bluuebunny/crossref_metadata_2025_split huggingface dataset:
Id3 is a critical mediator of lineage commitment and functional maturation of γδ-T cells (36.63)
Authors: Lee Sang-Yun , Zuniga-Pflucker Juan-Carlos , Wiest David 
Published: January 2023

Abstract
αβ and γδ T cells are thought to arise from a common precursor during development in the thymus. However, the basis for separation of these lineages is poorly understood. Previously, we showed that strong TCR signals promote γδ lineage choice, while weaker signals favor adoption of the αβ lineage. Here we show that the HLH factor Id3 plays a defining role in this process. We found that Id3 is required for strong TCR signals to both promote adoption of the γδ-fate and oppose the αβ-fate outcome. Importantly, the effects of Id3-deficiency on γδ lineage cells appear to differ depending on the γδ subset. In Id3-/- mice, development of the Vγ2 subset and Vγ3 dendritic epidermal T cell (DETC) subset are both reduced, while innate type NK γδ T cells bearing a Vγ1.1/Vδ6.3 TCR are dramatically expanded. Our analysis suggests that the γδ subsets whose development is impaired by Id3-deficiency are dependent on TCR signals of intermediate intensity. In contrast, those which are expanded (Vγ1.1Vδ6.3) in Id3-deficient mice may normally be deleted, perhaps by high-affinity ligand. In support this view, KN6 γδ TCR transgenic thymocytes normally deleted by high affinity ligand (T-10/22b) are rescued by Id3-defciency. Likewise, the junctional sequences of the TCR subunits of Vγ1.1Vδ6.3 T cells in Id3-/- exhibited almost no variation, suggesting strong selective pressure. These results indicate that Id3 not only in regulates fate selection, but also in shapes the γδ TCR repertoire.
The expression of semaphorins 4A, 4D and 7A in early hematopoietic T progenitors in the bone marrow of C57BL/6 mice. (36.65)
Authors: Chatterjea Devavani , Añó Leonor , Linder Grace , Obodo Udochukwu , Matthes David 
Published: January 2023

Abstract
Semaphorins are a group of transmembrane, secreted, and GPI-linked proteins that have been thoroughly studied in the nervous system where they function as ‘traffic’ enzymes in guiding axonal growth. Although most exhaustively characterized in this realm, they are also expressed in several other physiological systems. We have characterized the expression and localization of T cell semaphorins 4A, 4D and 7A in developing thymocytes. We show here that hematopoietic T cell progenitor cells (CD90+) enriched from the Bone Marrow have high levels of sema4A and 4D expression, but no sema7A. PlexinD1 and C1 (the receptors for sema4A and 7A) were also expressed in this subset, but there was no PlexinB1 or CD72 (the receptors for sema4A and 4D respectively). This provides further evidence of the dynamic expression and regulation of sema4A, 4D and 7A in early T cell development.
GABPalpha is required for normal T cell development (36.67)
Authors: Yu Shuyang , Zhao Dongmei , Jothi Raja , Xue Hai-hui 
Published: January 2023

Abstract
GA binding protein (GABP) consists of GABPalpha and GABPbeta subunits. GABPalpha is a member of Ets family transcription factors and binds DNA via its conserved Ets domain, whereas GABPbeta does not bind DNA but possesses transactivation activity. In T cells, GABP has been demonstrated to regulate the gene expression of interleukin-7 receptor alpha chain (IL-7Ralpha) and postulated to be critical in T cell development. To directly investigate its function in early thymocyte development, we used GABPalpha conditional knockout mice where the exons encoding the Ets DNA-binding domain are flanked with LoxP sites. Ablation of GABPalpha with the Lck-Cre transgene greatly diminished thymic cellularity, blocked thymocyte development at the double negative (DN)-3 stage, and resulted in reduced expression of T cell receptor (TCR) beta chain in DN4 thymocytes. By chromatin immunoprecipitation, we demonstrated in DN thymocytes that GABPalpha is associated with transcription initiation sites of genes encoding key molecules in TCR rearrangements. Among these GABP-associated genes, knockdown of GABPalpha expression by RNA interference diminished expression of DNA ligase IV, Artemis, and Ku80 components in DNA-dependent protein kinase complex. Interestingly, forced expression of pre-arranged TCR but not IL-7Ralpha can alleviate the DN3 block in GABPalpha-targeted mice. Our observations collectively GABP is critically required for TCR rearrangements and hence normal T cell development.
ThPOK induction by gdTCR signaling promotes gd maturation (36.68)
Authors: Park Kyewon , He Xi , Lee Hyung-Ok , Hua Xiang , Wiest David , Kappes Dietmar 
Published: January 2023

