RESUMEN
Polyamine synthesis represents one of the most profound metabolic changes during T cell activation, but the biological implications of this are scarcely known. Here, we show that polyamine metabolism is a fundamental process governing the ability of CD4+ helper T cells (TH) to polarize into different functional fates. Deficiency in ornithine decarboxylase, a crucial enzyme for polyamine synthesis, results in a severe failure of CD4+ T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage-defining transcription factors across TH cell subsets. Polyamines control TH differentiation by providing substrates for deoxyhypusine synthase, which synthesizes the amino acid hypusine, and mice in which T cells are deficient for hypusine develop severe intestinal inflammatory disease. Polyamine-hypusine deficiency caused widespread epigenetic remodeling driven by alterations in histone acetylation and a re-wired tricarboxylic acid (TCA) cycle. Thus, polyamine metabolism is critical for maintaining the epigenome to focus TH cell subset fidelity.
Asunto(s)
Linaje de la Célula , Poliaminas/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromatina/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Colitis/inmunología , Colitis/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Epigenoma , Histonas/metabolismo , Inflamación/inmunología , Inflamación/patología , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ornitina Descarboxilasa/metabolismo , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Células Th17/efectos de los fármacos , Células Th17/inmunología , Factores de Transcripción/metabolismoRESUMEN
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.
Asunto(s)
Fosfatos de Fosfatidilinositol , Fosfatidilinositoles , Fosfatidilinositoles/metabolismo , Transducción de Señal , Fosfolipasas de Tipo C/metabolismo , Linfocitos T CD8-positivos/metabolismoRESUMEN
T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.
Asunto(s)
Antígenos CD28/metabolismo , Activación de Linfocitos , Mitocondrias/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Animales , Carnitina O-Palmitoiltransferasa , Inhibidores Enzimáticos/farmacología , Compuestos Epoxi/farmacología , Humanos , Interleucina-15/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/metabolismo , Estrés Fisiológico , Linfocitos T/metabolismoRESUMEN
Human plasmacytoid dendritic cells (pDCs) are interleukin-3 (IL-3)-dependent cells implicated in autoimmunity, but the role of IL-3 in pDC biology is poorly understood. We found that IL-3-induced Janus kinase 2-dependent expression of SLC7A5 and SLC3A2, which comprise the large neutral amino acid transporter, was required for mammalian target of rapamycin complex 1 (mTORC1) nutrient sensor activation in response to toll-like receptor agonists. mTORC1 facilitated increased anabolic activity resulting in type I interferon, tumor necrosis factor, and chemokine production and the expression of the cystine transporter SLC7A11. Loss of function of these amino acid transporters synergistically blocked cytokine production by pDCs. Comparison of in vitro-activated pDCs with those from lupus nephritis lesions identified not only SLC7A5, SLC3A2, and SLC7A11 but also ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) as components of a shared transcriptional signature, and ENPP2 inhibition also blocked cytokine production. Our data identify additional therapeutic targets for autoimmune diseases in which pDCs are implicated.
Asunto(s)
Sistemas de Transporte de Aminoácidos/genética , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Regulación de la Expresión Génica , Sistemas de Transporte de Aminoácidos/metabolismo , Autoinmunidad , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Metabolismo Energético , Humanos , Inmunidad , Transducción de SeñalRESUMEN
Sustained glucose and glutamine transport are essential for activated T lymphocytes to support ATP and macromolecule biosynthesis. We found that glutamine and glucose also fuel an indispensable dynamic regulation of intracellular protein O-GlcNAcylation at key stages of T cell development, transformation and differentiation. Glucose and glutamine are precursors of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a substrate for cellular glycosyltransferases. Immune-activated T cells contained higher concentrations of UDP-GlcNAc and increased intracellular protein O-GlcNAcylation controlled by the enzyme O-linked-ß-N-acetylglucosamine (O-GlcNAc) glycosyltransferase as compared with naive cells. We identified Notch, the T cell antigen receptor and c-Myc as key controllers of T cell protein O-GlcNAcylation via regulation of glucose and glutamine transport. Loss of O-GlcNAc transferase blocked T cell progenitor renewal, malignant transformation and peripheral T cell clonal expansion. Nutrient-dependent signaling pathways regulated by O-GlcNAc glycosyltransferase are thus fundamental for T cell biology.
