ABSTRACT
Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
Subject(s)
Autophagy , CD8-Positive T-Lymphocytes , Humans , Animals , Mice , Dinoprostone , Genes, Mitochondrial , GlutathioneABSTRACT
The eukaryotic genome, first packed into nucleosomes of about 150 bp around the histone core, is organized into euchromatin and heterochromatin, corresponding to the A and B compartments, respectively. Here, we asked if individual nucleosomes in vivo know where to go. That is, do mono-nucleosomes by themselves contain A/B compartment information, associated with transcription activity, in their biophysical properties? We purified native mono-nucleosomes to high monodispersity and used physiological concentrations of biological polyamines to determine their condensability. The chromosomal regions known to partition into A compartments have low condensability and vice versa. In silico chromatin polymer simulations using condensability as the only input showed that biophysical information needed to form compartments is all contained in single native nucleosomes and no other factors are needed. Condensability is also strongly anticorrelated with gene expression, and especially so near the promoter region and in a cell type dependent manner. Therefore, individual nucleosomes in the promoter know whether the gene is on or off, and that information is contained in their biophysical properties. Comparison with genetic and epigenetic features suggest that nucleosome condensability is a very meaningful axis onto which to project the high dimensional cellular chromatin state. Analysis of condensability using various condensing agents including those that are protein-based suggests that genome organization principle encoded into individual nucleosomes is electrostatic in nature. Polyamine depletion in mouse T cells, by either knocking out ornithine decarboxylase (ODC) or inhibiting ODC, results in hyperpolarized condensability, suggesting that when cells cannot rely on polyamines to translate biophysical properties of nucleosomes to control gene expression and 3D genome organization, they accentuate condensability contrast, which may explain dysfunction known to occur with polyamine deficiency.
ABSTRACT
Immune cells must adapt to different environments during the course of an immune response. We studied the adaptation of CD8 + T cells to the intestinal microenvironment and how this process shapes their residency in the gut. CD8 + T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate expression of mitochondrial genes. Human and mouse gut-resident CD8 + T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We found that the intestinal microenvironment is rich in prostaglandin E 2 (PGE 2 ), which drives mitochondrial depolarization in CD8 + T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE 2 sensing promotes CD8 + T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell population. Thus, a PGE 2 -autophagy-glutathione axis defines the metabolic adaptation of CD8 + T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
ABSTRACT
How lipidome changes support CD8+ effector T (Teff) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIPn with 3-4 double bonds), Teff cells have unique PIPn marked by saturated fatty acyl chains (0-2 double bonds). PIPn are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP2) exclusively supported signaling immediately upon T cell antigen receptor activation. In late Teff cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP2 into downstream mediators, waned, and saturated PIPn became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP2 with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIPn impaired Teff cell fitness and function, even in cells with abundant polyunsaturated PIPn. Glucose was the substrate for de novo PIPn synthesis, and was rapidly utilized for saturated PIP2 generation. Thus, separate PIPn pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.
Subject(s)
Phosphatidylinositol Phosphates , Phosphatidylinositols , Phosphatidylinositols/metabolism , Signal Transduction , Type C Phospholipases/metabolism , CD8-Positive T-Lymphocytes/metabolismABSTRACT
The behaviour of Dictyostelium discoideum depends on nutrients1. When sufficient food is present these amoebae exist in a unicellular state, but upon starvation they aggregate into a multicellular organism2,3. This biology makes D. discoideum an ideal model for investigating how fundamental metabolism commands cell differentiation and function. Here we show that reactive oxygen species-generated as a consequence of nutrient limitation-lead to the sequestration of cysteine in the antioxidant glutathione. This sequestration limits the use of the sulfur atom of cysteine in processes that contribute to mitochondrial metabolism and cellular proliferation, such as protein translation and the activity of enzymes that contain an iron-sulfur cluster. The regulated sequestration of sulfur maintains D. discoideum in a nonproliferating state that paves the way for multicellular development. This mechanism of signalling through reactive oxygen species highlights oxygen and sulfur as simple signalling molecules that dictate cell fate in an early eukaryote, with implications for responses to nutrient fluctuations in multicellular eukaryotes.