Abstract
Current models suggest that the transcription factor ThPOK, the “master regulator” of CD4 commitment, is selectively induced in developing abTCR+ thymocytes by strong/persistent TCR signals, although direct evidence for this conjecture is lacking. We show that strong TCR signals mediated by antibody treatment or high affinity endogenous ligands cause ThPOK induction in thymocytes of the distinct gd T cell lineage. A key ThPOK cis-acting element, the distal regulatory element (DRE), is sufficient to mediate TCR dependent gene activation in gd thymocytes. Additionally, we demonstrate that ThPOK controls maturation and repertoire selection of developing gd thymocytes. Thus, lack of functional ThPOK causes a severe reduction in mature gdTCR+ thymocytes and a shift in Vg usage, while constitutive ThPOK expression leads to a striking increase in mature gd thymocytes. These results demonstrate that ThPOK expression in gd thymocytes is regulated by the strength of TCR signaling, define an important new role for ThPOK in gd T cell development/maturation, and lend strong support to the view that development of most gd T cells depends on TCR engagement/signaling.
Complement activation on Chlamydia pneumoniae is accelerated by direct binding of native properdin to its surface (37.10)
Authors: Cortes Claudio , Ferreira Viviana , Pangburn Michael 
Published: January 2023

Abstract
Activation of complement represents one means of natural resistance to infection from a wide variety of potential pathogens. Recently properdin, a positive regulator of the alternative pathway of complement, has been shown to bind to surfaces and activate complement de novo. Here we studied the molecular mechanisms of properdin-mediated complement activation on Chlamydia pneumoniae, an obligate intracellular gram-negative bacterium that causes upper respiratory tract infections. We analyzed the ability of properdin to initiate complement activation by binding to C. pneumoniae directly, providing a platform for de novo convertase assembly. We determined for the first time that the physiological P2-P4 forms of human properdin bind to the surface of C. pneumoniae. The binding of these physiological forms initiates and accelerates complement activation on the C. pneumoniae surface, as measured by C3b and C9 deposition. Finally, properdin-depleted serum could not control C. pneumoniae infection of HEp-2 cells when compared with normal human serum. However, addition of native properdin to properdin depleted serum recovered the ability of serum to control the infection. Altogether, our data suggest that properdin is a pattern recognition molecule that plays a role in resistance to Chlamydia infection.
IL-18 is critical to cytotoxic NK and CD8+T cell activation and susceptibility to Ehrlichia-induced septic shock-like syndrome (37.19)
Authors: Ismail Nahed , Fang Rong , Ghose Purnima , Pulliam Stephanie 
Published: January 2023

Abstract
Ehrlichia chaffeensis is a Gram negative bacteria that cause septic shock where disease pathogenesis is mediated by IFN-γ and TNF-α producing, cytotoxic NK and CD8+ T cells, and late apoptosis of CD4+Th1 cells. We tested here the hypothesis that IL-18 signaling through IL-18Rα is involved in the pathogenesis of Ehrlichia-induced shock. Mice deficient of IL-18 or treated with anti-IL-18Rα blocking antibody were infected with virulent Ehrlichia that cause fatal disease. IL-18-/-mice have enhanced resistance to Ehrlichia infection as indicated by lower bacterial burden, which was accompanied by increased number of CD11b+ macrophages, decreased maturation of dendritic cells and B cells, and decreased number of granulocytes on day 3 post-infection (p.i.) compared to infected wild type controls. On day 7 p.i, absence of IL-18 or signaling via IL-18Rα resulted in decreased number of Fas-expressing, TNF-α producing-CD8+T cells and NK cells, increased number of IFN-γ producing NKT and CD4+Th1 cells, reduced expression of Fas on CD4+T and non T cells. Interestingly, infected mice treated with anti-IL-18Rα exhibited an increased number of TNF-α by NK and CD3+ Tcells, suggesting that a TNF-α inhibitory -endogenous ligand engages IL-18Rα following lethal ehrlichial infection. These data suggest that IL-18 play a pathogenic role in Ehrlichia-induced shock via activation of pathogenic NK and CD8 T cell responses and down regulation of protective IFN-γ producing NKT and CD4+ Th1 responses.
The opportunistic intracellular parasite Toxoplasma gondii infects and functionally inactivates human plasmacytoid dendritic cells. (37.30)
Authors: Pierog Piotr , Zhao Yanlin , Singh Sukwinder , Yap George , Fitzgerald-Bocarsly Patricia 
Published: January 2023

