bluuebunny/crossref_metadata_2025_split huggingface dataset:
Innate lymphoid cell composition shift upon Campylobacter jejuni induced colitis, a process inhibited by targeting mTOR signaling in Il10−/− mice
Authors: Tang Ying , He Zhen , Shirley James F. , Ohland Christina L. , Pope Jillian L. , Jobin Christian , Glover Sarah 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) are important innate effector cells involved in host mucosal immunity. The role of ILCs in regulating homeostasis following commensal bacterial colonization and enteropathogenic bacterial infection is unclear. Herein, we profiled ILC repertoire following Campylobacter jejuni (C. jejuni)-induced colitis as well as responses following anti-inflammatory treatment. Germ-free (GF) Il10−/− mice were colonized with SPF biota or human clinical isolate C. jejuni 81-176. Rapamycin (1.5mg/kg, daily), an inhibitor of mTOR signaling, was used to inhibit C. jejuni-induced colitis. ILC profile was assayed by Flow Cytometry analysis using specific markers (Lineage marker, CD90.2, CD127, CD117, ST2, and NKp46). Inflammatory cytokine production was detected using RNAscope. Compared to WT-C57Bl6 mice, ILC distribution was similar in absence of intestinal microbiome (GF mice), whereas presence of microbiota leaded to elevated NCR−ILC3 (30% vs 5%, P&lt; 0.01) and lower ILC2 (1% vs 21%, P&lt; 0.05) in the colon of Il10−/− mice. C. jejuni-induced colitis caused an increase of ILC1 (50% vs 18%, P&lt; 0.0001) with decrease of NCR−ILC3 (13% vs 43%, P&lt; 0.0001) in the colonic lamina propria, compared to uninfected mice. RNAscope revealed an augmented inflammatory cytokines, such as IFN-γ, IL-17A, TNF-α, and IL-22, in mucosal immune cells, and elevated IL-33 expression in epithelial cells. Rapamycin treatment inhibited C. jejuni-induced colitis (histology score 0.07 vs 4.0, P&lt; 0.0001), which associated with re-establishment of ILC profile and decreased cytokine production. In conclusion, ILC trans differentiation correlates with the development of C. jejuni-induced colitis, a process inhibited by blocking mTOR signaling.
LIGHT-HVEM Signaling in Group3 Innate Lymphoid Cells Protects Against Enteric Bacterial Infection
Authors: Seo Goo-Young , Shui Jr-Wen , Takahashi Daisuke , Song Christina , Wang Qingyang , Kim Kenneth , Mikulski Zbigniew , Chandra Shilpi , Giles Daniel A. , Zahner Sonja , Kim Pyeung-Hyeun , Cheroutre Hilde , Colonna Marco , Kronenberg Mitchell 
Published: January 2023

Abstract
Innate lymphoid cells (ILC) are important regulators of early infection at mucosal barriers. They are known to be activated by cytokines and neuropeptides, but it remains to be determined if they integrate other signals in providing protection. The herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily, is expressed by all intestinal ILC subsets. Here, we show that HVEM signaling of ILC3 is important for host defense against oral infection with the enteric bacterial pathogen Yersinia enterocolitica (Y. enterocolitica). Surprisingly, IFNγ production by CCR6 negative ILC3 was strongly implicated in protection, likely because these cells were more numerous than other innate lymphocytes that produced IFNγ early after infection. We identified the TNF superfamily member LIGHT, as the ligand inducing HVEM signals in ILC. Therefore, our results demonstrate a novel role for LIGHT-HVEM signaling in regulating ILC3 IFNγ production and protection following infection.
Interplay between type I interferon signaling and AIM2 inflammasome in Francisella novicida infection
Authors: Zhu Qifan , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Inflammasomes are crucial for mediating protection against microbial infection. Type I interferon (IFN) signaling is required for driving activation of the AIM2 inflammasome in macrophages in response to infection by Francisella tularensis subspecies novicida (F. novicida). Here, we showed that mice lacking type I IFN signaling had intact inflammasome responses after F. novicida infection. Mice lacking the type I IFN receptor subunit, IFNAR1 or IFNAR2, and core components of the type I IFN signaling pathway were resistant to infection by F. novicida compared with wild-type mice, whereas mice lacking AIM2 were more susceptible. Importantly, we found that mice lacking both AIM2 and IFNAR2 were more resistant to the infection with an impaired ability to induce activation of apoptotic caspases than infected wild-type mice. These results suggested that while type I IFN signaling and AIM2 were essential for activation of the Francisella-induced inflammasome in macrophages, they have strikingly opposing effects in vivo. Furthermore, type I IFN signaling is a dominant regulator of anti-microbial activity during F. novicida infection in vivo even in the absence of AIM2 responses.
Gasdermin-D controls cytokine responses in Francisella infection.
Authors: Banerjee Ishita , Behl Bharat , Shrivastava Gaurav , Russo Ashley J. , Vanaja Sivapriya Kailasan , Rathinam Vijay A. 
Published: January 2023