Subject(s)
Dictyostelium/cytology , Dictyostelium/metabolism , Food Deprivation/physiology , Nutrients/metabolism , Sulfur/metabolism , Amino Acids, Essential/metabolism , Amino Acids, Essential/pharmacology , Antioxidants/metabolism , Cell Aggregation/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cell Respiration/drug effects , Cysteine/chemistry , Cysteine/metabolism , Cysteine/pharmacology , Dictyostelium/drug effects , Glutathione/chemistry , Glutathione/metabolism , Glutathione/pharmacology , Iron-Sulfur Proteins/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Oxygen/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effectsABSTRACT
The aim of this study was to determine the prevalence and incidence of Systemic Lupus Erythematosus (SLE) in Tucumán, Argentina. METHODS: The study included inpatient and outpatient charts from four public hospitals and private practice rheumatology clinics, all of them members of the Tucumán Rheumatology Society. Patients older than 16 years with diagnosis of SLE between January 2005 and December 2012 were included. Prevalence and annual incidence were calculated as the number of cases per 100.000 inhabitants during the period 2005 to 2012. RESULTS: Three hundred fifty-three patients were identified. The mean age at diagnosis was 30.5 ± 11.7 years, 93.5% women, 83% mestizos. Prevalence was 24.3 cases/100.000 inhabitants (CI 95% 22.6-28.8) and age-adjusted (≥16 years) of 34.9 cases/100.000 inhabitants (CI 95% 32.8-41.1). The annual incidence in 2005 was 1.8 cases/100.000 inhabitants (95% CI 1-2.9) and 2012 of 4.2 cases/100.000 inhabitants (95% CI 2.9-5.8). Mortality was 9.1%, with infections being the most frequent cause (14/32). CONCLUSION: The prevalence of SLE in the province of Tucumán was 34.9 cases/100.000 inhabitants.
Subject(s)
Lupus Erythematosus, Systemic/epidemiology , Adolescent , Adult , Age Distribution , Argentina/epidemiology , Female , Humans , Incidence , Lupus Erythematosus, Systemic/mortality , Male , Prevalence , Sex Distribution , Young AdultABSTRACT
The identification of effective new therapies for prostate cancer (PCa) requires a better understanding of the multiple molecular interactions between tumor cells and their associated microenvironment. In this context, galectin-1 (Gal-1) is a key molecule in the determination of the prostatic carcinoma microenviroment; therefore, it is essential to understand all the molecular processes in which this protein is involved. Most of the previous studies found in the literature have focused on the microenvironment remodeling properties of tumor-secreted Gal-1, through its interactions with the glyco-receptors at the cell membrane and the extracellular matrix. This report shows original aspects of the lectin by focusing on the role of lymphocyte endogenous Gal-1 in controlling anti-prostate tumor immunity. Using a murine preclinical model of prostate cancer, our results demonstrate that endogenous Gal-1 in lymphocytes modulates their proliferative rate and cytotoxic function in conditions of high extracellular Gal-1 concentration, mainly derived from tumor cells. In such conditions, the absence of Gal-1 in T lymphocytes potentiates anti-tumor immune responses. Further studies demonstrated that endogenous Gal-1 in CD4+, but mainly in CD8+T cells, acts as a negative regulator of anti-tumor immunity. In conclusion, prostate tumors require Gal-1 in lymphocytes to evade immune responses. This report lays the foundation for an original immunotherapy strategy for prostate cancer.
Subject(s)
Galectin 1/immunology , Prostatic Neoplasms/immunology , T-Lymphocytes/immunology , Tumor Microenvironment/immunology , Animals , Cell Line, Tumor/transplantation , Cell Proliferation , Disease Models, Animal , Galectin 1/genetics , Galectin 1/metabolism , Humans , Immunotherapy/methods , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , T-Lymphocytes/metabolismABSTRACT
Antecedentes: el carcinoma adenoquístico es el tumor maligno más frecuente de las glándulas sub-maxilar y menores. A pesar de su lento crecimiento y diseminación regional, muestra un pronóstico desfavorable debido a su tardía diseminación a distancia. Objetivo: analizar la serie propia a la luz de la bibliografia. Material y métodos: 44 pacientes con una edad media de 52,47 años y predominio del género femenino. De ellos, el 61,3% fueron tumores de glándula salival menor, 20,4% de submaxilar y 18,2% de parótida. En todos se realizó resección completa del tumor, seguida de vaciamiento cervical en el 34%. En el 43,2%, la cirugía fue seguida de Co60 radioterapia. El seguimiento medio de la muestra fue 52,5 (1-120) meses. Resultados: la curva de recurrencia acumulada fue del 36,8% a 5 años. La supervivencia global fue del 60 y 36% a 5 y 10 años, respectivamente, y se vio afectada con significación estadística por los márgenes insuficientes de la resección, el requerimiento de radioterapia adyuvante y el estadio. El análisis multivariado demostró que solo los márgenes insuficientes conservaron su significación estadística para la supervivencia y una tendencia desfavorable para el intervalo libre de enfermedad. Conclusiones: la extensión de la cirugía al cuello y la radioterapia adyuvante dependieron del estadio, los márgenes quirúrgicos, el compromiso nervioso, la presencia de adenopatas positivas y el subtpo histológico.
