Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 52
Filtrar
1.
mBio ; 15(8): e0073224, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-38953353

RESUMO

Candida albicans, an opportunistic fungal pathogen, produces the quorum-sensing molecule farnesol, which we have shown alters the transcriptional response and phenotype of human monocyte-derived dendritic cells (DCs), including their cytokine secretion and ability to prime T cells. This is partially dependent on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), which has numerous ligands, including the sphingolipid metabolite sphingosine 1-phosphate. Sphingolipids are a vital component of membranes that affect membrane protein arrangement and phagocytosis of C. albicans by DCs. Thus, we quantified sphingolipid metabolites in monocytes differentiating into DCs by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Farnesol increased the activity of serine palmitoyltransferase, leading to increased levels of 3-keto-dihydrosphingosine, dihydrosphingosine, and dihydrosphingosine 1-phosphate and inhibited dihydroceramide desaturase by inducing oxidative stress, leading to increased levels of dihydroceramide and dihydrosphingomyelin species and reduced ceramide levels. Accumulation of dihydroceramides can inhibit mitochondrial function; accordingly, farnesol reduced mitochondrial respiration. Dihydroceramide desaturase inhibition increases lipid droplet formation, which we observed in farnesol-treated cells, coupled with an increase in intracellular triacylglycerol species. Furthermore, inhibition of dihydroceramide desaturase with either farnesol or specific inhibitors impaired the ability of DCs to prime interferon-γ-producing T cells. The effect of farnesol on sphingolipid metabolism, triacylglycerol synthesis, and mitochondrial respiration was not dependent on PPAR-γ. In summary, our data reveal novel effects of farnesol on sphingolipid metabolism, neutral lipid synthesis, and mitochondrial function in DCs that affect their instruction of T cell cytokine secretion, indicating that C. albicans can manipulate host cell metabolism via farnesol secretion.IMPORTANCECandida albicans is a common commensal yeast, but it is also an opportunistic pathogen which is one of the leading causes of potentially lethal hospital-acquired infections. There is growing evidence that its overgrowth in the gut can influence diseases as diverse as alcohol-associated liver disease and COVID-19. Previously, we found that its quorum-sensing molecule, farnesol, alters the phenotype of dendritic cells differentiating from monocytes, impairing their ability to drive protective T cell responses. Here, we demonstrate that farnesol alters the metabolism of sphingolipids, important structural components of the membrane that also act as signaling molecules. In monocytes differentiating to dendritic cells, farnesol inhibited dihydroceramide desaturase, resulting in the accumulation of dihydroceramides and a reduction in ceramide levels. Farnesol impaired mitochondrial respiration, known to occur with an accumulation of dihydroceramides, and induced the accumulation of triacylglycerol and oil bodies. Inhibition of dihydroceramide desaturase resulted in the impaired ability of DCs to induce interferon-γ production by T cells. Thus, farnesol production by C. albicans could manipulate the function of dendritic cells by altering the sphingolipidome.


Assuntos
Candida albicans , Células Dendríticas , Farneseno Álcool , Monócitos , Percepção de Quorum , Esfingolipídeos , Farneseno Álcool/farmacologia , Farneseno Álcool/metabolismo , Humanos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/imunologia , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Esfingolipídeos/metabolismo , Percepção de Quorum/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/microbiologia , Monócitos/imunologia , PPAR gama/metabolismo , PPAR gama/genética , Espectrometria de Massas em Tandem , Citocinas/metabolismo
2.
bioRxiv ; 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38328096

RESUMO

Objectives: Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. Methods: Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 ( Stim1/2 Foxp3 ), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells from Stim1/2 Foxp3 mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. Results: Stim1/2 Foxp3 mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation in Stim1/2 Foxp3 mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells from Stim1/2 Foxp3 mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4 + T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. Conclusions: We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.

3.
Nat Commun ; 14(1): 6858, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37891230

RESUMO

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.