Abstract
The innate immune system is essential for detection and elimination of pathogenic microbes. Francisella is an intracellular pathogen that replicates in the cytosol of macrophages. In the cytosol, it can be recognized by host defense sensors. Francisella is sensed by cyclic GMP-AMP synthase (c-GAS) leading to the production of type I Interferons (IFN). It can also be recognized by the PYHIN DNA sensor absent in melanoma (AIM2) resulting in the activation of inflammasome responses i.e. production of pro-inflammatory cytokines IL-1b and IL-18 as well as pyroptosis. While mice deficient in inflammasome components are more susceptible to Francisella infection, type I interferon signaling deficient mice are resistant to Francisella bacterial infection. Inflammasome activation results in gasdermin-D cleavage leading to pyroptotic cell death. Our results show that gasdermin-D activation plays an important role in the nature of cytokine responses to Francisella infection, therefore influencing the outcome of the infection. These findings have major implications in understanding the balance of cytokine production in response to cytosolic immune surveillance.
Anti-Flagellin antibodies dampen TLR5 and NLRC4 innate immune responses to flagellin
Authors: Yeoh Beng San , Gewirtz Andrew T. , Vijay-Kumar Matam 
Published: January 2023

Abstract
The host immune system is constantly exposed to diverse microbial ligands, including flagellin (FliC; a ligand for TLR5 and NLRC4) and lipopolysaccharide (LPS; a ligand for TLR4), whose ability to induce immune tolerance to subsequent exposure is well-documented in vitro. In this study, we investigated the extent to which FliC and LPS could induce immune cross-tolerance to one another in vivo, as well as the interaction between the innate and adaptive immune response to FliC. Mice pre-treated with LPS displayed attenuated serum keratinocyte-derived chemokine [KC; alias interleukin (IL)-8] and IL-6 response to FliC; however, the administration of FliC followed by LPS instead resulted in an additive response. LPS also augmented the serum IL-18 response to FliC; the increment was more pronounced when LPS was administered before, than after, FliC. Intriguingly, the generation of anti-FliC antibodies was notably impaired in mice sequentially challenged with LPS and FliC, compared to mice given only FliC. A strong negative correlation between high anti-FliC titer and reduced KC, IL-6 and IL-18 responses to FliC re-challenge was observed in these mice, suggesting that adaptive immunity could tolerize TLR5 and NLRC4. Indeed, the serum from WT mice with high anti-FliC titer, but not Rag1KO mice, was able to dampen FliC-induced secretion of IL-8 from the human epithelial cell line HT-29. These observations may be relevant in the context of bacterial infection, as we demonstrated that anti-FliC response are protective against systemic infection by Salmonella typhimurium. Taken together, our study delineates a distinct co-operative and reciprocal interaction between the innate and adaptive arms of immunity in modulating their responses to FliC.
Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis
Authors: Sharma Deepika , Malik Ankit , Guy Cliff , Vogel Peter , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary autoinflammatory disease and severe IBD. Inflammatory bowel diseases (IBD) increase the risk for colorectal cancer. Expression of MEFV, a sensor protein that the initiates assembly of the inflammasome complex, is increased in colon biopsies from patients with colorectal cancer. We investigated the role of pyrin in intestinal homeostasis in mice. Mefv−/− and C57/BL6 mice were subjected to azoxymethane - dextran sodium sulfate (AOM-DSS) model of colitis and tumorigenesis. Pyrin was expressed in colons of control mice and expression increased during chronic and acute inflammation. Mefv−/− mice developed more severe colitis than control mice, with a greater extent of epithelial hyperplasia and a larger tumor burden. Mefv−/− mice had increased epithelial permeability early during DSS administration and increased levels of inflammatory cytokines and chemokines during acute colitis. On the other hand, IL18, which depends on the inflammasome for maturation and release, was significantly lower in colons of Mefv−/− mice. Further, the inflammatory milieu in Mefv−/− mice was pro-tumorigenic with increased STAT3 activation, and stem cell activity in the colon and reduced cytotoxic T cell activation in draining lymph nodes and spleen. Administration of rIL18 to Mefv−/− mice reduced epithelial permeability, intestinal inflammation, the severity of colitis, and colon tumorigenesis. In conclusion, we found that pyrin (MEFV) is required for inflammasome activation and IL18 maturation, which promote intestinal barrier integrity and prevent colon inflammation and tumorigenesis.
Distinct lymph node entry efficiencies for CD8+ and CD4+ T cells are eliminated during malnourishment.
Authors: Gubbels Bupp Melanie R. , Gibson David , Goulmamine Syreen , Little Amie , Murphy Sarah , Patrick Kristin , Thoner Timothy 
Published: January 2023