Asunto(s)
Glucosa/metabolismo , Glutamina/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/fisiología , Uridina Difosfato N-Acetilglucosamina/metabolismo , Animales , Proliferación Celular/genética , Autorrenovación de las Células/genética , Transformación Celular Neoplásica/genética , Células Clonales , Femenino , Activación de Linfocitos/genética , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , N-Acetilglucosaminiltransferasas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Receptores Notch/metabolismoRESUMEN
We used high-resolution mass spectrometry to map the cytotoxic T lymphocyte (CTL) proteome and the effect of the metabolic checkpoint kinase mTORC1 on CTLs. The CTL proteome was dominated by metabolic regulators and granzymes, and mTORC1 selectively repressed and promoted expression of a subset of CTL proteins (~10%). These included key CTL effector molecules, signaling proteins and a subset of metabolic enzymes. Proteomic data highlighted the potential for negative control of the production of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) by mTORC1 in CTLs. mTORC1 repressed PtdIns(3,4,5)P3 production and determined the requirement for mTORC2 in activation of the kinase Akt. Our unbiased proteomic analysis thus provides comprehensive understanding of CTL identity and the control of CTL function by mTORC1.
Asunto(s)
Complejos Multiproteicos/metabolismo , Proteoma/inmunología , Linfocitos T Citotóxicos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Células Cultivadas , Cromatografía , Ensayo de Inmunoadsorción Enzimática , Femenino , Immunoblotting , Masculino , Espectrometría de Masas , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Complejos Multiproteicos/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Linfocitos T Citotóxicos/inmunología , Serina-Treonina Quinasas TOR/inmunologíaRESUMEN
CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Mitocondrias , Células Th17 , Glutamina/metabolismo , Interleucina-17/metabolismo , Mitocondrias/metabolismo , NAD/metabolismo , Fosfoglicerato-Deshidrogenasa/metabolismo , Serina/biosíntesis , Serina/metabolismo , Células Th17/citología , Células Th17/inmunología , Células Th17/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Ciclo del Ácido Cítrico , GTP Fosfohidrolasas/deficiencia , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismoRESUMEN
Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression.
Asunto(s)
Núcleo Celular/efectos de los fármacos , Dinoprostona/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Animales , Núcleo Celular/genética , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica , Células HEK293 , Humanos , Interleucina-4/farmacología , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/genética , Macrófagos/metabolismo , Macrófagos/ultraestructura , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Fiebre/inmunología , Mitocondrias/metabolismo , Biosíntesis de Proteínas , Animales , Antineoplásicos/metabolismo , Linfocitos T CD8-positivos/ultraestructura , Citocinas/biosíntesis , Glucosa/metabolismo , Leucemia Mieloide/inmunología , Leucemia Mieloide/patología , Leucemia Mieloide/prevención & control , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Mitocondrias/ultraestructura , Modelos Biológicos , TemperaturaRESUMEN
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.
Asunto(s)
Autofagia , Linfocitos T CD8-positivos , Humanos , Animales , Ratones , Dinoprostona , Genes Mitocondriales , GlutatiónRESUMEN
Little is known about the effects of high-fat diet (HFD)-induced obesity on resident colonic lamina propria (LP) macrophages (LPMs) function and metabolism. Here, we report that obesity and diabetes resulted in increased macrophage infiltration in the colon. These macrophages exhibited the residency phenotype CX3CR1hiMHCIIhi and were CD4-TIM4-. During HFD, resident colonic LPM exhibited a lipid metabolism gene expression signature that overlapped that used to define lipid-associated macrophages (LAMs). Via single-cell RNA sequencing, we identified a sub-cluster of macrophages, increased in HFD, that were responsible for the LAM signature. Compared to other macrophages in the colon, these cells were characterized by elevated glycolysis, phagocytosis, and efferocytosis signatures. CX3CR1hiMHCIIhi colonic resident LPMs had fewer lipid droplets (LDs) and decreased triacylglycerol (TG) content compared to equivalent cells in lean mice and exhibited increased phagocytic capacity, suggesting that HFD induces adaptive responses in LPMs to limit bacterial translocation.
RESUMEN
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.