Assuntos
Glicólise , Neoplasias , Animais , Camundongos , Linfócitos T CD8-Positivos , Neoplasias/terapia , Mitocôndrias , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
4.
Cell Rep ; 42(6): 112583, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37267106

RESUMO

Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.


Assuntos
Montagem e Desmontagem da Cromatina , Histonas , Humanos , Histonas/metabolismo , Acetilcoenzima A/metabolismo , Linfócitos T CD4-Positivos/metabolismo
5.
Int J Mol Sci ; 24(9)2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-37175478

RESUMO

By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca2+ homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca2+ uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca2+ uptake. Recently, MCU has been shown to modulate Ca2+ signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation. The mechanisms underlying this modulation and whether MCU has additional T cell subpopulation-specific effects remain elusive. However, mice with germline or tissue-specific ablation of Mcu did not show impaired T cell responses in vitro or in vivo, indicating that 'chronic' loss of MCU can be functionally compensated in lymphocytes. The current work aimed to specifically investigate whether and how MCU influences the suppressive potential of regulatory CD4 T cells (Treg). We show that, in contrast to genetic ablation, acute siRNA-mediated downregulation of Mcu in murine Tregs results in a significant reduction both in mitochondrial Ca2+ uptake and in the suppressive capacity of Tregs, while the ratios of Treg subpopulations and the expression of hallmark transcription factors were not affected. These findings suggest that permanent genetic inactivation of MCU may result in compensatory adaptive mechanisms, masking the effects on the suppressive capacity of Tregs.


Assuntos
Canais de Cálcio , Linfócitos T Reguladores , Animais , Camundongos , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Regulação para Baixo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Linfócitos T Reguladores/metabolismo
6.
iScience ; 26(3): 106234, 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36926655

RESUMO

In thymus, the ablation of T cell receptor (TCR)-activated transcription factor NFATc1 or its inducible isoforms during the double-negative (DN) stages of thymocyte development leads to a marked increase in γδ thymocytes whereas the development of αß thymocytes remains mostly unaffected. These γδ thymocytes are characterized by the upregulation of the promyelocytic leukemia zinc-finger factor (PLZF), the "master regulator" of natural killer T (NKT) cell development, and the acquisition of an NKT γδ cell phenotype with higher cell survival rates. The suppressive function of NFATc1 in NKT γδ cell formation critically depends on the remote enhancer E2, which is essential for the inducible expression of NFATc1 directed by its distal promoter P1. Thus, the enhancer deciphers a strong γδ TCR signal into the expression of inducible NFATc1 isoforms resulting in high levels of NFATc1 protein that are essential to control the numbers of NKT γδ cells.

7.
Eur J Pharmacol ; 945: 175552, 2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-36739076

RESUMO

Increased aerobic glycolysis is a metabolic hallmark of proinflammatory leukocytes including macrophages and T cells. To take up glucose from the environment and fuel glycolysis, activated leukocytes upregulate the glucose transporter GLUT1. The orally bioavailable selective GLUT1 inhibitor BAY-876 was developed primarily as an anti-tumor drug. Our study assessed its activity on activated macrophages and CD4+ T cells. BAY-876 significantly attenuated glucose uptake by cultured CD4+ T cells and macrophages by 41% and 15%, respectively. Extracellular flux analysis of activated CD4+ T cells in vitro showed that BAY-876 significantly decreases glycolytic proton flux rate and lactate production, effects that are accompanied by an increased oxidative phosphorylation-mediated ATP production rate, leaving intracellular ATP levels per cell unchanged. However, GLUT1 inhibition reduced CD4+ T cell proliferation without compromising cell viability and reduced IFN-γ secretion by 20%. Moreover, TNF secretion from macrophages was reduced by 27%. We conclude that GLUT1-specific inhibitors, like BAY-876, deserve further in vivo testing in a broad range of (auto-) inflammatory disease models.


