bluuebunny/crossref_metadata_2025_split huggingface dataset:
SA-FasL-Induced Localized Allotolerance to Pancreatic Islets Is Mediated by Phagocytes/TGF-β Axis (145.6)
Authors: Bandura-Morgan Laura , Yolcu Esma , Zhao Hong , Madireddi Shravan , Shirwan Haval 
Published: January 2023

Abstract
We recently showed that pancreatic islets engineered to display on their surface a recombinant SA-FasL protein induce robust localized tolerance. Tolerance was initiated by FasL-induced alloreactive T cell apoptosis and sustained by Treg cells. We herein tested if tolerance induction involves phagocytes engulfing T cells apoptotic bodies as a means of regulation. C57BL/6 mice were transplanted with BALB/c SA-FasL-islets with the transient use of rapamycin given on the day of Tx daily for 15 days. The role of phagocytes and TGF-β in the induced tolerance was tested by using clodronate-loaded liposomes depletion and an Ab to TGF-β. Depletion of phagocytes using clodronate-loaded liposomes one day prior to Tx resulted in prompt rejection of SA-FasL-engineered islets (n=7). Similarly, in vivo blockade of TGF-β early (day 0, n=5), but not late (&gt;100 days, n=5), postTx resulted in acute rejection of long-term allogeneic SA-FasL-islets. Immunohistochemical analysis revealed that only SA-FasL-engineered islets scored positive for TGF-β and have more macrophages localized in the periphery of islet as compared with SA control. In in vitro cultures, we demonstrated that T cells undergoing SA-FasL-mediated apoptosis expressed membrane-bound TGF-β and these cells were engulfed by macrophages. These data suggest that phagocytosis of apoptotic bodies by phagocytes leads to the secretion of TGF-β, which in turn may facilitate the induction of Treg cells that maintain tolerance.
PARP-1 regulates pro-inflammatory cell death (34.13)
Authors: Malireddi RK Subbarao , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
PARP-1(poly (ADP-ribose) polymerase 1), an enzyme involved in DNA repair, is a nuclear chromatin associated multifunctional protein and belongs to a large family of enzymes that can synthesize long branched polymers of ADP-ribose units by using NAD+( Nicotinamide adenine dinucleotide) as the substrate. DNA strand nicks and breaks activate PARP-1 and the activated enzyme makes branched chains of up to 200 ADP-ribose units and adds covalently to various nuclear proteins such as histones and especially PARP-1 itself. PARP-1 has been shown to play a major role in a number of pathophysiological situations. In this study, we show that cytokine and chemokine profiles from PARP-WT and -KO BMDM showed no significant differences. However, IL1-β secretion is reduced in PARP-1 deficient macrophages, suggesting a role for PARP-1 in pro-inflammatory signaling. PARP-1 deficient macrophages had displayed prominent protection from pro-inflammatory cell death in response to LPS+ATP stimuli. Together, these results demonstrate that PARP-1 contribute to the pathophysiology by regulating the pro-inflammatory cytokine profiles.
Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells (35.10)
Authors: Vimala Raveendran Vineesh , Tan Xiaoyu , Levant Beth , Stechschulte Daniel , Dileepan Kottarappat 
Published: January 2023

Abstract
Histamine (HIS) is a well-recognized modulator of vascular inflammation. We have shown that HIS, acting via H1 receptors (H1R), synergizes LPS-induced production of IL-6, IL-8, PGE2 and PGI2 by endothelial cells. The synergy between HIS and LPS was partly attributed to HIS-induced expression of TLR4. In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) and enhances HIS responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in 2- to 4-fold increases in H1R mRNA expression in a time and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. LPS-induced H1R expression was maximum at 4h after LPS treatment which returned to the basal level by 8h. The LPS-induced H1R gene expression was mediated through TLR4 because gene silencing by TLR4-siRNA inhibited LPS effect. The specific binding of [3H]-pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was 3-fold higher than the untreated cells. When HCAEC were pretreated with LPS for 24h, washed and subsequently challenged with HIS, 15-, 17- and 10-fold increases in IL-6, PGI2 and PGE2 production, respectively, were noted. HIS-induced syntheses of IL-6, PGE2 and PGI2 by LPS-primed HCAEC were completely blocked by the H1R antagonist cetirizine. These results demonstrate that LPS upregulates the expression and function of H1R in HCAEC leading to agonist-induced increase in IL-6, PGI2 and PGE2 production.
Transcriptional regulation of innate αβ CD8+ T cell development in Itk deficient mice (36.35)
Authors: Kraus Zachary , Horai Reiko , Schwartzberg Pamela 
Published: January 2023