RESUMEN
Due to the alarming spread of resistance to classic antimicrobial agents, innovative therapeutic methods to combat antibiotic-resistant bacterial pathogens are urgently required. This minireview examines the enhancement of antibiotic efficacy by their combination with new antimicrobials, such as plant-derived compounds, metal ions and nanoparticles and bacteriophage lytic enzymes. The mechanisms of the observed synergy are also described. The promising results of basic research indicate that in future, combined therapy may be applied in human and veterinary medicine, agriculture and the food industry to combat bacterial pathogens.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Bacteriocinas/farmacología , Animales , Infecciones Bacterianas/microbiología , Sinergismo Farmacológico , Quimioterapia Combinada , HumanosRESUMEN
Jak inhibitors are increasingly used in dermatology. Despite broad inhibitory effects on cytokine signaling cascades, they only modestly increase the risk for infectious diseases. To address the molecular mechanisms underlying this unexpected clinical observation, we investigated how tofacintib (tofa), a first-in-class Jak inhibitor, regulates host defense responses in toll-like receptor 4-activated human macrophages. Specifically, we asked whether tofa inhibits anti-inflammatory IL-10 signaling, thereby counteracting the downregulation of inflammatory, host-protective pathways. We found that tofa blocked macrophage responses to IL-10 at the level of signal transducer and activator of transcription 3 phosphorylation. Furthermore, toll-like receptor 4-induced, autocrine/paracrine IL-10/IL-10R activation promoted the expression of hepcidin, the master regulator of iron metabolism, resulting in intracellular iron sequestration. In contrast, autocrine/paracrine IL-10/IL-10R activation repressed the expression of cathelicidin antimicrobial peptide as well as antigen-presenting molecules, thus together, inducing a pathogen-favoring environment. Although tofa further repressed cathelicidin, it prevented the induction of intracellular HAMP and restored the expression of antigen-presentation molecules in toll-like receptor 4-activated macrophages. Our study supports the concept that induction of IL-10/IL-10R signaling drives a complex immune evasion strategy of intracellular microbes. Moreover, we conclude that tofa has diverging effects on macrophage host response pathways, and we identify the toll-like receptor 4-IL-10-signal transducer and activator of transcription 3-HAMP axis as a potential therapeutic target to counteract immune evasion.
Asunto(s)
Inhibidores de las Cinasas Janus , Receptor Toll-Like 4 , Humanos , Interleucina-10/metabolismo , Hierro/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Macrófagos/metabolismo , Piperidinas , Pirimidinas , Factor de Transcripción STAT3/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Macrophages populate every organ during homeostasis and disease, displaying features of tissue imprinting and heterogeneous activation. The disconnected picture of macrophage biology that has emerged from these observations is a barrier for integration across models or with in vitro macrophage activation paradigms. We set out to contextualize macrophage heterogeneity across mouse tissues and inflammatory conditions, specifically aiming to define a common framework of macrophage activation. We built a predictive model with which we mapped the activation of macrophages across 12 tissues and 25 biological conditions, finding a notable commonality and finite number of transcriptional profiles, in particular among infiltrating macrophages, which we modeled as defined stages along four conserved activation paths. These activation paths include a "phagocytic" regulatory path, an "inflammatory" cytokine-producing path, an "oxidative stress" antimicrobial path, or a "remodeling" extracellular matrix deposition path. We verified this model with adoptive cell transfer experiments and identified transient RELMÉ expression as a feature of monocyte-derived macrophage tissue engraftment. We propose that this integrative approach of macrophage classification allows the establishment of a common predictive framework of monocyte-derived macrophage activation in inflammation and homeostasis.
Asunto(s)
Activación de Macrófagos , Macrófagos , Animales , Citocinas/metabolismo , Homeostasis , Inflamación/metabolismo , RatonesRESUMEN
Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We discovered that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) induced a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect. Notably, adoptive transfer of trained AMs resulted in increased bacterial loads and tissue damage upon subsequent pneumococcal infection. In contrast, intranasal pre-exposure to LPS promoted bacterial clearance, highlighting the complexity of stimulus-induced immune responses, which likely involve multiple cell types and may depend on the local immunological and metabolic environment. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and reveal tissue-specific features of trained immunity.