Assuntos
Linfócitos T CD4-Positivos , Glucose , Transportador de Glucose Tipo 1/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Glucose/metabolismo , Glicólise , Macrófagos/metabolismo , Trifosfato de Adenosina/metabolismo
8.
Sci Adv ; 8(40): eabn6552, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36206339

RESUMO

T cell activation and function depend on Ca2+ signals mediated by store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels formed by ORAI1 proteins. We here investigated how SOCE controls T cell function in pulmonary inflammation during a T helper 1 (TH1) cell-mediated response to influenza A virus (IAV) infection and TH2 cell-mediated allergic airway inflammation. T cell-specific deletion of Orai1 did not exacerbate pulmonary inflammation and viral burdens following IAV infection but protected mice from house dust mite-induced allergic airway inflammation. ORAI1 controlled the expression of genes including p53 and E2F transcription factors that regulate the cell cycle in TH2 cells in response to allergen stimulation and the expression of transcription factors and cytokines that regulate TH2 cell function. Systemic application of a CRAC channel blocker suppressed allergic airway inflammation without compromising immunity to IAV infection, suggesting that inhibition of SOCE is a potential treatment for allergic airway disease.


Assuntos
Canais de Cálcio , Vírus da Influenza A , Alérgenos , Animais , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Citocinas/metabolismo , Fatores de Transcrição E2F , Inflamação , Camundongos , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo
9.
Cell Metab ; 34(4): 516-532.e11, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35316657

RESUMO

Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.


Assuntos
ATP Citrato (pro-S)-Liase , Transportador de Glucose Tipo 3 , Células Th17 , ATP Citrato (pro-S)-Liase/metabolismo , Acetilcoenzima A/metabolismo , Animais , Epigênese Genética , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 3/metabolismo , Glicólise/genética , Humanos , Camundongos , Células Th17/metabolismo
10.
Cardiovasc Res ; 118(1): 37-52, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33537710

RESUMO

The interplay between the cardiovascular system, metabolism, and inflammation plays a central role in the pathophysiology of a wide spectrum of cardiovascular diseases, including heart failure. Here, we provide an overview of the fundamental aspects of the interrelation between inflammation and metabolism, ranging from the role of metabolism in immune cell function to the processes how inflammation modulates systemic and cardiac metabolism. Furthermore, we discuss how disruption of this immuno-metabolic interface is involved in the development and progression of cardiovascular disease, with a special focus on heart failure. Finally, we present new technologies and therapeutic approaches that have recently emerged and hold promise for the future of cardiovascular medicine.


Assuntos
Metabolismo Energético , Insuficiência Cardíaca/metabolismo , Coração/fisiopatologia , Sistema Imunitário/metabolismo , Inflamação/metabolismo , Miocárdio/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Coração/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Mediadores da Inflamação , Miocárdio/imunologia , Transdução de Sinais
11.
J Invest Dermatol ; 141(7): 1646-1655.e3, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33609554

RESUMO

Bullous pemphigoid-like epidermolysis bullosa acquisita (EBA) is an autoantibody-driven, granulocyte-mediated skin disease. The role of cellular metabolism and its potential as a therapeutic target in EBA are unknown. We investigated the effect of 2-deoxy-D-glucose and metformin in the antibody transfer model of EBA. Both metformin and 2-deoxy-D-glucose attenuated disease in this model. Subsequently, we demonstrate that the stimulation of neutrophils by immune complexes increases the rate of aerobic glycolysis and that this increase is required to induce the release of leukotriene B4 and ROS critical for EBA. Accordingly, 2-deoxy-D-glucose as an inhibitor of the glycolytic enzymes hexokinase and phosphoglucose isomerase and heptelidic acid, an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, blunted this neutrophil response. Decreasing oxidative phosphorylation, metformin also inhibited this neutrophil response but only when applied in suprapharmacological doses, rendering a direct effect of metformin on neutrophils in vivo unlikely. Considering that the oxidative phosphorylation inhibitor oligomycin likewise inhibits these neutrophil responses and that immune complex stimulation does not alter the rate of oxidative phosphorylation, these results, however, suggest that intact mitochondria are necessary for neutrophil responses. Collectively, we highlight 2-deoxy-D-glucose and metformin as potential drugs and both glycolysis and oxidative phosphorylation in neutrophils as promising therapeutic targets in EBA.