Abstract
Inducible T cell kinase (Itk) deficient mice develop a large population of αβ CD8+ innate-like T cells that possess a memory-like phenotype and are dependent on IL-15. Similar to other innate T cell lineages, these cells are positively selected by hematopoietic cells instead of thymic stroma in a SAP dependent manner that involves the interaction of signaling activation molecule (SLAM) family members. While much work has been done to characterize these cells, very little is known about the molecular pathways that prevent (Wt) or initiate (Itk-/-) the expansion of innate CD8+ T cells. One clue came from work examining mice with a T-cell specific deletion of CREB binding protein (CBP) driven from the Lck proximal promoter. These mice revealed a similar expansion of CD8 T cells with an innate phenotype. CBP is a transcriptional co-activator, which possesses histone acetyl transferase (HAT) activity and is known to associate with a wide range of transcription factors, most notably the cAMP response element binding protein (CREB). We find that TCR stimulation induces robust phosphorylation of CREB that is impaired in Itk-deficient T cells. We are currently further evaluating how Itk-deficiency affects CREB/CBP activation, and the impact of these pathways on transcriptional programs leading to innate T cell development.
Hematopoietic stem and progenitor cell defects in the Ts65Dn mouse model of Down Syndrome: implications for the role of oxidative stress in immune dysfunction (36.58)
Authors: Lorenzo Laureanne , Chen Haiyan , Clark Sarah , Yarowsky Paul , Williams Mark 
Published: January 2023

Abstract
Down Syndrome (DS) is a genetic disease caused by trisomy 21. In addition to cognitive defects, it is characterized by hematologic disorders. Previous studies have linked oxidative stress to the pathology of DS. Using the Ts65Dn mouse model of DS, we found increased levels of reactive oxygen species (ROS) in the hematopoietic progenitor cells (HPC) of these mice. We hypothesize that increased oxidative stress in HPC leads to functional changes that contribute to hematologic disorders in DS patients. Analysis of bone marrow cells (BMC) showed that Ts65Dn mice have fewer hematopoietic stem cells (HSC) and common lymphoid progenitors (CLP). Competitive reconstitution studies in vivo and colony-forming assays in vitro were consistent with functional changes in these populations. Hematopoietic defects were also observed in the thymus. A decrease in both thymic cellularity and the percentage of pro-T cells was observed. Decreased expression of the IL-7Rα chain may be a mechanism for defects in CLP and thymic populations. The IL-7Rα chain is part of the receptor for IL-7, a cytokine essential for lymphoid development and homeostasis. Consistent with the pro-survival and proliferative effects of IL-7, ex vivo expression of Bcl-2 and measures of in vivo proliferation were diminished in thymocytes from Ts65Dn mice. The data suggest that HPC defects underlie the immune dysfunction in DS and that oxidative stress may be involved in the hematologic abnormalities observed in Ts65Dn mice.
Normal and Pathological Regulation of DNA Damage Response to T-cell Receptor Gene Rearrangement (36.61)
Authors: Livak Ferenc , Hathcock Karen , Hodes Richard , Bowen Steven 
Published: January 2023

Abstract
The T-cell receptor (TCR) is encoded by tandem arrays of variable (V), diversity (D), and joining (J) gene segments that are somatically rearranged during thymic development. During this process the RAG recombinase introduces transient DNA double strand breaks (DSBs) which are repaired by non-homologous end joining (NHEJ). Additionally, the DSBs are detected by components of the cellular DNA damage response (DDR) which bind to the chromatin within 1 megabase of the break forming foci. One component of DDR, Ataxia Telangiectasia mutated (ATM), plays a major role in activating downstream effectors involved in apoptosis, cell cycle arrest and DNA repair. ATM-deficiency is characterized by reduced rearrangement at the TCR-α locus in CD4/CD8 double positive (DP) thymocytes, high frequency of thymic lymphomas carrying translocations at the TCR-α locus, and increased frequency of TCR-β/TCR-γ trans-rearrangements. Since TCR-β, γ and δ recombination occurs in CD4/CD8 double negative (DN) cells, we examined the effect of ATM deficiency on these rearrangements. We found that rearrangement is impaired at the TCR-β, γ and δ loci. We also demonstrate increased frequency of TCR-β/TCR-γ trans-rearrangements in ATM deficient cells. Such trans-rearrangements may be the result of concurrent recombination at multiple TCR loci in DN cells. We are currently testing this hypothesis using combined immunofluorescence detection of DDR foci and fluorescent in situ hybridization of TCR loci.
Identification and characterization of zebrafish Rpl22 and its role in T cell development in vivo (36.66)
Authors: Zhang Yong , Sun Xiaoli , Rhodes Jennifer , Wiest David 
Published: January 2023

