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iNKT Cell Activation Exacerbates the Development of Huntington's Disease in R6/2 Transgenic Mice.
Park HJ, Lee SW, Im W, Kim M, Van Kaer L, Hong S
(2019) Mediators Inflamm 2019: 3540974
MeSH Terms: Animals, Brain, Cytokines, Disease Models, Animal, Disease Progression, Galactosylceramides, Genotype, Huntington Disease, Leukocytes, Lymphocyte Activation, Mice, Mice, Knockout, Natural Killer T-Cells
Show Abstract · Added March 26, 2019
Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFN and IL4 upon stimulation with the glycolipid -galactosylceramide (-GalCer). By employing both R6/2 Tg mice (murine HD model) and J18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that J18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with -GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated -GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.
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13 MeSH Terms
How Superantigens Bind MHC.
Van Kaer L
(2018) J Immunol 201: 1817-1818
MeSH Terms: Animals, Antigens, Bacterial, Clonal Deletion, Enterotoxins, Histocompatibility Antigens, Humans, Lymphocyte Activation, Minor Lymphocyte Stimulatory Antigens, Peptide Fragments, Protein Binding, Receptors, Antigen, T-Cell, alpha-beta, Superantigens, T-Lymphocytes
Added March 26, 2019
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13 MeSH Terms
Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes.
Felton JL, Maseda D, Bonami RH, Hulbert C, Thomas JW
(2018) J Immunol 201: 861-873
MeSH Terms: Animals, Antigen Presentation, Autoantibodies, Autoantigens, B-Lymphocyte Subsets, Diabetes Mellitus, Type 1, Female, Immune Tolerance, Inflammation, Insulin, Insulin Antibodies, Lymphocyte Activation, Male, Mice, Mice, Inbred NOD, Mice, Transgenic, Receptors, Antigen, B-Cell
Show Abstract · Added July 20, 2018
Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.
Copyright © 2018 by The American Association of Immunologists, Inc.
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17 MeSH Terms
B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.
Raybuck AL, Cho SH, Li J, Rogers MC, Lee K, Williams CL, Shlomchik M, Thomas JW, Chen J, Williams JV, Boothby MR
(2018) J Immunol 200: 2627-2639
MeSH Terms: Animals, B-Lymphocytes, Cell Differentiation, Gene Expression, Germinal Center, Immunity, Humoral, Immunoglobulin G, Immunologic Memory, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mutation, Plasma Cells, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Transcription Factors
Show Abstract · Added March 14, 2018
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.
Copyright © 2018 by The American Association of Immunologists, Inc.
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17 MeSH Terms
Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes.
Siska PJ, Kim B, Ji X, Hoeksema MD, Massion PP, Beckermann KE, Wu J, Chi JT, Hong J, Rathmell JC
(2016) J Immunol Methods 438: 51-58
MeSH Terms: Amino Acid Transport System y+, B-Lymphocytes, Cell Line, Tumor, Cellular Reprogramming, Cystine, Flow Cytometry, Fluorescein-5-isothiocyanate, Fluorescence, Fluorescent Dyes, Glutathione, Humans, Lymphocyte Activation, Microscopy, Fluorescence, Reactive Oxygen Species, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Up-Regulation
Show Abstract · Added January 29, 2018
T and B lymphocytes undergo metabolic re-programming upon activation that is essential to allow bioenergetics, cell survival, and intermediates for cell proliferation and function. To support changes in the activity of signaling pathways and to provide sufficient and necessary intracellular metabolites, uptake of extracellular nutrients increases sharply with metabolic re-programming. One result of increased metabolic activity can be reactive oxygen species (ROS), which can be toxic when accumulated in excess. Uptake of cystine allows accumulation of cysteine that is necessary for glutathione synthesis and ROS detoxification. Cystine uptake is required for T cell activation and function but measurements based on radioactive labeling do not allow analysis on single cell level. Here we show the critical role for cystine uptake in T cells using a method for measurement of cystine uptake using a novel CystineFITC probe. T cell receptor stimulation lead to upregulation of the cystine transporter xCT (SLC7a11) and increased cystine uptake in CD4+ and CD8+ human T cells. Similarly, lipopolysaccharide stimulation increased cystine uptake in human B cells. The CystineFITC probe was not toxic and could be metabolized to prevent cystine starvation induced cell death. Furthermore, blockade of xCT or competition with natural cystine decreased uptake of CystineFITC. CystineFITC is thus a versatile tool that allows measurement of cystine uptake on single cell level and shows the critical role for cystine uptake for T cell ROS regulation and activation.
Copyright © 2016 Elsevier B.V. All rights reserved.
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18 MeSH Terms
Development of Human Monoclonal Antibodies Against Respiratory Syncytial Virus Using a High Efficiency Human Hybridoma Technique.