Background: adenoid cystic carcinoma is the most frequent malignant tumor of submaxillary and mi-nor salivary glands. Despite its slow growth, it shows an unfavorable prognosis because of its distant disseminaton. Objective: to analyse our series of patents in relaton to the literature. Materials and methods: 44 patents with mean age 52.47 years female gender. Of them, 61.3% were of minor salivary glands, 20.4% of submaxillary gland, and 18.2% the parotid gland. All patents underwent complete resecton of the tumor followed by neck dissecton in 34%. Co60 radiotherapy was administered to 43.2%. Mean follow up was 52.5 (range, 1-120) months. Results: 5-year recurrence rate was 36.8%. At 5 and 10 years, overall survival was 60 and 36%,respect-vely. Close surgical margins, requirement of adjuvant radiotherapy and stage significantly afected survival rate. The multivariate analysis showed that close margins was statstically significant for survival and associated with an unfavorable tendency for disease-free interval. Conclusions: extenton of surgery to the neck and adyuvant radiotherapy was dependent of stage, clear surgical margins, neural invasion, positive nodes in the neck and hystological subtype.
Subject(s)
Humans , Coronary Disease/therapy , Drug-Eluting Stents/history , Drug-Eluting Stents , Coronary Thrombosis/complications , Coronary Thrombosis/etiology , Angioplasty, Balloon, Coronary , Drug Delivery Systems , Prosthesis Design , Prosthesis Failure , Paclitaxel/administration & dosage , Risk , Sirolimus/administration & dosage , United States Food and Drug AdministrationABSTRACT
Las metástasis en Cabeza y Cuello de primarios ubicados debajo de las clavículas son poco frecuentes, pero aquellas originadas en neoplasias renales son más raras aún. El objetivo de la presente comunicación analiza 2 enfermos con metástasis únicas en Cabeza y Cuello cuyo primario se hallaba en riñón...Las metástasis del carcinoma de Células Clras de riñón suelen ser múltiples y ganglionares. Rara vez son únicas y extranodales. El tratamiento de elección en estas últimas es el quirúrgico(AU)
Subject(s)
Humans , Neoplasm Metastasis/diagnosis , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/surgery , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/surgeryABSTRACT
El sarcoma sinovial es un tumor raro. Más aún, lo es su localización en cabeza y cuello. Las metástasis en glándula tiroides habitualmente son un hallazgo. El diagnóstico preoperatorio es difícil porque clínicamente no se diferencian de un carcinoma difernciado de tiroides. El propósito del trabajo es comunicar un enfermo portador de metástasis en glándula tiroides de un sarcoma sinovial de miembro inferior(AU)
Subject(s)
Female , Humans , Thyroid Gland/pathology , Sarcoma, Synovial/diagnosis , Sarcoma, Synovial/surgery , Sarcoma, Synovial/diagnostic imagingABSTRACT
Las metástasis en Cabeza y Cuello de primarios ubicados debajo de las clavículas son poco frecuentes, pero aquellas originadas en neoplasias renales son más raras aún. El objetivo de la presente comunicación analiza 2 enfermos con metástasis únicas en Cabeza y Cuello cuyo primario se hallaba en riñón...Las metástasis del carcinoma de Células Clras de riñón suelen ser múltiples y ganglionares. Rara vez son únicas y extranodales. El tratamiento de elección en estas últimas es el quirúrgico
Subject(s)
Humans , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/diagnosis , Neoplasm Metastasis/diagnosis , Head and Neck Neoplasms/surgery , Head and Neck Neoplasms/diagnosisABSTRACT
El sarcoma sinovial es un tumor raro. Más aún, lo es su localización en cabeza y cuello. Las metástasis en glándula tiroides habitualmente son un hallazgo. El diagnóstico preoperatorio es difícil porque clínicamente no se diferencian de un carcinoma difernciado de tiroides. El propósito del trabajo es comunicar un enfermo portador de metástasis en glándula tiroides de un sarcoma sinovial de miembro inferior