Abstract
Mutations in a number of ribosomal proteins (RP) disrupt hematopoiesis in such syndromes as Diamond Blackfan Anemia; however, RP mutations had not previously been reported to disrupt T lymphocyte development. We recently reported that germline ablation of Rpl22 in mice caused a selective block in development of αβ lineage T cells. To gain insight into the basis by which Rpl22 mutations disrupt T cell development, we are exploiting the zebrafish model system. We identified the zebrafish ortholog of rpl22 (zgc:123327). Whole mount in situ hybridization showed that zebrafish rpl22 is expressed both maternally and zygotically throughout early development, with relative enrichment in the aorta-gonad mesonephros (AGM) and intermediate cellular mass (ICM) which are the sites of primitive (erythroid and myeloid) and definitive (lymphoid) hematopioesis in zebrafish. Despite being highly expressed in the sites of primitive and early definitive hematopoiesis, knocking down Rpl22 using antisense morpholinos did not block either of these processes. However, morpholino knockdown of Rpl22 did block T cell development. Therefore, unlike other ribosomal protein (e.g., Rps19) whose loss primarily impairs erythropoiesis, Rpl22 function appears to be dispensable for erythroid development and is instead selectively important for T cell development. Efforts to exploit the zebrafish system to address the mechanism underlying rpl22 function in T cell development and thymopoiesis are ongoing.
iNKT cell subsets are associated with distinct clinical manifestations of pulmonary sarcoidosis. (37.16)
Authors: Koth Laura , Woodruff Prescott , Nixon Douglas , Snyder-Cappione Jennifer 
Published: January 2023

Abstract
Sarcoidosis is an inflammatory disease of unknown etiology that presents with a wide range of clinical courses, from complete recovery to irreversible lung fibrosis. Invariant Natural Killer T (iNKT) cells are implicated in the progression of many diseases, including sarcoidosis. Given the known phenotypic heterogeneity of this unique T cell subset, we hypothesized that the iNKT cell compartment of individuals with sarcoidosis will have a skewed subset distribution that may track with disease outcome. We used flow cytometry to compare both total iNKT frequencies and distribution of CD4, CD8, CD56, and CD161 subsets in the PBMC of sarcoidosis subjects with a wide range of lung disease severity and healthy controls. We found the lowest iNKT frequencies in subjects with fibrotic lung disease and worst prognosis (Stage IV). This group was also characterized by a higher percentage of CD4/CD8 double-positive (DP) and a lower percentage of CD161+ iNKT cells, a marker profile indicative of recent thymic emigration. In contrast, the percentage of CD56+ iNKT cells correlated directly with a favorable clinical outcome (Stage I), as well as highest total iNKT frequencies among diseased individuals. In summary, we found that distinct iNKT cell subsets tracked with lung disease severity, and may possess different functional properties that directly influence sarcoidosis disease course.
Activation of TLR signalling by Salmonella causes erythropoesis. (37.22)
Authors: Jackson Amy , McSorley Stephen 
Published: January 2023

Abstract
Salmonella infection causes splenomegaly that is often assumed to be due to the increased number of infected phagocytes in the spleen. However, we infected mice with Salmonella and determined that erythrocytes accounted for the largest cell population that increased in the spleen. These splenic erythrocytes were not recruited from peripheral blood and were at an immature stage of development, indicating erythropoesis due to infection. Indeed, erythropoietin (Epo) was induced within days of Salmonella infection and was directly responsible for the observed erythropoiesis. Production of Epo was almost completely inhibited in the absence of TLR signaling indicating that erythropoesis occurs a consequence of early innate activation. Our data suggest that erythropoesis may be a key feature of systemic bacterial infection and we are currently examining whether this is important for the disregulation of splenic architecture or inhibition of adaptive immune responses during Salmonellosis
HCV core/gC1qR ligation activates STAT3 in human innate immune cells via an IL-6 autocrine pathway. (37.23)
Authors: Tacke Robert , Nguyen Virginia , Tosello-Trampont Annie , Mullins David , Hahn Young 
Published: January 2023