Assuntos
Epidermólise Bolhosa Adquirida/imunologia , Glucose/metabolismo , Glicólise/imunologia , Neutrófilos/efeitos dos fármacos , Pele/efeitos dos fármacos , Animais , Autoanticorpos/imunologia , Desoxiglucose/administração & dosagem , Modelos Animais de Doenças , Epidermólise Bolhosa Adquirida/tratamento farmacológico , Epidermólise Bolhosa Adquirida/metabolismo , Glucose/antagonistas & inibidores , Glicólise/efeitos dos fármacos , Humanos , Leucotrieno B4/metabolismo , Metformina/administração & dosagem , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Pele/imunologia
12.
Front Immunol ; 12: 791100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35069572

RESUMO

CD4+CXCR5+Foxp3+ T-follicular regulatory (TFR) cells control the germinal center responses. Like T-follicular helper cells, they express high levels of Nuclear Factor of Activated T-cells c1, predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. As one type of effector Treg, TFR cells express B lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 can directly repress Cxcr5 and NFATc1/αA is necessary to overcome this Blimp-1-mediated repression. Interestingly, Blimp-1 even reinforces the recruitment of NFATc1 to Cxcr5 by protein-protein interaction and by those means cooperates with NFATc1 for Cxcr5 transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA and preserve the Treg identity. This is because although NFATc1/αA strengthens the follicular development of Tregs, it bears the inherent risk of causing an ex-Treg phenotype.


Assuntos
Movimento Celular/imunologia , Centro Germinativo/imunologia , Fatores de Transcrição NFATC/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Animais , Movimento Celular/genética , Camundongos , Camundongos Transgênicos , Fatores de Transcrição NFATC/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética
13.
Front Pharmacol ; 12: 734078, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34987384

RESUMO

T cell activation and differentiation is associated with metabolic reprogramming to cope with the increased bioenergetic demand and to provide metabolic intermediates for the biosynthesis of building blocks. Antigen receptor stimulation not only promotes the metabolic switch of lymphocytes but also triggers the uptake of calcium (Ca2+) from the cytosol into the mitochondrial matrix. Whether mitochondrial Ca2+ influx through the mitochondrial Ca2+ uniporter (MCU) controls T cell metabolism and effector function remained, however, enigmatic. Using mice with T cell-specific deletion of MCU, we here show that genetic inactivation of mitochondrial Ca2+ uptake increased cytosolic Ca2+ levels following antigen receptor stimulation and store-operated Ca2+ entry (SOCE). However, ablation of MCU and the elevation of cytosolic Ca2+ did not affect mitochondrial respiration, differentiation and effector function of inflammatory and regulatory T cell subsets in vitro and in animal models of T cell-mediated autoimmunity and viral infection. These data suggest that MCU-mediated mitochondrial Ca2+ uptake is largely dispensable for murine T cell function. Our study has also important technical implications. Previous studies relied mostly on pharmacological inhibition or transient knockdown of mitochondrial Ca2+ uptake, but our results using mice with genetic deletion of MCU did not recapitulate these findings. The discrepancy of our study to previous reports hint at compensatory mechanisms in MCU-deficient mice and/or off-target effects of current MCU inhibitors.

14.
J Exp Med ; 218(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-32986812

RESUMO

Posttranslational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is largely unexplored. The NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell-mediated immune responses in vivo is unclear. To this end, we generated a novel transgenic mouse in which SUMO modification of NFATc1 is prevented. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. Elevated IL-2 production in T cells promoted T reg expansion and suppressed autoreactive or alloreactive immune responses. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself, as well as the induced, proliferation-associated survival factor Bcl2A1. Collectively, these data demonstrate that prevention of NFATc1 SUMOylation fine-tunes T cell responses toward lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell-mediated inflammatory diseases.


