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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.
0 Communities
1 Members
0 Resources
21 MeSH Terms
DC isoketal-modified proteins activate T cells and promote hypertension.
Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, Bikineyeva AT, Dikalov S, Xiao L, Chen W, Saleh MA, Trott DW, Itani HA, Vinh A, Amarnath V, Amarnath K, Guzik TJ, Bernstein KE, Shen XZ, Shyr Y, Chen SC, Mernaugh RL, Laffer CL, Elijovich F, Davies SS, Moreno H, Madhur MS, Roberts J, Harrison DG
(2014) J Clin Invest 124: 4642-56
MeSH Terms: Aged, Aldehydes, Angiotensin II, Animals, Antigen-Presenting Cells, B7-1 Antigen, B7-2 Antigen, Cell Proliferation, Cohort Studies, Dendritic Cells, Female, Gene Expression Regulation, Humans, Hypertension, Inflammation, Interleukin-17, Interleukin-1beta, Interleukin-23, Interleukin-6, Kidney, Lymphocyte Activation, Male, Mice, Mice, Transgenic, Middle Aged, Oxidative Stress, Oxygen, Superoxides, T-Lymphocytes
Show Abstract · Added September 26, 2014
Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8+ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease.
3 Communities
6 Members
0 Resources
29 MeSH Terms
Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo.
Liu C, Lewis CM, Lou Y, Xu C, Peng W, Yang Y, Gelbard AH, Lizée G, Zhou D, Overwijk WW, Hwu P
(2012) J Immunother 35: 276-82
MeSH Terms: Adoptive Transfer, Animals, Antibodies, Monoclonal, Antigen Presentation, B7-1 Antigen, B7-2 Antigen, Bone Marrow Cells, CD40 Antigens, Cell Line, Female, Interleukin-2, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, gp100 Melanoma Antigen
Show Abstract · Added April 11, 2014
CD40, a member of the tumor necrosis factor receptor superfamily, is broadly expressed on antigen-presenting cells and other cells, including fibroblasts and endothelial cells. Binding of CD40 and its natural ligand CD40L (CD154) triggers cytokine secretion, and increased expression of costimulatory molecules is required for T-cell activation and proliferation. However, to our knowledge, the use of agonistic antibodies to CD40 to boost adoptively transferred T cells in vivo has not been investigated. The purpose of this study was to determine whether anti-CD40 monoclonal antibody (mAb) in combination with interleukin (IL)-2 could improve the efficacy of in vitro-activated T cells to enhance antitumor activity. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without anti-CD40 mAb. In this model, the combination of anti-CD40 mAb with IL-2 led to expansion of adoptively transferred T cells and induced a more robust antitumor response. Furthermore, the expression of CD40 on bone marrow-derived cells and the presence of CD80/CD86 in the host were required for the expansion of adoptively transferred T cells. The use of neutralizing mAb to IL-12 provided direct evidence that enhanced IL-12 secretion induced by anti-CD40 mAb was crucial for the expansion of adoptively transferred T cells. Collectively, these findings provide a rationale to evaluate the potential application of anti-CD40 mAb in adoptive T-cell therapy for cancer.
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1 Members
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17 MeSH Terms
Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension.
Vinh A, Chen W, Blinder Y, Weiss D, Taylor WR, Goronzy JJ, Weyand CM, Harrison DG, Guzik TJ
(2010) Circulation 122: 2529-37
MeSH Terms: Abatacept, Angiotensin II, Animals, Antihypertensive Agents, B7-1 Antigen, B7-2 Antigen, CD28 Antigens, Cells, Cultured, Gene Deletion, Hypertension, Immunoconjugates, Immunosuppressive Agents, Ligands, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Random Allocation, T-Lymphocytes
Show Abstract · Added December 10, 2013
BACKGROUND - The pathogenesis of hypertension remains poorly understood, and treatment is often unsuccessful. Recent evidence suggests that the adaptive immune response plays an important role in this disease. Various hypertensive stimuli cause T-cell activation and infiltration into target organs such as the vessel and the kidney, which promotes vascular dysfunction and blood pressure elevation. Classically, T-cell activation requires T-cell receptor ligation and costimulation. The latter often involves interaction between B7 ligands (CD80 and CD86) on antigen-presenting cells with the T-cell coreceptor CD28. This study was therefore performed to examine the role of this pathway in hypertension.
METHODS AND RESULTS - Angiotensin II-induced hypertension increased the presence of activated (CD86(+)) dendritic cells in secondary lymphatic tissues. Blockade of B7-dependent costimulation with CTLA4-Ig reduced both angiotensin II- and deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Activation of circulating T cells, T-cell cytokine production, and vascular T-cell accumulation caused by these hypertensive stimuli were abrogated by CTLA4-Ig. Furthermore, in mice lacking B7 ligands, angiotensin II caused minimal blood pressure elevation and vascular inflammation, and these effects were restored by transplantation with wild-type bone marrow.
