RESUMEN
Memory T cells are critical for long-term immunity against reinfection and require interleukin-7 (IL-7), but the mechanisms by which IL-7 controls memory T cell survival, particularly metabolic fitness, remain elusive. We discover that IL-7 induces expression of the glycerol channel aquaporin 9 (AQP9) in virus-specific memory CD8+ T cells, but not naive cells, and that AQP9 is vitally required for their long-term survival. AQP9 deficiency impairs glycerol import into memory CD8+ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage. These defects can be rescued by ectopic expression of TAG synthases, which restores lipid stores and memory T cell survival. Finally, we find that TAG synthesis is a central component of IL-7-mediated survival of human and mouse memory CD8+T cells. This study uncovers the metabolic mechanisms by which IL-7 tailors the metabolism of memory T cells to promote their longevity and fast response to rechallenge.
Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Supervivencia Celular , Memoria Inmunológica , Triglicéridos/metabolismo , Animales , Acuaporinas/metabolismo , Infecciones por Arenaviridae/inmunología , Linfocitos T CD8-positivos/metabolismo , Glicerol/metabolismo , Humanos , Interleucina-7/metabolismo , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones , Transducción de SeñalRESUMEN
Memory CD8(+) T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4(+) regulatory T cells (Treg cells) was necessary for the maturation of memory CD8(+) T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell-derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase 'restored' the maturation of memory CD8(+) T cells in IL-10-deficient mice. Our data indicate that Treg cell-derived IL-10 is needed to insulate CD8(+) T cells from inflammatory signals, and reveal that the resolution phase of infection is a critical period that influences the quality and function of developing memory CD8(+) T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Interleucina-10/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Perfilación de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Memoria Inmunológica/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/trasplanteRESUMEN
Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naive, MP, and TE CD8+ T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro-effector genes in MP cells, indicative of multipotency. Polycomb repressive complex 2 deficiency impaired clonal expansion and TE cell differentiation, but minimally impacted CD8+ memory T cell maturation. Abundant H3K27me3 deposition at pro-memory genes occurred late during TE cell development, probably from diminished transcription factor FOXO1 expression. These results outline a temporal model for loss of memory cell potential through selective epigenetic silencing of pro-memory genes in effector T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Cromatina/inmunología , Complejo Represivo Polycomb 2/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/genética , Cromatina/genética , Cromatina/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Citometría de Flujo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/inmunología , Proteína Forkhead Box O1/metabolismo , Expresión Génica/inmunología , Histonas/inmunología , Histonas/metabolismo , Immunoblotting , Memoria Inmunológica/genética , Memoria Inmunológica/inmunología , Lisina/inmunología , Lisina/metabolismo , Metilación , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Modelos Inmunológicos , Células Madre Multipotentes/inmunología , Células Madre Multipotentes/metabolismo , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The differentiation of CD4(+) helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells. These findings were not the result of generalized signaling attenuation in Tfh cells, because they retained the ability to flux calcium and activate NFAT-transcription-factor-dependent cytokine production. These data identify the interleukin-2 (IL-2)-mTORc1 axis as a critical orchestrator of the reciprocal balance between Tfh and Th1 cell fates and their respective metabolic activities after acute viral infection.