Abstract
Hepatitis C virus (HCV) infection in humans is highly efficient in the establishment of persistent infection. Persistent HCV infection can lead to the development of chronic liver disease and hepatocellular carcinoma. T cells in persistently infected individuals exhibit impaired function, and fail to clear virus. HCV core protein secreted from infected hepatocytes, has been reported to inhibit T cell function by inhibiting the pro-inflammatory response of APCs (i.e. monocytes, macrophages, and dendritic cells). To further characterize the molecular basis for APC regulation by extracellular HCV core, we examined the ability of HCV core to induce STAT3 activation. STAT3 plays a pivotal role in regulating the inflammatory response and differentiation of APCs. In this study we report the activation of STAT3 following ligation of HCV core with complement receptor, gC1qR, as well as with a gC1qR agonistic monoclonal antibody. HCV core-mediated STAT3 activation is dependant on the activation of the PI3K/AKT pathway. Additionally, transcription and translation are required for gC1qR mediated STAT3 activation. Lastly, we show that multi-functional cytokine IL-6 is essential for HCV core-induced STAT3 activation. These results suggest that HCV core-mediated STAT3 activation may contribute to alteration of inflammatory responses by monocytes, macrophages, and dendritic cells, leading to impaired T cell responses during HCV infection.
Insight into AhR-mediated increases in neutrophilia during infection: iNOS as a potentially new AhR target gene (37.26)
Authors: Head Jennifer , Begy Beth , Lawrence B. Paige 
Published: January 2023

Abstract
There are many known factors that can affect immune responses to respiratory viral infections such as influenza A virus. Indeed, recent epidemiological studies indicate that in addition to host genetics, age and pathogen sub-types, a variety of environmental factors also impact the immune response to infections. Many of these environmental factors, including diesel exhaust and cigarette smoke, contain ligands for the aryl hydrocarbon receptor (AhR), an environment-sensing transcription factor shown to affect multiple facets of the immune system. Our laboratory has shown that activation of the AhR by the persistent environmental contaminant dioxin exacerbates neutrophil recruitment and increases the expression of inducible nitric oxide synthase (iNOS) in the lungs of influenza virus-infected mice. We show that depleting neutrophils during viral infection does not abrogate AhR-mediated increases in iNOS expression, demonstrating that neutrophil recruitment is downstream of elevated iNOS. We also show that AhR activation in iNOS-deficient mice infected with influenza virus does not affect neutrophil recruitment to the lung. Thus, these findings suggest that these AhR-mediated events are linked, and that increased iNOS expression could be a novel mechanism regulating neutrophil migration the infected lung. Additionally these studies implicate iNOS as a novel AhR target gene and provide new insights into the mechanisms underlying leukocyte recruitment during viral infections.
Induction of distinct neurological disease manifestations during Relapsing fever requires T lymphocytes (40.11)
Authors: Liu Hongqi , Fitzgerald Denise , Gran Bruno , Leong John , Alugupalli Kishore 
Published: January 2023

Abstract
Relapsing fever (RF) borreliosis is a multi-systemic infection characterized primarily by bacteremia but can extend to the central nervous system (CNS). The incidence of CNS disease manifestations in humans depends on the infecting RF Borrelia species. In the murine model of Borrelia hermsii infection we found distinct signs of CNS disease that ranged from a flaccid tail to complete paralysis of hind limbs. Infiltration of large number of T cells into the spinal cord of B. hermsii-infected mice and the up-regulation of MHC-II and CD80 on infiltrating macrophages and on microglial cells indicated a role for T cell and antigen-presenting cell interactions in this pathogenesis. Indeed, B. hermsii infection did not induce CNS disease manifestations in T cell-deficient mice (TCR-βxδ-/-), although it resulted in bacteremia comparable to wildtype level. Moreover the infiltration of immune cells into the spinal cord of TCR-βxδ-/- mice was reduced and the resident microglial cells were not activated. Histopathological analysis of lumbar sections of the spinal cord confirmed severe inflammation in wildtype but not in TCR-βxδ-/- mice. This study demonstrates that distinct neurological disease manifestations develop during RF and that T cells play a critical role in the induction of neuropathogenesis.
Strain-dependent requirement for IFN-γ for respiratory control and immunotherapy in murine gammaherpesvirus infection (42.1)
Authors: Tsai Ching-Yi , Zhang Weijun , Usherwood Edward 
Published: January 2023