Abstract
Previous work has suggested that glucocorticoids upregulate expression of the IL-7 receptor component, CD127 on peripheral T cells, even though the total number of peripheral T cells declines dramatically during malnourishment. We have proposed that CD127 up-regulation contributes to peripheral T cell diminishment by increasing the scavenge rate of IL-7 and thereby providing a mechanism to rapidly adjust the total number of T cells during malnutrition. As such, each malnourished T cell would receive a higher dose of IL-7 than control T cells. We next wondered if increased exposure to IL-7 during malnourishment might confer additional energy-saving behaviors. Thus, we compared lymph node entry rates of adoptively-transferred malnourished and control T cells in malnourished and control recipients. As expected, control CD4+ T cells were more efficient than control CD8+ T cells at entering the lymph nodes. Interestingly, regardless of recipient diet, malnourished CD4+ and CD8+T cells entered the lymph nodes at equivalent rates. The molecular events that enable faster CD4+ T cell entry into lymph nodes in control mice is currently unknown. An improved understanding of T cell-intrinsic changes that occur during malnourishment should enhance our knowledge of CD4+ and CD8+ T cell migration, as well as uncover strategies to improve vaccination responses in malnourished children.
Memory CD8+ T Cell Development is Controlled by the Sympathetic Nervous System
Authors: Farrar John David , Estrada Leonardo , Agac Didem , Wise Aaron , Maples Robert , Chen Beibei , Cobanoglu Murat Can 
Published: January 2023

Abstract
Immune memory is critical for protection from repeated infections by pathogenic organisms and is the basis for the success of vaccines. Memory CD8+ T cell development is guided by important signals that alter their function and transcriptional program, enabling them to persist as pools of primed memory cells capable of rapid response. Lymphoid organs are highly innervated by sympathetic neurons that secrete norepinephrine as the primary neurotransmitter, which places the nervous and immune systems in direct communication. CD8+ T cells express the β2-adrenergic receptor (ADRB2), and we found that it was required for the development of long-lived memory cells in response to virus infection. The failure of Adrb2−/− T cells to form memory populations correlated with profound differences in gene expression and predicted upstream regulators during the early stages of T cell priming. Thus, the sympathetic nervous system controls memory CD8+ T cell development through ADRB2 signaling.
Gimap5-dependent inactivation of GSK3β is required for CD4+ T cell homeostasis and prevention of immune pathology
Authors: Patterson Andrew R. , Endale Mehari , Lampe Kristin , Flagg Aron , Woodgett James , Bleesing Jack , Hoebe Kasper 
Published: January 2023

Abstract
GTPase of immunity-associated protein 5 (Gimap5) has been linked with lymphocyte survival, autoimmunity and colitis, but its mechanisms of action are unclear. Here we show that Gimap5 is essential for inactivation of glycogen synthase kinase-3β (GSK3β) following T cell activation. In the absence of Gimap5, constitutive GSK3β activity constrains c-Myc induction as well as NFATc1 nuclear import, thereby reducing the frequency of CD4+ T cells that complete cell cycle. Additionally, Gimap5 facilitates phosphorylation of GSK3β at Ser389 and its nuclear translocation. Impairment in the latter steps of GSK3β regulation by Gimap5 is associated with increased DNA damage and reduced survival of activated CD4+ T cells. Importantly, pharmacological targeting and genetic deletion of GSK3β in mice can override Gimap5-deficiency in CD4+ T cells, limiting DNA damage and enhancing T cell proliferation and survival. Additionally, this ameliorates immune-mediated pathology in vivo caused by loss of Gimap5. Finally, we show that a human patient with a GIMAP5 loss-of-function mutation has lymphopenia and impaired T cell proliferation. T cells from this patient exhibit impaired proliferation, but can be rescued in vitro with GSK3 inhibitors. Given the restricted expression of Gimap5 in lymphocytes, we propose that its control of GSK3b activity is an important checkpoint in lymphocyte proliferation and function.
Helios expression defines a phenotypically distinct population of Treg cells
Authors: Thornton Angela M. , Korty Patricia E. , Kim Yong Chan , Martens Craig , Shevach Ethan M. 
Published: January 2023