Assuntos
Autoimunidade , Encefalomielite Autoimune Experimental/imunologia , Fatores de Transcrição NFATC/imunologia , Sumoilação/imunologia , Linfócitos T Reguladores/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Encefalomielite Autoimune Experimental/genética , Camundongos , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Fatores de Transcrição NFATC/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Sumoilação/genética
15.
Curr Opin Physiol ; 17: 207-223, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33103016

RESUMO

T cells are an essential component of the immune system that provide antigen-specific acute and long lasting immune responses to infections and tumors, ascertain the maintenance of immunological tolerance and, on the flipside, mediate autoimmunity in a variety of diseases. The activation of T cells through antigen recognition by the T cell receptor (TCR) results in transient and sustained Ca2+ signals that are shaped by the opening of Ca2+ channels in the plasma membrane and cellular organelles. The dynamic regulation of intracellular Ca2+ concentrations controls a variety of T cell functions on the timescale of seconds to days after signal initiation. Among the more recently identified roles of Ca2+ signaling in T cells is the regulation of metabolic pathways that control the function of many T cell subsets. In this review, we discuss how Ca2+ regulates several metabolic programs in T cells such as the activation of AMPK and the PI3K-AKT-mTORC1 pathway, aerobic glycolysis, mitochondrial metabolism including tricarboxylic acid (TCA) cycle function and oxidative phosphorylation (OXPHOS), as well as lipid metabolism.

16.
Nat Immunol ; 21(11): 1397-1407, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32989328

RESUMO

Antiviral CD8+ T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells, which in turn are critical for optimal priming of CD8+ T cells. Here we show that BATF3 was expressed transiently within the first days after T cell priming and had long-lasting T cell-intrinsic effects. T cells that lacked Batf3 showed normal expansion and differentiation, yet succumbed to an aggravated contraction and had a diminished memory response. Vice versa, BATF3 overexpression in CD8+ T cells promoted their survival and transition to memory. Mechanistically, BATF3 regulated T cell apoptosis and longevity via the proapoptotic factor BIM. By programing CD8+ T cell survival and memory, BATF3 is a promising molecule to optimize adoptive T cell therapy in patients.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Reprogramação Celular/genética , Memória Imunológica/genética , Proteínas Repressoras/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Diferenciação Celular , Sobrevivência Celular/genética , Expressão Gênica , Humanos , Imunofenotipagem , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Trends Immunol ; 41(10): 878-901, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32711944

RESUMO

Calcium (Ca2+) signals play fundamental roles in immune cell function. The main sources of Ca2+ influx in mammalian lymphocytes following antigen receptor stimulation are Ca2+ release-activated Ca2+ (CRAC) channels. These are formed by ORAI proteins in the plasma membrane and are activated by stromal interaction molecules (STIM) located in the endoplasmic reticulum (ER). Human loss-of-function (LOF) mutations in ORAI1 and STIM1 that abolish Ca2+ influx cause a unique disease syndrome called CRAC channelopathy that is characterized by immunodeficiency autoimmunity and non-immunological symptoms. Studies in mice lacking Stim and Orai genes have illuminated many cellular and molecular mechanisms by which these molecules control lymphocyte function. CRAC channels are required for the differentiation and function of several T lymphocyte subsets that provide immunity to infection, mediate inflammation and prevent autoimmunity. This review examines new insights into how CRAC channels control T cell-mediated immunity.


