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1.
Mol Cell ; 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38925114

ABSTRACT

Signal transduction proteins containing a pLxIS motif induce interferon (IFN) responses central to antiviral immunity. Apart from their established roles in activating the IFN regulator factor (IRF) transcription factors, the existence of additional pathways and functions associated with the pLxIS motif is unknown. Using a synthetic biology-based platform, we identified two orphan pLxIS-containing proteins that stimulate IFN responses independent of all known pattern-recognition receptor pathways. We further uncovered a diversity of pLxIS signaling mechanisms, where the pLxIS motif represents one component of a multi-motif signaling entity, which has variable functions in activating IRF3, the TRAF6 ubiquitin ligase, IκB kinases, mitogen-activated protein kinases, and metabolic activities. The most diverse pLxIS signaling mechanisms were associated with the highest antiviral activities in human cells. The flexibility of domains that regulate IFN signaling may explain their prevalence in nature.

2.
J Immunol ; 199(7): 2536-2546, 2017 10 01.
Article in English | MEDLINE | ID: mdl-28814601

ABSTRACT

IL-15 is an essential cytokine known to promote T cell survival and activate the effector function of memory phenotype CD8 T cells. Blocking IL-15 signals also significantly impacts tissue-specific effector and memory CD8 T cell formation. In this study, we demonstrate that IL-15 influences the generation of memory CD8 T cells by first promoting their accumulation into mucosal tissues and second by sustaining expression of Bcl-6 and T-bet. We show that the mechanism for this recruitment is largely dependent on mammalian target of rapamycin and its subsequent inactivation of FoxO1. Last, we show that IL-15 complexes delivered locally to mucosal tissues without reinfection is an effective strategy to enhance establishment of tissue resident memory CD8 T cells within mucosal tissues. This study provides mechanistic insight into how IL-15 controls the generation of memory CD8 T cells and influences their trafficking and ability to take up residence within peripheral tissues.


Subject(s)
CD8-Positive T-Lymphocytes/physiology , Immunologic Memory , Interleukin-15/physiology , Mucous Membrane/immunology , Animals , CD8-Positive T-Lymphocytes/drug effects , Cell Differentiation/drug effects , Cell Movement , Forkhead Box Protein O1/metabolism , Interleukin-15/genetics , Interleukin-15/pharmacology , Mice , Mice, Inbred C57BL , Mucous Membrane/cytology , Mucous Membrane/drug effects , Proto-Oncogene Proteins c-bcl-6/genetics , Signal Transduction/drug effects , Sirolimus/pharmacology , T-Box Domain Proteins/genetics , T-Lymphocyte Subsets/drug effects , TOR Serine-Threonine Kinases/metabolism
3.
J Immunol ; 193(5): 2067-71, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25070853

ABSTRACT

Mucosal tissues are subject to frequent pathogen exposure and are major sites for transmission of infectious disease. CD8 T cells play a critical role in controlling mucosa-acquired infections even though their migration into mucosal tissues is tightly regulated. The mechanisms and signals that control the formation of tissue-resident memory CD8 T cells are poorly understood; however, one key regulator of memory CD8 T cell differentiation, mammalian target of rapamycin kinase, can be inhibited by rapamycin. We report that, despite enhancing the formation of memory CD8 T cells in secondary lymphoid tissues, rapamycin inhibits the formation of resident memory CD8 T cells in the intestinal and vaginal mucosa. The ability of rapamycin to block the formation of functional resident CD8 T cells in mucosal tissues protected mice from a model of CD8 T cell-mediated lethal intestinal autoimmunity. These findings demonstrate an opposing role for mammalian target of rapamycin in the formation of resident versus nonresident CD8 T cell immunity.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Mucosal/physiology , Immunologic Memory/physiology , Intestinal Mucosa/injuries , Models, Immunological , TOR Serine-Threonine Kinases/immunology , Animals , Autoimmunity/physiology , CD8-Positive T-Lymphocytes/cytology , Female , Intestinal Mucosa/cytology , Mice , Vagina/cytology , Vagina/immunology
4.
Neuropathol Appl Neurobiol ; 41(4): 544-56, 2015 Jun.
Article in English | MEDLINE | ID: mdl-24750178

ABSTRACT

AIMS: Use of enriched environment (EE) housing has been shown to promote recovery from cerebral ischaemic injury but the underlying mechanisms of their beneficial effects remains unclear. Here we examined whether the beneficial effects of EE housing on ischaemia-induced neurodegeneration and cognitive impairment are associated with increased insulin-like growth factor-1 (IGF-1) signalling in the hippocampus. METHODS: Forty-two adult male Wistar rats were included in the study and received either ischaemia or sham surgery. Rats in each group were further randomized to either: EE or standard laboratory cage housing (control). Rats were placed in their assigned housing condition immediately after recovery from anaesthesia. Behavioural testing in the cued learning and discrimination learning tasks were conducted 2 weeks after ischaemia. Rats were euthanized after behavioural testing and the hippocampus was analysed for IGF-1 level, IGF-1 receptor (IGF-1R) activation, protein kinase B (Akt) pathway activation, neurone loss and caspase 3 expression. RESULTS: Our data showed that EE housing: (1) mitigated ischaemia-induced neuronal loss; (2) attenuated ischaemia-induced increase in caspase 3 immunoreactivity in the hippocampus; (3) ameliorated ischaemia-induced cognitive impairments; and (4) increased IGF-1R activation and signalling through the Akt pathway after ischaemic injury. CONCLUSION: Ultimately, these findings suggest the possibility that IGF-1 signalling may be one of the underlying mechanisms involved in the beneficial effects of EE in optimizing recovery following cerebral ischaemic injury.


Subject(s)
Environment , Insulin-Like Growth Factor I/metabolism , Ischemic Attack, Transient/metabolism , Animals , Apoptosis , Hippocampus/metabolism , Hippocampus/pathology , Ischemic Attack, Transient/pathology , Ischemic Attack, Transient/psychology , Male , Maze Learning , Phosphorylation , Rats , Rats, Wistar , Recovery of Function , Signal Transduction , Up-Regulation
5.
Hum Pathol ; 81: 78-88, 2018 11.
Article in English | MEDLINE | ID: mdl-29958927

ABSTRACT

Composite neoplasms (CNs) are rare and diagnostically challenging lesions that require differentiating between mixed clonal tumors with divergent phenotypes (MT), collision of 2 independent tumors adjacent to each other (CT), and tumor-to-tumor metastasis (TTM). To that end, pathologists have traditionally used immunohistochemistry and limited molecular studies, such as Sanger sequencing. Herein we evaluate the potential application of NGS in the differential diagnosis of these rare neoplasms. Four CNs were included in the study. Two were diagnosed as MT (mixed adenoneuroendocrine carcinoma of the gallbladder and metastatic papillary thyroid carcinoma with squamous dedifferentiation) and 2 were interpreted as TTM (esophageal adenocarcinoma to lung adenocarcinoma and small cell carcinoma of the lung to meningeal melanoma). Diagnoses were made using clinical, histologic, and immunophenotypic information, with the aid of limited molecular studies in 2 cases. Formalin-fixed, paraffin-embedded tissue was dissected for DNA and RNA extraction, and NGS was performed using the Oncomine Comprehensive Panel. The 2 tumors initially interpreted as MT showed shared genetic aberrations in the different neoplastic components, supporting the pathologic diagnosis. NGS results for the lesion diagnosed as esophageal adenocarcinoma metastatic to lung adenocarcinoma did not support the histopathologic interpretation and were deemed inconclusive. However, the identification of an identical CDKN2A mutation in all components and in the adjacent benign lung parenchyma suggests a possible germline aberration. Sequencing results in the last case were clearly supportive of TTM. This study illustrates the role of NGS in the diagnostic workup of CNs, as an adjunct to light microscopy and immunohistochemistry.


Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Profiling/methods , Genetic Variation , High-Throughput Nucleotide Sequencing , Neoplasms, Complex and Mixed/genetics , Aged , Biomarkers, Tumor/analysis , Chicago , Diagnosis, Differential , Female , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasms, Complex and Mixed/chemistry , Neoplasms, Complex and Mixed/pathology , Phenotype , Predictive Value of Tests
7.
Behav Brain Res ; 168(2): 261-71, 2006 Apr 03.
Article in English | MEDLINE | ID: mdl-16356557

ABSTRACT

In this study we examined whether expression of microtubule-associated protein 2 (MAP2) after transient global cerebral ischemia can be influenced by behavioral experience and if the changes are associated with functional improvement. Rats received either ischemia or sham surgery then assigned to: complex environment housing (EC) or social housing (SC) as controls for 14 days followed by water maze testing. Upregulation of MAP2 was seen in all ischemic animals with a significant overall increase evident in the EC housed rats. Behaviorally, all animals learned to perform the water maze task over time but the ischemia SC rats had the worst performance overall while all the EC housed animals demonstrated the best performance in general. Regression analysis showed that increase MAP2 expression was able to explain some of the variance in the behavioral parameters in the water maze suggesting that this cytoskeletal protein probably played a role in mediating enhanced functional outcomes.


Subject(s)
Cognition Disorders/etiology , Environment , Ischemic Attack, Transient/complications , Ischemic Attack, Transient/metabolism , Microtubule-Associated Proteins/metabolism , Animals , Behavior, Animal , Cell Count/methods , Disease Models, Animal , Fluoresceins , Gene Expression Regulation/physiology , Hippocampus/metabolism , Hippocampus/pathology , Immunohistochemistry/methods , Male , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Organic Chemicals , Rats , Rats, Wistar , Reaction Time/physiology , Regression Analysis , Swimming
8.
Behav Brain Res ; 171(1): 17-25, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16621046

ABSTRACT

In this study we examined whether astrocytic and basic fibroblast growth factor changes after cerebral ischemia can be influenced by rehabilitation training and if these changes are associated with functional improvement. After receiving either ischemia or sham surgery, male adult Wistar rats were assigned to one of two rehabilitation training group: complex environment housing (EC) or paired housing as controls (CON). Rats were tested in the water maze after 14 days of rehabilitation training. Results showed increased expression of reactive astrocytes (GFAP) in all ischemic animals and in the sham EC rats with a significant overall increased seen in the ischemia EC housed animals. The pattern of basic fibroblast growth factor (FGF-2) expression seen was somewhat similar to that of GFAP. Behavioral data showed that even though all animals learned to perform the water maze task over time, the ischemia CON rats took longer to learn the task while all the ischemia EC animals performed as well as the sham groups. Regression analysis showed that increased GFAP was able to explain some of the variances in the behavioral parameters in the water maze of the ischemia EC rats suggesting that the activation of astrocytes in this group probably mediated enhanced functional recovery. Lastly, it is possible that the favorable effect of astrocyte activation after cerebral ischemia was mediated by FGF-2.


Subject(s)
Astrocytes/pathology , Brain Ischemia/pathology , Fibroblast Growth Factor 2/metabolism , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/pathology , Maze Learning/physiology , Analysis of Variance , Animals , Astrocytes/metabolism , Brain Ischemia/metabolism , Brain Ischemia/therapy , Disease Models, Animal , Gliosis/pathology , Gliosis/prevention & control , Hippocampus/metabolism , Housing, Animal , Immunohistochemistry , Male , Motor Activity/physiology , Neurons/pathology , Random Allocation , Rats , Rats, Wistar , Recovery of Function/physiology , Regression Analysis , Social Environment , Tissue Distribution
9.
Brain Res ; 1033(1): 51-7, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15680339

ABSTRACT

Damage to the adult brain can result in adaptive plasticity in regions adjacent to the site of the principal insult and that the plastic changes may be modulated by post-injury rehabilitation training. In this study, we examined the effects of rehabilitation training on synaptic morphology in the dentate gyrus following transient global cerebral ischemia and the metabolic correlates of the ultrastructural changes. Forty adult male Wistar rats were included in the study and assigned to either ischemia or sham group. Following ischemic or sham surgery, rats were randomized to either complex environment housing (EC), exercise (EX), or social condition (SC, paired housing) group. Electron microscopy and unbiased stereological methods were used to evaluate synaptic plasticity and the number and size of mitochondria in synaptic axon terminals. Increased number of granule neurons was seen in all ischemic groups and in the sham EC rats. Changes in the number of synapses per neuron in the outer and inner molecular layers of the dentate gyrus parallel those seen in granule neurons. Similarly, ischemia and behavioral experience in EC independently increased the number of synaptic mitochondria in presynaptic terminals in both the outer and inner molecular layers; however, no significant changes were seen in mitochondrial size. These data suggest a link between behavioral training and synaptic plasticity in the region adjacent to the injury and that the likely metabolic correlate of this synaptic plasticity is increased number of mitochondria at synaptic axon terminals.


Subject(s)
Brain Ischemia/physiopathology , Brain Ischemia/rehabilitation , Dentate Gyrus/pathology , Exercise Therapy/methods , Mitochondria/physiology , Presynaptic Terminals/physiology , Synapses/physiology , Animals , Behavior, Animal , Cell Count/methods , Disease Models, Animal , Male , Microscopy, Electron, Transmission/methods , Mitochondria/ultrastructure , Neurons/physiology , Rats , Rats, Wistar
10.
Acta Neuropathol Commun ; 1: 57, 2013 09 06.
Article in English | MEDLINE | ID: mdl-24252176

ABSTRACT

BACKGROUND: Persistent neuroinflammation and disruptions in brain energy metabolism is commonly seen in traumatic brain injury (TBI). Because of the lack of success of most TBI interventions and the documented benefits of environmental enrichment (EE) in enhancing brain plasticity, here we focused our study on use of EE in regulating injury-induced neuroinflammation and disruptions in energy metabolism in the prefrontal cortex and hippocampus. Adult male Wistar rats were used in the study and randomly assigned to receive either: mild TBI (mTBI) using the controlled cortical injury model or sham surgery. Following surgery, rats from each group were further randomized to either: EE housing or standard laboratory housing (CON). After 4 weeks of recovery, cognitive testing was performed using the non-matching-to-sample and delayed non-matching-to-sample tasks. After completion of behavioral testing, levels of the pro-inflammatory cytokines IL-1ß and TNF-α and the anti-inflammatory cytokine IL-10 were measured. In addition, levels of AMPK (adenosine monophosphate-activated protein kinase), phosphorylated AMPK and uMtCK (ubiquitous mitochondrial creatine kinase) were assessed as measures of brain energy homeostasis. RESULTS: Our results showed that EE: (1) decreased the pro-inflammatory cytokines IL-1ß and TNF-α and enhanced levels of the anti-inflammatory cytokine IL-10 after mTBI; (2) mitigated mTBI-induced cognitive impairment; and (3) attenuated mTBI-induced downregulation in pAMPK/AMPK ratio and uMtCK levels. CONCLUSIONS: Our data demonstrated the potential of EE to modulate the persistent: (1) neuroinflammatory response seen following mTBI, and (2) persistent disturbance in brain energy homeostasis. It is possible that through the mechanism of modulating neuroinflammation, EE housing was able to restore the disruption in energy metabolism and enhanced functional recovery after mTBI.


Subject(s)
Brain Injuries/physiopathology , Brain Injuries/therapy , Hippocampus/physiopathology , Housing, Animal , Neuroimmunomodulation/physiology , Prefrontal Cortex/physiopathology , AMP-Activated Protein Kinases/metabolism , Animals , Brain Injuries/complications , Cognition Disorders/etiology , Cognition Disorders/physiopathology , Cognition Disorders/therapy , Creatine Kinase, Mitochondrial Form/metabolism , Disease Models, Animal , Environment , Homeostasis/physiology , Male , Phosphorylation , Random Allocation , Rats, Wistar , Recovery of Function/physiology
11.
PLoS One ; 7(7): e41240, 2012.
Article in English | MEDLINE | ID: mdl-22911764

ABSTRACT

Adoptive T cell therapy has proven to be beneficial in a number of tumor systems by targeting the relevant tumor antigen. The tumor antigen targeted in our model is Mammaglobin-A, expressed by approximately 80% of human breast tumors. Here we evaluated the use of adoptively transferred Mammaglobin-A specific CD8 T cells in combination with low dose irradiation to induce breast tumor rejection and prevent relapse. We show Mammaglobin-A specific CD8 T cells generated by DNA vaccination with all epitopes (Mammaglobin-A2.1, A2.2, A2.4 and A2.6) and full-length DNA in vivo resulted in heterogeneous T cell populations consisting of both effector and central memory CD8 T cell subsets. Adoptive transfer of spleen cells from all Mammaglobin-A2 immunized mice into tumor-bearing SCID/beige mice induced tumor regression but this anti-tumor response was not sustained long-term. Additionally, we demonstrate that only the adoptive transfer of Mammaglobin-A2 specific CD8 T cells in combination with a single low dose of irradiation prevents tumors from recurring. More importantly we show that this single dose of irradiation results in the down regulation of the macrophage scavenger receptor 1 on dendritic cells within the tumor and reduces lipid uptake by tumor resident dendritic cells potentially enabling the dendritic cells to present tumor antigen more efficiently and aid in tumor clearance. These data reveal the potential for adoptive transfer combined with a single low dose of total body irradiation as a suitable therapy for the treatment of established breast tumors and the prevention of tumor recurrence.


Subject(s)
Adoptive Transfer , Breast Neoplasms/immunology , Breast Neoplasms/therapy , CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Mammaglobin A/immunology , Whole-Body Irradiation , Animals , Breast Neoplasms/mortality , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Cytotoxicity, Immunologic , Dendritic Cells/immunology , Dendritic Cells/metabolism , Epitopes, T-Lymphocyte/genetics , Female , Humans , Immunologic Memory , Interferon-gamma/biosynthesis , Interleukin-7 Receptor alpha Subunit/metabolism , L-Selectin/metabolism , Lipid Metabolism , Mammaglobin A/chemistry , Mice , Mice, SCID , Mice, Transgenic , Scavenger Receptors, Class A/metabolism , Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Vaccines, DNA/immunology
12.
J Neurotrauma ; 28(12): 2485-92, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21612313

ABSTRACT

In this study, we examined whether enriched environment (EE) housing has direct neuroprotective effects on oxidative damage following transient global cerebral ischemia. Fifty-two adult male Wistar rats were included in the study and received either ischemia or sham surgery. Once fully awake, rats in each group were randomly assigned to either: EE housing or socially paired housing (CON). Animals remained in their assigned environment for 7 days, and then were killed. Our data showed that glutamate receptor expression was significantly higher in the hippocampus of the ischemia CON group than in the ischemia EE group. Furthermore, the oxidative DNA damage, protein oxidation, and neurodegeneration in the hippocampus of the ischemia CON group were significantly increased compared to the ischemia EE group. These results suggest that EE housing possibly modulated the ischemia-induced glutamate excitotoxicity, which then attenuated the oxidative damage and neurodegeneration in the ischemia EE rats.