Abstract
IFN-γ and perforin are important effector mechanisms used by CD8 T cells to clear virus-infected cells. Previous research has shown that either IFN-γ or pfp was non-essential for viral control after intranasal infection of mice with MHV-68. In this study, we use IFN/pfp double knockout mice to address if these two effector molecules play redundant roles in the control of acute infection with MHV-68 in Balb/C mice. Pfp KO mice and WT mice cleared infectious virus from the lungs, even following high dose infection. However IFN-γ KO and IFN/pfp DKO groups had higher virus titers in the lungs at day 10 post-infection and both groups had higher mortality rates. In IFN/pfp DKO mice, the virus titer and mortality rate were significant higher than IFN-γ KO mice, indicating a role for pfp in protection from disease. WT mice given IFN-γ blocking Ab also showed significant higher viral titers. In contrast, IFN-γ KO mice on a B6 background controlled respiratory infection comparably to WT mice. These data showed that pfp plays a redundant role in the control of virus replication but IFN-γ plays an essential role in Balb/C mice infected with MHV-68. We conclude that there is a marked strain-dependent difference in the effector mechanisms needed to control acute MHV-68 infection between B6 and Balb/C mice. In addition we show that immune therapy that re-establishes viral control after spontaneous reactivation in CD4-deficient mice depends upon pfp in B6 mice but IFN-γ in Balb/C mice.
MAP kinase phosphatase (MKP)-1 in the innate immune response to influenza infection (42.4)
Authors: Wancket Lyn , de Oliveira Stephanie , Liu Yusen 
Published: January 2023

Abstract
MKP-1 is a critical negative regulator of p38 and JNK MAP kinases. While loss of Mkp-1 function enhances cytokine production after bacterial challenge, little is known about the role of Mkp-1 in the innate immune response to viral infections. In this study we examined the role of Mkp-1 in the pulmonary immune response during influenza infection in mice. Mkp-1+/+ and Mkp-1-/- mice were intranasally inoculated with 1,000 plaque-forming units of the mouse-adapted H1N1 A/WSN/33 strain of influenza. Mice were monitored up to 6 days post inoculation and evaluated for altered host physiology, viral replication, and host immune response. Compared to Mkp-1+/+ animals, Mkp-1-/- mice exhibited accelerated weight loss and hypothermia. cDNA array analysis indicated that over 50 immune response-related genes were more robustly expressed in the lungs of Mkp-1-/- mice than in the Mkp-1+/+ mice upon influenza infection. The levels of IL-6, IL-10, and IFN-β were also higher in bronchoalveolar lavage fluid from Mkp-1-/- mice. Mechanistically, p38 and JNK activation was prolonged in Mkp-1 deficient cells treated with agents mimicking viral RNA. Together, these data support the model that Mkp-1 plays an important role in the feedback control of p38 and JNK, thus limiting harmful innate immune response and preventing severe clinical disease during pulmonary influenza infection.
Ad5-vectored FMDV vaccine elicits antigen-specific CTL responses in swine. (43.10)
Authors: Patch Jared , Pedersen Lasse , Moraes Mauro , Grubman Marvin , Golde William 
Published: January 2023

Abstract
Foot-and-mouth disease virus (FMDV) is a highly infectious picornavirus that causes disease in cloven-hoofed animals. Neutralizing antibodies are thought to play a primary role in FMDV immunity, and their induction forms the basis for current vaccine approaches. However, the role of cytotoxic T-lymphocytes (CTLs) in recovery and protection has remained largely unexplored. Immune evasion strategies of FMDV are predicted to impair the development of functional CTL assays. Specifically, virus encoded proteases inhibit expression of Class I MHC molecules by infected cells. In order to overcome these difficulties, we have analyzed the response to a recombinant, human Adenovirus 5 (huAd5) vectored, FMDV vaccine. Swine homozygous for MHC were vaccinated with a replication-defective huAd5 expressing the unprocessed capsid polyprotein of FMDV, strain A24. An MHC-matched cell line was used for antigen stimulation and as a source of target cells in cellular cytotoxicity assays. PBMCs from vaccinated animals were incubated with Ad5-infected target cells for 3-5 days. CD6+ T cells were isolated and mixed with Ad5-FMDV infected target cells. Antigen-specific killing was detected relative to control target cells. This suggests that vaccination with adenovirus vectored vaccine constructs can induce a functional CTL response against epitopes of FMDV in a MHC restricted manner.