Assuntos
Canais de Cálcio Ativados pela Liberação de Cálcio , Sinalização do Cálcio , Linfócitos T , Animais , Canais de Cálcio Ativados pela Liberação de Cálcio/genética , Canais de Cálcio Ativados pela Liberação de Cálcio/imunologia , Sinalização do Cálcio/imunologia , Humanos , Imunidade Celular/genética , Imunidade Celular/imunologia , Proteína ORAI1/genética , Proteína ORAI1/imunologia , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/imunologia , Linfócitos T/imunologia
18.
EMBO Mol Med ; 12(8): e11592, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32609955

RESUMO

Immunity to fungal infections is mediated by cells of the innate and adaptive immune system including Th17 cells. Ca2+ influx in immune cells is regulated by stromal interaction molecule 1 (STIM1) and its activation of the Ca2+ channel ORAI1. We here identify patients with a novel mutation in STIM1 (p.L374P) that abolished Ca2+ influx and resulted in increased susceptibility to fungal and other infections. In mice, deletion of STIM1 in all immune cells enhanced susceptibility to mucosal C. albicans infection, whereas T cell-specific deletion of STIM1 impaired immunity to systemic C. albicans infection. STIM1 deletion impaired the production of Th17 cytokines essential for antifungal immunity and compromised the expression of genes in several metabolic pathways including Foxo and HIF1α signaling that regulate glycolysis and oxidative phosphorylation (OXPHOS). Our study further revealed distinct roles of STIM1 in regulating transcription and metabolic programs in non-pathogenic Th17 cells compared to pathogenic, proinflammatory Th17 cells, a finding that may potentially be exploited for the treatment of Th17 cell-mediated inflammatory diseases.


Assuntos
Cálcio , Células Th17 , Animais , Antifúngicos , Cálcio/metabolismo , Canais de Cálcio/genética , Humanos , Camundongos , Proteínas de Neoplasias , Proteína ORAI1 , Molécula 1 de Interação Estromal/genética , Células Th17/metabolismo
19.
Sci Signal ; 12(578)2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015290

RESUMO

Store-operated Ca2+ entry (SOCE) channels are highly selective Ca2+ channels activated by the endoplasmic reticulum (ER) sensors STIM1 and STIM2. Their direct interaction with the pore-forming plasma membrane ORAI proteins (ORAI1, ORAI2, and ORAI3) leads to sustained Ca2+ fluxes that are critical for many cellular functions. Mutations in the human ORAI1 gene result in immunodeficiency, anhidrotic ectodermal dysplasia, and enamel defects. In our investigation of the role of ORAI proteins in enamel, we identified enamel defects in a patient with an ORAI1 null mutation. Targeted deletion of the Orai1 gene in mice showed enamel defects and reduced SOCE in isolated enamel cells. However, Orai2-/- mice showed normal enamel despite having increased SOCE in the enamel cells. Knockdown experiments in the enamel cell line LS8 suggested that ORAI2 and ORAI3 modulated ORAI1 function, with ORAI1 and ORAI2 being the main contributors to SOCE. ORAI1-deficient LS8 cells showed altered mitochondrial respiration with increased oxygen consumption rate and ATP, which was associated with altered redox status and enhanced ER Ca2+ uptake, likely due to S-glutathionylation of SERCA pumps. Our findings demonstrate an important role of ORAI1 in Ca2+ influx in enamel cells and establish a link between SOCE, mitochondrial function, and redox homeostasis.


Assuntos
Calcificação Fisiológica/fisiologia , Sinalização do Cálcio/fisiologia , Esmalte Dentário/metabolismo , Proteína ORAI1/metabolismo , Animais , Linhagem Celular , Camundongos , Camundongos Knockout , Proteína ORAI1/genética , Oxirredução , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Molécula 2 de Interação Estromal/genética , Molécula 2 de Interação Estromal/metabolismo
20.
Nat Commun ; 10(1): 1183, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30862784

RESUMO

T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells.


Assuntos
Doenças Autoimunes/imunologia , Canais de Cálcio Ativados pela Liberação de Cálcio/fisiologia , Cálcio/metabolismo , Diferenciação Celular/imunologia , Linfócitos T Reguladores/fisiologia , Animais , Autoanticorpos/imunologia , Doenças Autoimunes/genética , Transplante de Medula Óssea , Cátions Bivalentes/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Molécula 2 de Interação Estromal/genética , Molécula 2 de Interação Estromal/metabolismo , Quimeras de Transplante
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA