermick Jennifer 
Published: November 2024

Abstract
A murine model of E. coli sepsis results in significant mortality in pups but universal survival in adults despite equivalent immune responses, suggesting that neonatal susceptibility is due to immune-independent factors. Previous data shows that increased intraperitoneal(IP) iron in pups contributes to increased E. coli growth and subsequent mortality. Neonates are known to have decreased intestinal barrier function, so we hypothesized this iron-rich depot was due to a leaky intestinal barrier allowing iron to more freely pass from the intestinal lumen into the IP cavity. To determine if altering intestinal barrier function would influence sepsis-associated mortality, neonates were enterally gavaged with lactoferrin(LF) or glutamine(Gln) daily. LF decreased intestinal permeability when measured by FITC-dextran assay(p&lt;0.0001) and resulted in less IP iron (p&lt;0.0001). LF also resulted in decreased E.coli translocation following E.coli oral gavage sepsis(p=0.0011) and decreased mortality following E.coli IP sepsis(p&lt;0.05). Gln increased intestinal permeability when measured by FITC-dextran assay(p&lt;0.0001) but had no effect on IP iron. Gln increased E.coli translocation(p&lt;0.05) and burden(p&lt;0.05) following E.coli oral gavage sepsis. Gln also increased mortality following E.coli IP sepsis(p&lt;0.05). Overall, early-life supplementation can alter intestinal permeability and iron status, and these alterations influence neonatal E.coli sepsis-associated mortality.
TRPV1+ Sensory nerves modulate antigen specific immune responses
Authors: Tynan Aisling , Tsaava Téa , Bravo Iñiguez Carlos , Chavan Sangeeta , Tracey Kevin 
Published: November 2024

Abstract
Sensory neurons recognize harmful or noxious stimuli and initiate a protective response by eliciting pain and defensive behavior. Nociceptors also interact with immune cells to regulate immune responses and play a key role in modulating antibody class switching to IgE. However, it is still unknown whether nociceptors participate in regulating primary IgG antibody responses to novel antigens. Here, we show that TRPV1 expressing nociceptors are required to develop an antigen specific immune response and that direct activation of TRPV1+ signals by selective optogenetic stimulation enhances primary IgG antibody responses to novel antigen. Specific ablation of TRPV1+ neurons, which include nociceptors, significantly blunts NP-specific IgG antibody responses in TRPV1-DTA mice compared to controls (anti-NP2 IgG AU, Day 28 control, 18,401 ± 3393 n=18 versus TRPV1-DTA, 9,028 ± 1,498, n=18, p&lt; 0.001). Selective optogenetic stimulation of TRPV1+ nociceptors on the dorsum of the paw with blue light (473nm, 3Hz, 20%DC, 15min) immediately prior to a local immunization in TRPV1-ChR2 mice significantly increases KLH-specific IgG antibody responses compared to sham stimulation controls (anti-KLH IgG ng/mL Day 28, TRPV1-ChR2: 2,581 ± 476, n= 6 versus Control, 1,224 ± 332, n=8; * p&lt;0.05). Together these studies with genetic and selective functional evidence indicates that nociceptors are required during immunization to produce primary antigen-specific IgG antibody responses to novel antigens.
Tularemia-associated hyperinflammation regulation by Natural Killer T cell subsets
Authors: Torres Cameron 
Published: November 2024

Abstract
Inflammation is critical for effective clearance of viral and bacterial challenges, while simultaneously a mechanism utilized by many highly infectious pathogens to cause disease. The bacterium Francisella tularensis (Ft), the causative agent of human tularemia, elicits a cytokine storm, in which the immune system over-responds to the presence of the bacterium causing a dysregulated release of proinflammatory and regulatory cytokines. Without treatment, tularemia mortality can be as high as 30%, with inhalation of as few as 10 CFUs inducing respiratory tularemia. Natural Killer T (NKT) cells are innate-like T lymphocytes with a diverse array of regulatory functions. NKT cells are activated very early following Ft infection suggesting a critical role in the innate immune response in tularemia. NKT cells are categorized into two distinct subsets, types I and II, with a yet to be defined understanding of their individual characteristics in regulating inflammation. Through a combination of in vitro and in vivo techniques, we have observed a cooperative suppression of inflammation when both subsets of NKT cells are present. This phenotypic suppression is disrupted when each subtype responds individually to Ft. The cellular mechanism controlling this interdependence of function will yield a better understanding of NKT-regulated inflammation in tularemia, and more broadly characterize their involvement and potential therapeutic application for a number of NIH priority pathogens.
IL-12p35 and IL-12p40 functionally synergize to active NK cells
Authors: Wang Jinghua , Erickson Christian , Renelt Mark , Gavino Vida , Sun Jing , Li Jun , Bi Ming , Person Anthony 
Published: November 2024

Abstract
IL-12 plays critical roles in regulating the immune response toward different effector pathways. The formation of functional IL-12 requires association of the IL-12p35 subunit with the IL-12p40 subunit. IL-12p40 can be released from these hematopoietic cells as a monomer. Previous studies have reported that IL-12p40 associates with p35 extracellularly to generate IL-12 like activities on T cells, but the biological significance on NK cells remains unclear. In this study, we show that only high concentrations of IL-12p35 could activate NK cells to secrete IFN-gamma and induce cell proliferation and IL-12p40 had no effect on NK cell activation. Interestingly, IL-12p35 and p40 functionally synergized to activate NK cells by inducing IFN-gamma secretion and cell proliferation in vitro. Surprisingly, pretreatment of NK cells with IL-12p35 or p40 didn’t affect IL-12 induced IFN-gamma secretion and cell proliferation in NK cells. Furthermore, a functional ELISA binding assay revealed that IL-12p35 binds to both IL-12R beta1 and IL-12R beta2 with a low affinity, while IL-12p40 only binds to IL-12R beta1 with a high affinity. Fluorescent conjugated human IL-12, IL-12p35 and IL-12p40 proteins all significantly bound to human NK cells and IL-12p35 and p40 didn’t significantly interfere with IL-12 binding to these cells. Collectively, the data we show herein indicates that IL-12 activity can come from the collaboration between the IL-12p35 and p40 subunits and impact NK cell activation.
The CD4 T cell-intrinsic C3-like molecule CD109 prevents hyper-inflammatory T cell responses
Authors: Merle Nicolas , Kolev Martin , Ding Jienyu , West Erin , Rahman Jubayer , Bibby Jack , Bingyu Yan , Kazemian Majid , Afzali Behdad , Biertuempfel Christian , Mizuno Naoko , Kemper Claudia 
Published: November 2024

Abstract
Immune cell autonomous complement expression and function emerges as pivotal regulator of tissue immunity and T cell biology. Specifically, CD4 T cell intrinsic engagement of CD46 by TCR stimulation-triggered generation of the CD46 ligand C3b, is required for IFN-γ production. In consequence, CD46-deficient patients are unable to generate normal Th1 responses. We identified CD109, a GPI anchored C3-like protein and a direct CD46 signaling induced target. Despite its known ability to regulate TGF-ßR1 signaling in cancer cells, a direct functional activity for CD109 on T cells remains unexplored.
Human CD4 T cells lacking CD109 expression displayed significantly augmented IFN-γ and IL-17 production upon in vitro stimulation under non-skewing conditions. Similarly, CD4 T cells from Cd109–/– mice showed in vitro Th1 and Th17 hyperactivation and caused more severe EAE pathology in vivo. Unexpectedly, T cell CD109 does not control TGF-ß signaling but restrains IFN-γ and/or IL-17 by binding to and inhibiting the activity of a non-canonical costimulatory molecule linked to Th1/Th17 biology. Guided by modeling and Cryo-EM data, we designed a CD109/costimulatory inhibitory peptide that recapitulates the phenotype observed in CD109-deficient T cells.
Together, these data suggest that the C3-like protein CD109 serves as an important molecular brake (or switch) on CD4 T cells by fine-tuning costimulatory signals upstream of the hyper-inflammatory Th1/Th17 induction pathways.
Neutrophil specific glycogen metabolism supports antifungal function in the infected tissues
Authors: Choi Wonseok , Li De-dong , Peroumal Doureradjou , Rahimi Hossein , Wang Shuxia , Biswas Partha 
Published: November 2024

Abstract
Neutrophils are critical for controlling systemic candidiasis (candidiasis), a bloodstream infection caused by Candida albicans. Neutrophils rely on extracellular glucose to fuel their antifungal activities at tissues. However, C. albicans consumes glucose, making it challenging for the neutrophils to survive and function at infected tissues. Hence, encountering fungal pathogens in glucose-depleted tissues exert metabolic challenges for neutrophils. It is unknown how neutrophils dynamically reprogram their metabolic pathways to function in glucose-deprived tissues in candidiasis. We show that neutrophils activate PYGL, an enzyme essential for the breakdown of intracellular glycogen storage to glucose, when glucose supply is limited. C. albicans regulate glycogenolysis in neutrophil in a dectin-1/Syk/Ca2+/PKA-axis dependent manner. Blockade of PYGL function in neutrophils inhibits fungicidal activities only when glucose availability is low and neutrophil specific PYGL ablated mice show increased susceptibility to candidiasis due to impaired ROS formation. Finally, treatment with β2-adrenergic receptor agonist, an approved drug and activator of PYGL function, improved antifungal activities of neutrophils in candidiasis. These results provide insights on how glycogenolysis supports compensatory metabolic reprograming required for antifungal function of neutrophils in the glucose-depleted infected tissues, a knowledge that can be therapeutically exploited by an approved drug.
Macrophages restrain pathological interferon responses during viral respiratory infection
Authors: Rodriguez-Morales Patricia , Hoagland Daisy , Mann Alexander , Yu Shuang , Lai Alicia , Baez Vazquez Alan , Medzhitov Ruslan , Franklin Ruth 
Published: November 2024