Abstract
Plasmacytoid dendritic cells (pDC) are a rare population of peripheral blood mononuclear cells with important functions during viral infection. In response to viral nucleic acids, pDC produce IFN-α which induces an antiviral state in neighboring cells, controls viral replication, and serves as an important link between innate and adaptive immunity. This immune response is attenuated in AIDS patients as previously reported by our lab, and can lead to susceptibility of these immunocompromised individuals to opportunistic infections like Toxoplasma gondii. Here, we investigated the effects of T.gondii infection on pDC function. We found that T.gondii infects pDC and establishes a parasitophorous vacuole membrane (PVM) without affecting pDC viability. pDC did not produce IFN-α or TNF-α in response to T.gondii; however, T.gondii-infected pDC were negatively affected in their ability to respond to viral stimulation. T.gondii-infected pDC exposed to HIV-MN or HSV-I secreted significantly lower quantities of IFN-α and TNF-α as compared to virus alone. To investigate the mechanism of IFN-alpha inhibition we used ImageStream, an imaging flow cytometer, and found that HSV-induced nuclear translocation of IRF-7 was inhibited in T.gondii-infected pDC. These results indicate that T.gondii evades innate immune responses by infecting and functionally inactivating plasmacytoid dendritic cells.
Intravital imaging of lymphocyte dynamics and signaling during immune Response to Listeria infection in the spleen (37.31)
Authors: Waite Janelle , Leiner Ingrid , Lauer Peter , Zheng Huan , Rae Chris , Portnoy Daniel , Pamer Eric , Dustin Michael 
Published: January 2023

Abstract
T cells play a major role in the adaptive immune response. T cells are primed by professional antigen presenting cells (APC), frequently dendritic cells (DC). T-DC interactions occur in lymphoid tissue where T cells are highly motile. Activation of the T cell receptor by cognate antigen triggers arrest in motility to allow stable and specialized contact with APC, termed the immunological synapse. Signaling that initiates and maintains stable T-DC contact has yet to be fully characterized. We employed intravital microscopy to image lymphocyte dynamics in the spleen, a major secondary lymphoid organ important for clearance of blood borne pathogens. We directly image a DC network in the subcapsular red pulp (scDC) where effector T cells migrate and arrest acutely in response to antigen. scDC internalized intravascular Listeria. Myelomonocytic cells were recruited and interdigitated with non-motile infected scDC as dynamic swarms and tight foci to contain Lm. Effector CD8+ T cells displayed a two-tiered reduction in motility with antigen independent and dependent components, including stable interactions with scDC. In addition, we monitored antigen induced intracellular calcium ([Ca2+]i) elevation in vivo. While [Ca2+]i elevation is sufficient to arrest crawling T cells, blocking [Ca2+]i elevation did not inhibit arrest. These data suggest there is an alternative antigen induced stopping pathway that allows stable T-APC contacts in the absence of [Ca2+]i elevation.
Yersinia pestis LOS stimulation of U937 cells shows different miRNA expression compared to Escherichia coli LPS stimulation (37.32)
Authors: Gibbons Jennifer , Pelletier Mark , Ernst Robert 
Published: January 2023

Abstract
Lipopolysaccharide (LPS)-stimulated activation of Toll-like Receptor 4 (TLR4) initiates downstream effects central to the inflammatory response that are important for host-pathogen interaction. In eukaryotes, microRNAs or miRNAs are small regulatory RNAs with multiple mRNA targets. There are ~1000 miRNAs encoded in the human genome, with the potential to regulate ~30% of the transcripts. The lipid A component of E. coli LPS is hexa-acylated, resulting in a highly proinflamatory response in human cells. Yersinia pestis synthesizes different lipid A structures depending on growth temperature, correlating to host conditions. Purified tetra-acylated lipooligosaccharide (LOS) of Y. pestis grown at 37○C, mimicking human infection, does not stimulate the innate immune system, whereas purified hexa-acylated LOS of Y. pestis grown at 25○C, mimicking flea infection, stimulates the innate immune system via TLR4, similar to E. coli LPS. Our hypothesis was that miRNA expression would be altered when human cells are incubated with purified LOS from Y. pestis grown at 25○C vs. 37○C. Initial studies in U937 cells using SABiosciences’ miRNA whole genome PCR arrays showed fewer miRNA expression changes in both LOS treatments than reported for LPS-stimulation. However, one modulation of interest is the 10-fold upregulation of miR-601 with 37○C LOS, compared to a 2-fold upregulation with 25○C. These data hint at a novel LOS-related mechanism, given recent reports of NFκB repression via miR-601.
Aberrant innate immune response to Leishmania major in the absence of secretory leukocyte protease inhibitor (SLPI) (37.38)
Authors: McCartney-Francis Nancy , Jin Wenwen , McGrady George , Wahl Sharon 
Published: January 2023