Subject(s)
Brain Ischemia/metabolism , DNA Damage/physiology , Environment , Oxidative Stress/physiology , Receptors, N-Methyl-D-Aspartate/metabolism , Social Environment , Animals , Brain Ischemia/prevention & control , Hippocampus/metabolism , Male , Random Allocation , Rats , Rats, Wistar
13.
PLoS One ; 6(2): e16529, 2011 Feb 18.
Article in English | MEDLINE | ID: mdl-21364749

ABSTRACT

Memory CD4 T cells play a vital role in protection against re-infection by pathogens as diverse as helminthes or influenza viruses. Inducible costimulator (ICOS) is highly expressed on memory CD4 T cells and has been shown to augment proliferation and survival of activated CD4 T cells. However, the role of ICOS costimulation on the development and maintenance of memory CD4 T cells remains controversial. Herein, we describe a significant defect in the number of effector memory (EM) phenotype cells in ICOS(-/-) and ICOSL(-/-) mice that becomes progressively more dramatic as the mice age. This decrease was not due to a defect in the homeostatic proliferation of EM phenotype CD4 T cells in ICOS(-/-) or ICOSL(-/-) mice. To determine whether ICOS regulated the development or survival of EM CD4 T cells, we utilized an adoptive transfer model. We found no defect in development of EM CD4 T cells, but long-term survival of ICOS(-/-) EM CD4 T cells was significantly compromised compared to wild-type cells. The defect in survival was specific to EM cells as the central memory (CM) ICOS(-/-) CD4 T cells persisted as well as wild type cells. To determine the physiological consequences of a specific defect in EM CD4 T cells, wild-type and ICOS(-/-) mice were infected with influenza virus. ICOS(-/-) mice developed significantly fewer influenza-specific EM CD4 T cells and were more susceptible to re-infection than wild-type mice. Collectively, our findings demonstrate a role for ICOS costimulation in the maintenance of EM but not CM CD4 T cells.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/physiology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/physiology , Immunologic Memory/genetics , Proteins/physiology , Animals , Antigens, Differentiation, T-Lymphocyte/genetics , CD4-Positive T-Lymphocytes/metabolism , Cell Survival/genetics , Cytoprotection/genetics , Cytoprotection/immunology , Genetic Predisposition to Disease , Immunologic Memory/physiology , Inducible T-Cell Co-Stimulator Ligand , Inducible T-Cell Co-Stimulator Protein , Influenza A virus/physiology , Interleukin-4/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/immunology , Phenotype , Proteins/genetics
14.
J Neurotrauma ; 26(4): 613-25, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19271963

ABSTRACT

In this study, we examined whether ischemia-induced amyloidogenesis could be modulated by environmental "experience," and whether this modulation is associated with improved cognitive functioning. Rats were subjected to either global ischemia or sham surgery and then were randomly assigned to either enriched environment housing (EE) or socially paired housing (controls). After 14 days of differential environmental housing, the rats were tested in the water maze. Our results show decreased C-terminal fragments of the beta-amyloid precursor protein (betaAPP) and decreased amyloid beta (Abeta) load in the ischemic EE rats compared to the ischemic control animals. In addition, Abeta oligomerization was significantly decreased in the ischemic EE animals compared to the ischemic control rats. Further, significantly increased levels of neprilysin, but not insulin-degrading enzyme, amyloid-degrading enzymes, were seen in the ischemic EE rats compared to the ischemic control animals. Behavioral analyses showed that ischemic EE rats performed significantly better on the memory task compared to the ischemic control group. These results suggest that use of multi-sensory environmental enrichment following cerebral ischemia may reduce the accumulation of Abeta peptide in the more pathologic oligomeric form, and consequently may enhance functional recovery.


Subject(s)
Amyloid beta-Peptides/metabolism , Cognition Disorders/therapy , Environment, Controlled , Hypoxia-Ischemia, Brain/metabolism , Hypoxia-Ischemia, Brain/therapy , Plaque, Amyloid/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Brain/metabolism , Brain/pathology , Brain/physiopathology , Cognition Disorders/etiology , Cognition Disorders/physiopathology , Disease Models, Animal , Hypoxia-Ischemia, Brain/physiopathology , Male , Maze Learning/physiology , Memory Disorders/etiology , Memory Disorders/physiopathology , Memory Disorders/therapy , Neprilysin/metabolism , Neuropsychological Tests , Plaque, Amyloid/pathology , Rats , Rats, Wistar , Recovery of Function/physiology , Treatment Outcome
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