Abstract
Uncontrolled inflammation triggered by infection can cause deleterious effects on human health. Therefore, it is important to understand the mechanisms that constrain inflammatory responses. We observed that macrophages, key regulators of inflammation, produce the cytokine Oncostatin M (OSM) in response to cellular stressors and viral stimuli. Upon challenge with influenza or the viral mimic, poly(I:C), Osm-deficient mice exhibited increased mortality and this phenotype was recapitulated in mice lacking OSM specifically in macrophages. Transcriptional and protein analyses revealed that mice lacking OSM specifically in macrophages display heightened lung type I interferon (IFN-I) responses, and excessive IFN-I production by lung epithelial cells. Acute blockade of IFN-I signaling protected mice lacking macrophage-derived OSM against morbidity and mortality, revealing that these mice succumb to viral stimuli due to heightened IFN-I responses. Moreover, reconstitution of OSM in the respiratory tract of mice lacking macrophage-derived OSM was sufficient to protect against morbidity, highlighting the importance of local OSM signaling. Altogether, these data suggest that macrophage-derived OSM restrains excessive IFN-I production by epithelial cells during exposure to viral stimuli. This work reveals a novel mechanism by which macrophages dampen inflammation in the lung through the negative regulation of IFN-I, thus providing protection against inflammation-induced pathology.
Spatial Analysis of NETotic Neutrophil Crosstalk with Monocytes/Mφ in Oral Squamous Cell Carcinoma
Authors: Lowery Austin , Zhao Juanjuan , Chiang Austin , Zhu Yanfang 
Published: November 2024

Abstract
Neutrophils are specialized immune cells that exhibit dual roles in cancer immunity; both pro and anti-tumor functions have been characterized thus far. It is now recognized that previously identified Myeloid-Derived Suppressor Cells (MDSCs) that impede anti-tumor immunity in various cancers are comprised of pathologic monocyte and neutrophil types. However, the interplay between tumor-associated neutrophils, monocytes, and their impact on tumor immunity remains unclear. Neutrophils execute their immune functions via NETosis, an exceptional mechanism that extrudes neutrophil extracellular traps (NETs), which play a dual role in cancer. In some cancers, NETs recruit macrophages toward an anti-tumor response, yet prolonged interaction induces apoptosis, contributing to immune suppression in the tumor microenvironment (TME). In oral squamous cell carcinoma (OSCC), linked to poor prognosis and high mortality, NETotic neutrophil infiltration at the tumor site correlates with improved survival. Conversely, heightened neutrophil presence in late-stage metastatic lymph nodes reduces survival. Consistently, elevated NET concentration in patient serum was identified. In this study, we use CosMx Spatial Molecular Imager (CosMx SMI) to investigate in-depth transcriptome changes of monocytes/Mφs induced by crosstalk with NETotic neutrophils in the tumor site from MOC2 tumors (OSCC mouse model) to demonstrate the contribution of NETotic neutrophil-monocyte/Mφ crosstalk to OSCC initiation.
Role of lipid droplets and prostaglandinE2 in Coxiella burnetii intracellular growth.
Authors: Biancaniello Maria , Mulye Minal 
Published: November 2024

Abstract
The obligate intracellular bacterium, Coxiella burnetii, causes human Q fever. Infection with Coxiella via inhalation presents as atypical pneumonia which may relapse years later, leading to potentially fatal endocarditis. Our goal is to determine the mechanisms Coxiella employs for long-term survival in the host. While the bacterium initially infects alveolar macrophages, in endocarditis patients Coxiella is found in foamy macrophages rich in neutral lipid storage organelles, lipid droplets (LDs). Our studies show that blocking LD breakdown inhibits bacterial growth suggesting that LD-derived lipids are crucial for Coxiella’s survival. LD breakdown releases arachidonic acids, precursors for the lipid immune mediator prostaglandinE2 (PGE2) which promotes immunosuppression in alveolar macrophages. We hypothesize that Coxiella manipulates host cell LD metabolism to promote a PGE2-mediated immunosuppressive environment and survive long-term in the host. To test this, we quantified PGE2 production in Coxiella-infected cells with and without LD breakdown inhibitor, atglistatin. ELISA showed a LD breakdown-dependent increase in PGE2 levels. Fluorescence microscopy revealed PGE2 production blockade with COX-2 inhibitors significantly decreased bacterial growth which was rescued by exogenous PGE2 suggesting that PGE2 promotes Coxiella survival. Ongoing studies are identifying the correlation between LDs and PGE2 production and the role of LDs in immunosuppression.