Abstract
Resistance to intracellular pathogens such as leishmania relies upon both innate and adaptive immune responses. Overexuberant host responses can lead to uncontrolled inflammation, highlighting a critical need for suppressive mechanisms to limit tissue damage. SLPI is an epithelial-derived protease inhibitor with anti-microbial and anti-inflammatory functions and is inducible in rodent phagocytes. Moreover, SLPI is induced by L. major and increased SLPI expression is evident within lesions following local infection with L. major. While resistance in C57Bl/6 mice is attributed to IFNγ-dominant Th1 responses, SLPI-deficient C57Bl/6 mice also develop strong Th1 responses, yet infection with L. major rapidly rages out of control with progression to systemic disease. To determine the mechanism of this dysregulated response, we infected SLPI-deficient and wildtype phagocytes with L. major and detected increased levels of inducible NO synthase (iNOS) and myeloperoxidase (MPO) coincident with altered arginase expression in the absence of SLPI. Intradermal infection with L. major revealed a rapid influx of phagocytes and modulation of iNOS, MPO and arginase. However, despite persistence of activated phagocytic cells, SLPI-deficient mice fail to resolve the inflammation or clear the infection. Our results define a novel contribution of SLPI to innate host defense against intracellular parasites and its potential use to hasten resolution of infection and inflammatory pathogenesis.
IL-4Rα signaling may enhance resolution of parasite-induced lung damage by inhibiting inflammation and mediating acute wound healing (37.8)
Authors: Chen Fei , Liu Zhugong , Liu Qian , Wu Wenhui , Bowdridge Scott , Millman Ariel , Rozo Cristina , Gause William 
Published: January 2023

Abstract
The parasitic nematode Nippostrongylus brasiliensis (Nb) third-stage larvae (L3) migrate to the host lung at about 24 to 48 hrs after infection, causing lung damage, inflammation and a potent Th2-type response. Yet, little is known about the mechanism causing lung damage and whether components of the Th2-type immune response contribute to acute lung wound repair. In this study we report that migrating Nb larvae (L3) induce lung inflammation that results in increased hemorrhaging in addition to mechanical damage in the lung. Neutrophil depletion reduced lung hemorrhage and both hemorrhaging and neutrophil infiltration were decreased in Nb-infected IL-17R KO mice. Resolution of acute hemorrhage and inflammation was dependent on either IL-4 or IL-13 as IL-4Rα KO mice, but not IL-13Rα or IL-4 deficient mice, induced significantly higher hemorrhaging, neutrophil influx, and IL-17 expression. Elevations in Arg1, IGF-1, and IL-10 were also inhibited in IL-4RαKO mice. In IL-10KO mice, resolution of inflammation was also blocked, control of hemorrhaging was partly suppressed, and Arg1 and IGF-1 elevations were not affected. These data suggest that the Th2-type immune response mediates acute wound healing and control of IL-17-dependent inflammation during helminth infection.
Activation of adenosine 2a receptor (A2aR) blocks IL-23/IL-17 mediated neutrophil migration in kidney ischemia-reperfusion injury (37.9)
Authors: Li Li , Huang Liping , Okusa Mark 
Published: January 2023

Abstract
Polymorphoneutrophils (PMNs) infiltration is the characteristic of kidney ischemia-reperfusion injury (IRI). Endogenous adenosine accumulating in kidney following IRI has a crucial role in terminating an overactive immune response through A2aRs. Our studies have demonstrated that the protective effect of the A2aR agonist, ATL146e, was mediated through bone marrow derived leukocytes. However, the mechanism by which A2aR agonists block neutrophil migration is unknown. Both kidney pedicles were clamped in C57BL/6 mice for 28 min and then released for 24 hrs. Kidneys from mice deficient of IL-23 (p19/40KO), IL-17A or IL-17R were protected from IRI with less neutrophil infiltration,CXCL1 and CXCL2 production and lower plasma creatinine levels (P&lt;0.01, compared to WT IRI). Blocking of p19 or 17A by using neutralization mAb reduced plasma creatinine following IRI compared to isotype control-treated mice (P&lt;0.001). Greater neutrophil accumulation was found in A2aRKO mouse kidneys subjected to IRI (P&lt;0.001) than in WT mice, suggesting an important role of A2aR on neutrophil migration. ATL313 significantly decreased Gr-1+ neutrophil infiltration 24h following kidney IRI (P&lt;0.001). Co-administration of IL-23+ATL313 or IL-17A+ATL313 significantly suppressed CD11b+GR-1+ peritoneal neutrophil migration (P&lt;0.01). A2AR activation is a unique and potent strategy in attenuating IRI by blocking IL-23/IL-17 mediated neutrophil migration.
Detection of Crimean-Congo hemorrhagic fever virus glycoprotein antigens (38.19)
Authors: Bagriacik Emin , Albayrak Nurhan , Uslu Kadriye , Ertek Mustafa 
Published: January 2023