Abstract
The transcription factor Helios is expressed by 65–75% of Treg and we have proposed that it is a marker of thymic derived Treg (tTreg). In order to study the differences between Helios+ and Helios− Treg, we have generated a Helios-GFP/Foxp3-RFP double reporter mouse. Helios+ Treg expressed a more activated phenotype and had higher suppressive capability in vitro. Both subsets were equivalent in their ability to suppress IBD in vivo, but Helios+ Treg were more protective against disease induced by the transfer of splenocytes from scurfy mice. Both subsets expressed a highly demethylated Foxp3 TSDR, with slightly higher demethylation in the Helios+ Treg subset. Upon transfer to normal mice, both Helios+ and Helios− Treg cells maintained equal Foxp3 stability. However, upon transfer to lymphopenic mice, the percentage of cells from the Helios− subset that maintained Foxp3 expression was significantly lower than that of the Helios+ subset. Upon transfer to both normal and lymphopenic mice, Foxp3+Helios+ Treg maintained stable expression of Helios, while 30% of the Helios− Treg acquired low levels of Helios expression upon transfer to normal mice and 70–80% of the Helios− Treg acquired Helios expression when transferred to lymphopenic mice. Gene expression profiling of the two populations demonstrated 1000 differentially expressed genes. Additionally, TCR repertoire deep sequencing analysis revealed little to no overlap of the two populations. Taken together, our data indicate that Helios expression can differentiate two distinct populations of Treg with overlapping functions, most likely representing tTreg (Helios+) and stable peripherally-induced pTreg (Helios−).
Supported by the Intramural Research Program of the NIH, NIAID.
Performance of the Syphilis Serology Algorithm Diagnosis
Authors: Balada-Llasat Joan-Miquel 
Published: January 2023

Abstract
Syphilis is a chronic, sexually transmitted disease caused by Treponema pallidum. The clinical manifestations of syphilis are often non-specific. Serology tests are used for diagnosis. The aim of this study was to evaluate the reverse algorithm used at The Ohio State Wexner Medical Center (OSUWMC) for the diagnosis of syphilis. The algorithm consist of a treponemal test (Bio-Rad BioPlex Syphilis IgG) a multiplex flow immunoassay (MFI), which utilizes treponemal antigens coated on microspheres to detect IgG to T. pallidum. If reactive, a nontreponemal test, rapid plasma reagin (RPR), is used to detect antibodies against cardiolipin-cholesterol-lecithin antigens, though not specific they are present in most patients with syphilis. If results are reactive with MFI but nonreactive with RPR, a second treponemal-specific antibody test using T. pallidum particle agglutination (TP-PA) is used. Sera submitted at OSUWMC between 01/1/2013 and 10/13/2017 were tested for syphilis using the described algorithm. A total of 70,849 specimens were tested using the MFI assay, of these 96.5% were nonreactive (n= 68,394), 3.3% were reactive (n=2,318) and 0.2% produced an equivocal result (n= 137). Of the MFI reactive results, 1.5% confirmed reactive with RPR (n=1,031) and 1.8% (n=1,287) were nonreactive and considered discrepant. The discrepant specimens were tested by TP-PA, 0.6% (n=438) were confirmed nonreactive and 1.2 % (n=849) were reactive. Furthermore, 137 specimens that produced an equivocal result by the MFI were tested by RPR and TP-PA, 133 were nonreactive and 4 were reactive. In summary, only 2% (n=1,424) of the specimens were discrepant and required a third test for resolution.
Intracerebral Mycobacterium tuberculosis infection induces robust myeloid and lymphocytic immunity in the central nervous system
Authors: Hernandez Gianna L. , Ritter Anna , Mergaert Aisha Mergaert , Rayasam Aditiya , Gerhart Christian , Sandor Matyas , Fabry Zsuzsanna 
Published: January 2023