Alvarado G, Crowe JE
(2016) Methods Mol Biol 1442: 63-76
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, B-Lymphocytes, Cell Line, Cell Proliferation, Humans, Hybridomas, Lymphocyte Activation, Neutralization Tests, Respiratory Syncytial Virus, Human
Show Abstract · Added April 13, 2017
Human monoclonal antibodies against RSV have high potential for use as prophylaxis or therapeutic molecules, and they also can be used to define the structure of protective epitopes for rational vaccine design. In the past, however, isolation of human monoclonal antibodies was difficult and inefficient. Here, we describe contemporary methods for activation and proliferation of primary human memory B cells followed by cytofusion to non-secreting myeloma cells by dielectrophoresis to generate human hybridomas secreting RSV-specific monoclonal antibodies. We also provide experimental methods for screening human B cell lines to obtain RSV-specific lines, especially lines secreting neutralizing antibodies.
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Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation.
Zhou W, Zhang J, Goleniewska K, Dulek DE, Toki S, Newcomb DC, Cephus JY, Collins RD, Wu P, Boothby MR, Peebles RS
(2016) J Immunol 197: 1577-86
MeSH Terms: Allergens, Animals, Antihypertensive Agents, Asthma, CD4-Positive T-Lymphocytes, Cell Proliferation, Chemokines, Epoprostenol, Hypersensitivity, Indomethacin, Inflammation, Interleukin-13, Interleukin-5, Lung, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Knockout, Ovalbumin, Receptors, Epoprostenol, STAT6 Transcription Factor, Signal Transduction, Th2 Cells
Show Abstract · Added March 14, 2018
Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration-approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.
Copyright © 2016 by The American Association of Immunologists, Inc.
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23 MeSH Terms
Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice.
Satoh M, Hoshino M, Fujita K, Iizuka M, Fujii S, Clingan CS, Van Kaer L, Iwabuchi K
(2016) Sci Rep 6: 28473
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adiponectin, Animals, Antigen Presentation, Antigens, CD1d, B7-1 Antigen, Diet, High-Fat, Disease Models, Animal, Disease Progression, Galactosylceramides, Insulin Resistance, Interferon-gamma, Lymphocyte Activation, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells, Obesity
Show Abstract · Added July 30, 2016
It has been shown that CD1d expression and glycolipid-reactive, CD1d-restricted NKT cells exacerbate the development of obesity and insulin resistance in mice. However, the relevant CD1d-expressing cells that influence the effects of NKT cells on the progression of obesity remain incompletely defined. In this study, we have demonstrated that 3T3-L1 adipocytes can present endogenous ligands to NKT cells, leading to IFN-γ production, which in turn, stimulated 3T3-L1 adipocytes to enhance expression of CD1d and CCL2, and decrease expression of adiponectin. Furthermore, adipocyte-specific CD1d deletion decreased the size of the visceral adipose tissue mass and enhanced insulin sensitivity in mice fed a high-fat diet (HFD). Accordingly, NKT cells were less activated, IFN-γ production was significantly reduced, and levels of adiponectin were increased in these animals as compared with control mice on HFD. Importantly, macrophage recruitment into the adipose tissue of adipocyte-specific CD1d-deficient mice was significantly blunted. These findings indicate that interactions between NKT cells and CD1d-expressing adipocytes producing endogenous NKT cell ligands play a critical role in the induction of inflammation and functional modulation of adipose tissue that leads to obesity.
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21 MeSH Terms
Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans.
Itani HA, McMaster WG, Saleh MA, Nazarewicz RR, Mikolajczyk TP, Kaszuba AM, Konior A, Prejbisz A, Januszewicz A, Norlander AE, Chen W, Bonami RH, Marshall AF, Poffenberger G, Weyand CM, Madhur MS, Moore DJ, Harrison DG, Guzik TJ
(2016) Hypertension 68: 123-32
MeSH Terms: Adult, Analysis of Variance, Angiotensin II, Animals, Antibodies, Monoclonal, Humanized, Cells, Cultured, Chi-Square Distribution, Disease Models, Animal, Humans, Hypertension, Kidney, Lymphocyte Activation, Mice, Middle Aged, Random Allocation, Reference Values, Sampling Studies, Statistics, Nonparametric, T-Lymphocytes, Regulatory
Show Abstract · Added May 25, 2016
Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and kidney revealed increased infiltration of human leukocytes (CD45(+)) and T lymphocytes (CD3(+) and CD4(+)) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3(+)/CD45RO(+)) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T-cell proliferation. We also observed an increase in circulating interleukin-17A producing CD4(+) T cells and both CD4(+) and CD8(+) T cells that produce interferon-γ in hypertensive compared with normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II.
© 2016 American Heart Association, Inc.
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The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy.
Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL
(2016) Expert Rev Clin Immunol 12: 763-73
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Anti-Inflammatory Agents, Autoantibodies, Autoimmune Diseases, Autoimmunity, B-Lymphocytes, Humans, Immune Tolerance, Lymphocyte Activation, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added July 18, 2017
Bruton's tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a "rheostat" rather than an "on-off" switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.
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13 MeSH Terms