Abstract
Crimean-Congo hemorrhagic fever (CCHF) is a viral infection caused by Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne virus (Nairovirus) of Bunyaviridae. Viral antigens of CCHFV can be detected by using various immunologic methodologies. We developed two methodologies to detect viral antigens of CCHFV using polyclonal antibodies isolated either from human plasma or from hyperimmunized horse serum. The first methodology is a western blot using human polyclonal antibodies. The second one is an antigen ELISA using horse antibodies. CCHFV isolates from vero-cell cultures were used as a source of the antigens. Additionally, CCHFV isolates obtained from Centers for Disease Control and Prevention (CDC) of USA were used as positive controls. The human polyclonal antibody pool detected several glycoproteins of various sizes ranging from approximately 35 KDa to 80 KDa or higher indicating that humans can develop antibody responses to different epitopes of the viral glycoproteins. Also, the ELISA can be used successfully to detect CCHFV with quite reproducible results. Our results indicated that both antibody sources could be convenient for rapid detection of CCHFV glycoprotein antigens.
CD73 and extracellular adenosine confer susceptibility to Toxoplasma gondii infection (38.7)
Authors: Mahamed Deeqa , Wang Yongmei , Bynoe Margaret 
Published: January 2023

Abstract
After tissue injury or infection, high levels of ATP inside cells is liberated and can serve as a danger signal that activates immune cells and promotes inflammation. The subsequent breakdown of extracellular ATP to adenosine by the cell-surface enzyme CD73 plays an important role in the resolution of the inflammatory response. Interestingly, the protozoan pathogen Toxoplasma gondii requires host adenosine for its purine needs as it cannot synthesize purines de novo. The role of extracellular adenosine in the immune response to T. gondii infection has not been previously elucidated. To investigate the role of CD73-generated adenosine in the immune response to infection with Toxoplasma gondii, wild-type C57BL/6 and CD73-/- mice were inoculated with T. gondii cysts by intragastric gavage. CD73-/- mice were less susceptible to T. gondii infection, with reduced intestinal inflammation and tissue damage during the acute stages of infection, and reduced parasite burden in the brain during chronic infection. In addition, cysts isolated from infected CD73-knockout mice were attenuated in their ability to cause pathology and mortality when inoculated into naïve wildtype or CD73-/- mice. In vitro, peritoneal macrophages and bone-marrow derived dendritic cells lacking CD73 were less permissive to the intracellular replication of T. gondii tachyzoites. These findings are the first to demonstrate that lack of CD73-generated adenosine impairs T. gondii pathogenesis.
Infection with Cytomegalovirus but not Herpes Simplex Virus induces the accumulation of late differentiated “senescent” T-cells in humans (39.13)
Authors: Pawelec Graham , Maier Andrea , Jahn Gerhard , Beck Robert , Haehnel Karin , Westendorp Rudi , Derhovanessian Evelyna 
Published: January 2023

Abstract
Infection with the persistent reactivating human cytomegalovirus (CMV) is associated with an age-associated increasing accumulation of late-differentiated CD8+ T-cells even in asymptomatic healthy carriers. It has been postulated that chronic exposure to any repetitively stimulating antigen (”chronic antigenic stress”) will have similar effects. Here, we have analyzed CMV and HSV infection status in the general population. Detailed analysis of T-cell subsets was performed using 10-colour flow cytometry in 100 individuals aged 40-80 yr. T-cells were characterized according to surface expression of CD45RA, CCR7, CD27 and CD28. Our results demonstrate that T-cell subset distribution was similar in CMV-matched, HSV-seropositive and HSV-seronegative individuals, whereas, in line with our and others previous data, individuals harboring CMV had lower frequencies of naïve T-cells (CD45RA+CCR7+CD27+CD28+) ad a reciprocal accumulation of late-differentiated effector memory (CD45RA-CCR7-CD27-CD28-) and TEMRA (CD45RA+CCR7-CD27-CD28-) subsets. These findings emphasize the apparently unique effect of CMV infection on the human immune system, providing evidence that infection with a different persisting herpesvirus does not show any effects similar to the observed large impact of CMV on the proportions of different T-cell subsets. This work was supported by EU 7FP LifeSpan (LSHG-CT-2007-036894), DFG-SFB685-B4 and DFG-PA 361-11/1