Asunto(s)
Interleucina-2/fisiología , Complejos Multiproteicos/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Transducción de Señal/fisiología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Serina-Treonina Quinasas TOR/fisiología , Animales , Apoptosis , Señalización del Calcio , Ciclo Celular , División Celular , Activación Enzimática , Glucosa/metabolismo , Glucólisis , Subunidad alfa del Receptor de Interleucina-2/fisiología , Virus de la Coriomeningitis Linfocítica/inmunología , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/fisiología , Consumo de Oxígeno , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Organismos Libres de Patógenos Específicos , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/virología , Células TH1/citología , Células TH1/inmunología , Células TH1/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1?FoxO1?PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Factores de Transcripción Forkhead/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Receptor de Muerte Celular Programada 1/biosíntesis , Linfocitos T Citotóxicos/inmunología , Animales , Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Antígenos CD28/inmunología , Diferenciación Celular/inmunología , Línea Celular Tumoral , Enfermedad Crónica , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Granzimas/biosíntesis , Humanos , Interferón gamma/biosíntesis , Células Jurkat , Activación de Linfocitos/inmunología , Coriomeningitis Linfocítica/virología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Receptores de Antígenos de Linfocitos T/inmunología , Sirolimus/farmacología , Linfocitos T Citotóxicos/citología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/biosíntesisRESUMEN
Immunity to many intracellular pathogens requires the proliferation, differentiation, and function of CD8(+) cytotoxic T lymphocytes (CTLs). While the majority of effector CTLs die upon clearance of the pathogen, a small proportion of them survive to become long-lived memory CTLs. Memory CTLs can provide protective immunity against re-exposure to the same pathogen and are the principle motivation behind T-cell- based vaccine design. While a large body of cellular immunologic research has proven invaluable to define effector and memory CTLs by their different phenotypes and functions, an emerging focus in the field has been to understand how environmental cues regulate CTL differentiation on a genomic level. Genome-wide studies to profile transcriptional and epigenetic changes during infection have revealed that dynamic changes in DNA methylation patterns and histone modifications accompany transcriptional signatures that define and regulate CTL differentiation states. In this review, we emphasize the importance of epigenetic regulation of CD8(+) T-cell differentiation and the likely role that transcription factors play in this process.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Diferenciación Celular , Metilación de ADN , Epigénesis Genética , Regulación de la Expresión Génica/inmunología , Interacción Gen-Ambiente , Humanos , Memoria Inmunológica/genética , Memoria Inmunológica/inmunología , Infecciones/genética , Activación Transcripcional , Vacunas/inmunologíaRESUMEN
Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.
RESUMEN
BACKGROUND: Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. RESULTS: Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. CONCLUSIONS: Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.
Asunto(s)
Modelos Animales de Enfermedad , Disbiosis , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Interleucina-10 , Animales , Humanos , Ratones , Enfermedades Inflamatorias del Intestino/microbiología , Disbiosis/microbiología , Interleucina-10/genética , Colitis/microbiología , Heces/microbiología , Colon/microbiología , Ratones Noqueados , Ratones Endogámicos C57BL , Femenino , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Inflamación , MasculinoRESUMEN
Several studies have examined levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. This meta-analysis was conducted to examine the association between obsessive-compulsive disorder (OCD) and plasma serum levels of proinflammatory cytokines. Twelve studies met inclusion criteria. The meta-analysis demonstrated a significant reduction in IL-1ß levels in OCD. No significant difference in plasma levels of IL-6 or TNF-α was demonstrated. Stratified subgroup analysis revealed possible moderating effects of age and medication use on IL-6 levels. Studies including children on psychotropic medication had lower plasma IL-6 levels. Stratified subgroup analysis revealed a moderating effect of comorbid depression on TNF-α levels. Elevated TNF-α levels were reported in studies that included individuals with comorbid depression. Future studies examining immune function in OCD should adjust for potential confounding due to medication use and comorbid depression. Further studies assessing cerebrospinal fluid cytokine levels in OCD are also needed.
Asunto(s)
Interleucina-1beta/sangre , Interleucina-6/sangre , Trastorno Obsesivo Compulsivo/sangre , Factor de Necrosis Tumoral alfa/sangre , Factores de Edad , Antipsicóticos/uso terapéutico , HumanosRESUMEN
Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle. Moreover, in histone 2B-GFP mice, the 2B-GFP label was retained in Tsp cells, indicative of a slow-cycling phenotype. Human Tsp cells displayed a distinct gene-expression profile that was enriched for genes overexpressed in Trm cells. In mice, proteins encoded by Tsp signature genes, including nuclear receptor subfamily 4 group A member 1 (NR4A1) and ATP-binding cassette (ABC) transporters, influenced the function and differentiation of Trm cells. Responses to adoptive transfer of human Tsp cells into immune-deficient mice and plerixafor therapy suggested that human Tsp cell mobilization could be manipulated as a potential cellular therapy. These data identify a distinct subset of human T cells with a quiescent/slow-cycling phenotype, propensity for tissue enrichment, and potential to mobilize into circulation, which may be harnessed for adoptive cellular therapy.