Asunto(s)
Interferón Tipo I , Macrófagos Alveolares , Interferón Tipo I/metabolismo , Lipopolisacáridos , Pulmón , Transducción de SeñalRESUMEN
Type 2 immunity is associated with adipose tissue (AT) homeostasis and infection with parasitic helminths, but whether AT participates in immunity to these parasites is unknown. We found that the fat content of mesenteric AT (mAT) declined in mice during infection with a gut-restricted helminth. This was associated with the accumulation of metabolically activated, interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and extracellular matrix (ECM)-producing stromal cells. These cells shared transcriptional features, including the expression of Dpp4 and Pi16, with multipotent progenitor cells (MPC) that have been identified in numerous tissues and are reported to be capable of differentiating into fibroblasts and adipocytes. Concomitantly, mAT became infiltrated with resident T helper 2 (TH2) cells that responded to TSLP and IL-33 by producing stromal cell-stimulating cytokines, including transforming growth factor ß1 (TGFß1) and amphiregulin. These TH2 cells expressed genes previously associated with type 2 innate lymphoid cells (ILC2), including Nmur1, Calca, Klrg1, and Arg1, and persisted in mAT for at least 11 months after anthelmintic drug-mediated clearance of infection. We found that MPC and TH2 cells localized to ECM-rich interstitial spaces that appeared shared between mesenteric lymph node, mAT, and intestine. Stromal cell expression of epidermal growth factor receptor (EGFR), the receptor for amphiregulin, was required for immunity to infection. Our findings point to the importance of MPC and TH2 cell interactions within the interstitium in orchestrating AT remodeling and immunity to an intestinal infection.
Asunto(s)
Inmunidad Innata , Interleucina-33 , Tejido Adiposo/metabolismo , Anfirregulina , Animales , Citocinas/metabolismo , Dipeptidil Peptidasa 4 , Receptores ErbB , Linfocitos , Ratones , Células Th2 , Factor de Crecimiento Transformador beta1RESUMEN
Adipose tissue (AT) plays a central role in systemic metabolic homeostasis, but its function during bacterial infection remains unclear. Following subcutaneous bacterial infection, adipocytes surrounding draining lymph nodes initiated a transcriptional response indicative of stimulation with IFN-γ and a shift away from lipid metabolism toward an immunologic function. Natural killer (NK) and invariant NK T (iNKT) cells were identified as sources of infection-induced IFN-γ in perinodal AT (PAT). IFN-γ induced Nos2 expression in adipocytes through a process dependent on nuclear-binding oligomerization domain 1 (NOD1) sensing of live intracellular bacteria. iNOS expression was coupled to metabolic rewiring, inducing increased diversion of extracellular L-arginine through the arginosuccinate shunt and urea cycle to produce nitric oxide (NO), directly mediating bacterial clearance. In vivo, control of infection in adipocytes was dependent on adipocyte-intrinsic sensing of IFN-γ and expression of iNOS. Thus, adipocytes are licensed by innate lymphocytes to acquire anti-bacterial functions during infection.
Asunto(s)
Señales (Psicología) , Células Asesinas Naturales , Adipocitos/metabolismo , Inmunidad , Interferón gamma/metabolismoRESUMEN
Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function.
Asunto(s)
Proteínas de Unión a Ácidos Grasos/fisiología , Metabolismo de los Lípidos , Mitocondrias/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Línea Celular Tumoral , ADN Mitocondrial/metabolismo , Humanos , Interferón Tipo I/metabolismo , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/patologíaRESUMEN
CD8+ effector T (TE) cell proliferation and cytokine production depends on enhanced glucose metabolism. However, circulating T cells continuously adapt to glucose fluctuations caused by diet and inter-organ metabolite exchange. Here we show that transient glucose restriction (TGR) in activated CD8+ TE cells metabolically primes effector functions and enhances tumour clearance in mice. Tumour-specific TGR CD8+ TE cells co-cultured with tumour spheroids in replete conditions display enhanced effector molecule expression, and adoptive transfer of these cells in a murine lymphoma model leads to greater numbers of immunologically functional circulating donor cells and complete tumour clearance. Mechanistically, TE cells treated with TGR undergo metabolic remodelling that, after glucose re-exposure, supports enhanced glucose uptake, increased carbon allocation to the pentose phosphate pathway (PPP) and a cellular redox shift towards a more reduced state-all indicators of a more anabolic programme to support their enhanced functionality. Thus, metabolic conditioning could be used to promote efficiency of T-cell products for adoptive cellular therapy.