CONCLUSIONS - T-cell costimulation via B7 ligands is essential for development of experimental hypertension, and inhibition of this process could have therapeutic benefit in the treatment of this disease.
1 Communities
1 Members
0 Resources
19 MeSH Terms
PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells.
Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, Kumar V, Wu L, Kaer LV
(2009) J Immunol 182: 2816-26
MeSH Terms: Animals, Antigens, Surface, Apoptosis Regulatory Proteins, B7-1 Antigen, B7-H1 Antigen, Clonal Anergy, Cytotoxicity, Immunologic, Female, Galactosylceramides, Genetic Variation, Lymphocyte Activation, Melanoma, Experimental, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells, Peptides, Programmed Cell Death 1 Receptor, Signal Transduction
Show Abstract · Added December 10, 2013
Invariant NKT (iNKT) cells recognize glycolipid Ags, such as the marine sponge-derived glycosphingolipid alpha-galactosylceramide (alphaGalCer) presented by the CD1d protein. In vivo activation of iNKT cells with alphaGalCer results in robust cytokine production, followed by the acquisition of an anergic phenotype. Here we have investigated mechanisms responsible for the establishment of alphaGalCer-induced iNKT cell anergy. We found that alphaGalCer-activated iNKT cells rapidly up-regulated expression of the inhibitory costimulatory receptor programmed death (PD)-1 at their cell surface, and this increased expression was retained for at least one month. Blockade of the interaction between PD-1 and its ligands, PD-L1 and PD-L2, at the time of alphaGalCer treatment prevented the induction iNKT cell anergy, but was unable to reverse established iNKT cell anergy. Consistently, injection of alphaGalCer into PD-1-deficient mice failed to induce iNKT cell anergy. However, blockade of the PD-1/PD-L pathway failed to prevent bacterial- or sulfatide-induced iNKT cell anergy, suggesting additional mechanisms of iNKT cell tolerance. Finally, we showed that blockade of PD-1/PD-L interactions enhanced the antimetastatic activities of alphaGalCer. Collectively, our findings reveal a critical role for the PD-1/PD-L costimulatory pathway in the alphaGalCer-mediated induction of iNKT cell anergy that can be targeted for the development of immunotherapies.
0 Communities
2 Members
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20 MeSH Terms
Versatile prostate cancer treatment with inducible caspase and interleukin-12.
Nikitina EY, Desai SA, Zhao X, Song W, Luo AZ, Gangula RD, Slawin KM, Spencer DM
(2005) Cancer Res 65: 4309-19
MeSH Terms: Adenocarcinoma, Adenoviridae, Animals, Apoptosis, B7-1 Antigen, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cancer Vaccines, Caspase 1, Dendritic Cells, Interferon-gamma, Interleukin-12, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Prostatic Neoplasms, T-Lymphocytes, Cytotoxic
Show Abstract · Added April 7, 2010
To establish optimized conditions for immunity against prostate cancer, we compared the efficacy of multiple approaches in autochthonous and s.c. transgenic adenocarcinoma of the mouse prostate (TRAMP)-based models. Mice immunized with interleukin (IL)-12-containing apoptotic, but not necrotic TRAMP-C2 cell-based, vaccines were resistant to TRAMP-C2 tumor challenge and re-challenge, independently of the route of vaccination (s.c. or i.p.). Administration of gamma-irradiated TRAMP-C2 cells preinfected with adenovirus containing both B7-1 and IL-12 genes, unlike adenovirus containing B7-1 alone, considerably protected C57BL/6 mice from TRAMP-C2 tumor growth and extended the life span of TRAMP mice. Vaccines that included dendritic cells, instead of IL-12, were equally efficient. Whereas injections of ligand-inducible caspase-1- and IL-12-containing adenoviruses cured small s.c. TRAMP-C2 tumors, nanopump-regulated delivery of viruses led to elimination of much larger tumors. The antitumor immune responses involved CD4+-, CD8+-, and natural killer cells and were strengthened by increasing the number of vaccinations. Intraprostatic administration of inducible caspase-1- and IL-12-containing adenoviruses resulted in local cell death and improved survival of adenocarcinoma-bearing TRAMP mice. Thus, tumor cell apoptosis induced by caspase in situ and accompanied by IL-12 is efficient against prostate cancer in a preclinical model.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Endotoxin-induced gamma interferon production: contributing cell types and key regulatory factors.