Abstract
Central nervous system tuberculosis (CNSTB) is a rare, highly devastating manifestation of extra-pulmonary tuberculosis. To date, research has focused on pulmonary tuberculosis, with no significant advancements being made in understanding the mechanisms associated with CNSTB. This study uses a small animal model of CNSTB that permits us to investigate the immune responses following CNS Mycobacterium tuberculosis infection. We use intracerebral infection of mice with Mtb H37rv which has been fluorescently tagged with tdTomato, allowing us to track it in vivo, and analyze the cellular composition of the subsequent immunological response in the brain. Starting at 7 days post-infection (PI), we show a robust infiltration of immune cells into the brain including the infiltration of CD11chigh dendritic cells, CD11b+ monocytes, and an IFNγ dominated T cell response. Mtb-containing granulomatous lesions develop starting at 1 week and continue to form until 7 weeks PI. Granuloma composition in the brain is dominated by CD11chigh dendritic cells, CD11b+ monocytes, CD4+ T cells and to a lesser extent, Tmem119+ microglia. We show robust immune cell infiltration in the choroid plexus during infection indicating a potential route for secondary dissemination and immune cell infiltration into the brain. We also discovered that anti-Mtb immunity in the brain develops as early as 1 week following intracerebral inoculation of Mtb, earlier than following peripheral inhalation infection in the lung. Finally, robust anti TB immunity leads to infection control in the brain at 7 weeks post-infection. This study provides new knowledge into the pathogenesis of CNSTB, and could provide possible treatment strategies to lessen its destructive outcome.
Oxidant sensor cation channel TRPM2 activates neutrophil extracellular trap formation by autophagy and plays a protective role in pneumoseptic Klebsiella pneumoniae infection
Authors: Tripathi Jitendra Kumar , Sharma Atul , Sukumaran Pramod , Mishra Bibhuti , Singh Brij , Sharma Jyotika 
Published: January 2023

Abstract
Neutrophil extracellular trap (NET) formation represents an important antimicrobial function of neutrophils, which partly depends on reactive oxygen species (ROS) and autophagy activation. However, the factors governing these processes remain unknown. In this study, we demonstrate that nonselective calcium permeable cation channel Transient receptor potential melastatin 2 (TRPM2), senses ROS and contributes to the NET formation. The NET forming function of TRPM2 in response to ROS stimulation requires autophagy activation through ADP ribose, AMPK phosphorylation and p38 MAPK activation. TRPM2 deficient neutrophils fail to activate this pathway with a block of NET release and a concomitant impairment of antimicrobial capacity. Trpm2−/− mice were found to be highly susceptible to pneumonic infection with Klebsiella pneumoniae owing to an impaired NET formation and high bacterial burden despite increased neutrophil infiltration in their lungs. Taken together our data identifies a key role of TRPM2 in NET formation by ROS sensing and links it to autophagy activation via AMPK/p38 pathway. Our study also provides evidence for a protective anti-microbial role of TRPM2 in pneumonic bacterial infection thus positing TRPM2-mediated NET formation as a valuable target for modulating NETs and related pathologies.
Suboptimal stimulation with staphylococcal enterotoxin C1 induces immunosuppressive CD4+CD25+ regulatory T cells by differential expression of FOXP3 isoforms
Authors: Lee Juyeun , Park Nogi , Park Joo Youn , Yoon Sunghyun , Park Juw Won , Pruett Stephen B. , Seo Keun Seok 
Published: January 2023

Abstract
Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and preventing excessive tissue damage upon immune activation. However, pathogens could exploit Tregs for their successful pathogenesis. We demonstrated that immunosuppressive CD4+CD25+FOXP3+ Tregs were induced by staphylococcal enterotoxin (SE) produced by an important human pathogen, Staphylococcus aureus. CD4+CD25+FOXP3+ T cells were induced from stimulation with SEC1 at a high (1 μg/ml) and low (1 ng/ml) concentrations that induced optimal stimulation and suboptimal stimulation, respectively. However, CD4+CD25+FOXP3+ T cells induced from suboptimal stimulation were functionally immunosuppressive, not from optimal stimulation. Immunosuppressive CD4+CD25+FOXP3+ T cells induced from suboptimal stimulation showed typical Treg surface markers such as CTLA-4, GITR, TNFR2, and CD45RO and produced immunomodulatory cytokines such as TGF-β and IL-10. However, suppression was mainly mediated by galectin-1 in a contact-dependent manner. We found that CD4+CD25+ Tregs from suboptimal stimulation highly express FOXP3 isoform lacking exon 2 (ΔE2) and partially lacking exon3 (ΔpE3) preferably localized to the nucleus, compared to those from optimal stimulation. Lentiviral transduction of FOXP3 isoforms (full length, ΔE2, ΔpE3) to Jurkat T cells did not result in immunosuppressive function. By contrast, when cultured in the media generated from suboptimal T cell stimulation, transduced Jurkat T cells became more immunosuppressive in an order of ΔE2 ΔpE3, and full length FOXP3. These results suggest that soluble factors generated from suboptimal T cell proliferation play an important role in induction of immunosuppressive Tregs.