Varma TK, Lin CY, Toliver-Kinsky TE, Sherwood ER
(2002) Clin Diagn Lab Immunol 9: 530-43
MeSH Terms: Animals, B7-1 Antigen, CD28 Antigens, Cells, Cultured, Dendritic Cells, Female, Gene Expression Profiling, Histocompatibility Antigens Class II, Interferon-gamma, Interleukin-12, Interleukin-15, Interleukin-18, Killer Cells, Natural, Lipopolysaccharides, Macrophages, Peritoneal, Mice, Mice, Inbred BALB C, RNA, Messenger, Signal Transduction, Spleen, T-Lymphocytes
Show Abstract · Added October 18, 2015
Gamma interferon (IFN-gamma) is an important mediator of endotoxin (lipopolysaccharide [LPS])-induced immune responses. However, the specific cell types that produce IFN-gamma in response to LPS and the cellular factors that regulate LPS-induced IFN-gamma production have not been fully determined. The present studies were undertaken to characterize the cell populations that produce IFN-gamma after LPS challenge in the spleens of mice and to determine the regulatory factors that modulate LPS-induced production of IFN-gamma. Our studies show that the levels of splenic IFN-gamma mRNA and protein production peak at 6 and 8 h, respectively, after systemic LPS challenge. Approximately 60% of IFN-gamma-producing cells are natural killer (NK) cells (CD3(-)DX5(+)) and 25% are NKT cells (CD3(+)DX5(+)). Most of the remaining IFN-gamma-producing cells are T cells (CD3(+)DX5(-)), macrophages, and dendritic cells. Functionally, interleukin-12 (IL-12) is the major IFN-gamma-stimulating factor after LPS challenge, with costimulation provided by IL-15, IL-18, and B7 proteins. IL-10 is a major inhibitor of LPS-induced IFN-gamma production. Unlike intact heat-killed gram-negative and gram-positive bacteria, the class II major histocompatibility complex did not play a functional role in LPS-induced IFN-gamma production. LPS is a potent stimulus for splenic IL-10, IL-12 p40, and IL-15 mRNA expression, whereas IL-12 p35 and IL-18 mRNAs, as well as B7 proteins, are constitutively expressed in the mouse spleen. Of the factors studied, IL-18 serves as the most potent costimulus with IL-12 for IFN-gamma production, followed by IL-15 and B7 proteins. These data demonstrate that NK cells and NKT cells are the most abundant IFN-gamma-producing cells in the mouse spleen after LPS challenge and that IL-10 and IL-12 are key functional regulators of LPS-induced IFN-gamma production.
0 Communities
1 Members
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21 MeSH Terms
Cellular mechanisms that cause suppressed gamma interferon secretion in endotoxin-tolerant mice.
Varma TK, Toliver-Kinsky TE, Lin CY, Koutrouvelis AP, Nichols JE, Sherwood ER
(2001) Infect Immun 69: 5249-63
MeSH Terms: Animals, B7-1 Antigen, CD28 Antigens, Cytokines, Female, Gene Expression Regulation, Humans, Immune Tolerance, Interferon-gamma, Interleukins, Killer Cells, Natural, Lipopolysaccharides, Macrophages, Peritoneal, Mice, Mice, Inbred BALB C, Spleen, T-Lymphocytes
Show Abstract · Added October 18, 2015
Endotoxin (lipopolysaccharide [LPS]) tolerance is a state of altered immunity characterized, in part, by suppression of LPS-induced gamma interferon (IFN-gamma) expression. However, the cellular mediators regulating LPS-induced production of IFN-gamma in normal mice and the effect of LPS tolerance on these mediators has not been well characterized. Our studies show that macrophage dysfunction is the primary factor causing suppressed IFN-gamma expression in LPS-tolerant mice. Specifically, LPS-tolerant macrophages have a markedly impaired ability to induce IFN-gamma secretion by T cells and NK cells obtained from either control or LPS-tolerant mice. However, T cells and NK cells isolated from LPS-tolerant mice produce normal levels of IFN-gamma when cocultured with control macrophages or exogenous IFN-gamma-inducing factors. Assessment of important IFN-gamma-regulating factors showed that interleukin-12 (IL-12) and costimulatory signals provided by IL-15, IL-18, and CD86 are largely responsible for LPS-induced IFN-gamma expression in control mice. IL-10 is an inhibitor of IFN-gamma production in both the control and LPS-tolerant groups. Expression of IL-12 and the IL-12 receptor beta1 (IL-12Rbeta1) and IL-12Rbeta2 subunits are suppressed in the spleens of LPS-tolerant mice. LPS-tolerant splenocytes also exhibit decreased production of IL-15 and IL-15Ralpha. However, expression of IL-18 and the B7 proteins CD80 and CD86 are unchanged or increased compared to controls after induction of LPS tolerance. CD28, a major receptor for B7 proteins, is also increased in the spleens of LPS-tolerant mice. Expression of the inhibitory cytokine IL-10 and the IL-10R are sustained after induction of LPS tolerance. These data show that suppression of IFN-gamma production in LPS-tolerant mice is largely due to macrophage dysfunction and provide insight into the cellular alterations that occur in LPS tolerance. This study also better defines the factors that mediate LPS-induced IFN-gamma production in normal mice.
0 Communities
1 Members
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17 MeSH Terms
Differential regulation of Th1 and Th2 functions of NKT cells by CD28 and CD40 costimulatory pathways.
Hayakawa Y, Takeda K, Yagita H, Van Kaer L, Saiki I, Okumura K
(2001) J Immunol 166: 6012-8
MeSH Terms: Animals, Antibodies, Monoclonal, Antigens, CD, Antineoplastic Agents, B7-1 Antigen, B7-2 Antigen, CD28 Antigens, CD40 Antigens, CD40 Ligand, Cytotoxicity, Immunologic, Galactosylceramides, Injections, Intraperitoneal, Interferon-gamma, Interleukin-4, Killer Cells, Natural, Lymphocyte Activation, Male, Melanoma, Experimental, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, T-Lymphocyte Subsets, Th1 Cells, Th2 Cells, Tumor Cells, Cultured
Show Abstract · Added December 10, 2013
Valpha14 NKT cells produce large amounts of IFN-gamma and IL-4 upon recognition of their specific ligand alpha-galactosylceramide (alpha-GalCer) by their invariant TCR. We show here that NKT cells constitutively express CD28, and that blockade of CD28-CD80/CD86 interactions by anti-CD80 and anti-CD86 mAbs inhibits the alpha-GalCer-induced IFN-gamma and IL-4 production by splenic Valpha14 NKT cells. On the other, the blockade of CD40-CD154 interactions by anti-CD154 mAb inhibited alpha-GalCer-induced IFN-gamma production, but not IL-4 production. Consistent with these findings, CD28-deficient mice showed impaired IFN-gamma and IL-4 production in response to alpha-GalCer stimulation in vitro and in vivo, whereas production of IFN-gamma but not IL-4 was impaired in CD40-deficient mice. Moreover, alpha-GalCer-induced Th1-type responses, represented by enhanced cytotoxic activity of splenic or hepatic mononuclear cells and antimetastatic effect, were impaired in both CD28-deficient mice and CD40-deficient mice. In contrast, alpha-GalCer-induced Th2-type responses, represented by serum IgE and IgG1 elevation, were impaired in the absence of the CD28 costimulatory pathway but not in the absence of the CD40 costimulatory pathway. These results indicate that CD28-CD80/CD86 and CD40-CD154 costimulatory pathways differentially contribute to the regulation of Th1 and Th2 functions of Valpha14 NKT cells in vivo.
0 Communities
1 Members
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27 MeSH Terms
Cooperativity of Staphylococcal aureus enterotoxin B superantigen, major histocompatibility complex class II, and CD80 for immunotherapy of advanced spontaneous metastases in a clinically relevant postoperative mouse breast cancer model.
Pulaski BA, Terman DS, Khan S, Muller E, Ostrand-Rosenberg S
(2000) Cancer Res 60: 2710-5
MeSH Terms: Animals, B7-1 Antigen, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Disease Models, Animal, Enterotoxins, Female, Humans, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Metastasis, Postoperative Care, Staphylococcus aureus, Superantigens, Transfection, Vaccination
Show Abstract · Added August 14, 2013
One of the leading causes of death for women is metastatic breast cancer. Because most animal tumors do not accurately model clinical metastatic disease, the development of effective therapies has progressed slowly. In this study, we establish the poorly immunogenic mouse 4T1 mammary carcinoma as a postsurgical animal model. 4T1 growth characteristics parallel highly invasive human metastatic mammary carcinoma and, at the time of surgery, the extent of disease is comparable with human stage IV breast cancer. Progress in understanding the immune response has led to innovative immune-based anticancer therapies. Here, we test in this postsurgical model, a novel cell-based vaccine, combining MHC class II, CD80(B7.1), and SEB superantigen. Effective treatment of tumor-bearing mice with this immunotherapy requires expression of all three molecules. Mean survival time is extended from 5-7.5 weeks for control-treated mice to 6-10.5 weeks for therapy-treated mice. Increased survival is accompanied by a maximum of 100-fold decrease in clonogenic lung metastases. These therapeutic effects are particularly noteworthy because: (a) the postoperative model demonstrates that early metastases responsible for morbidity are established by 2 weeks after tumor inoculation with 7 x 10(3) parental 4T1 cells into the mammary gland; (b) the immunotherapy is started 4 weeks after tumor inoculation when the mice contain extensive, pre-established, disseminated metastases; and (c) CD4+ and CD8+ T cells are required for the effect.
0 Communities
0 Members
2 Resources
18 MeSH Terms