RESUMEN
Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.
Asunto(s)
Interleucina-10 , Macrófagos , Ratones Endogámicos C57BL , Infarto del Miocardio , Linfocitos T Reguladores , Animales , Infarto del Miocardio/inmunología , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Linfocitos T Reguladores/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Interleucina-10/metabolismo , Interleucina-10/genética , Fenotipo , Miocardio/patología , Miocardio/inmunología , Miocardio/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/inmunología , Fibrosis , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Ratones NoqueadosRESUMEN
Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT inflammation which can impair insulin sensitivity and cause metabolic deregulation. Regulatory T cells (Tregs) that reside in the VAT suppress inflammation and protect from metabolic disease. The cellular components of VAT and its secretory products play a vital role in fostering the differentiation and maintenance of VAT Tregs. Critically, the physiology and inflammatory tone of VAT exhibit sex-specific disparities, resulting in substantial VAT Treg heterogeneity. Indeed, cytokines and sex hormones promote the differentiation of distinct populations of mature VAT Tregs, each characterized by unique phenotypes, homeostatic requirements, and functions. This review focuses on key findings that have significantly advanced our understanding of VAT Treg biology and the current state of the field, while also discussing open questions that require further exploration.
Asunto(s)
Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Animales , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/inmunología , Diferenciación Celular , Citocinas/metabolismo , Metabolismo Energético , Transcripción Genética , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Regulación de la Expresión Génica , Hormonas Esteroides Gonadales/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , HomeostasisRESUMEN
Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.
Asunto(s)
Proteína 1 Similar al Receptor de Interleucina-1 , Linfocitos T Reguladores , Femenino , Masculino , Humanos , Grasa Intraabdominal , Citocinas , Inflamación , GlucosaRESUMEN
The intestine is home to an intertwined network of epithelial, immune, and neuronal cells as well as the microbiome, with implications for immunity, systemic metabolism, and behavior. While the complexity of this microenvironment has long since been acknowledged, recent technological advances have propelled our understanding to an unprecedented level. Notably, the microbiota and non-immune or structural cells have emerged as important conductors of intestinal immunity, and by contrast, cells of both the innate and adaptive immune systems have demonstrated non-canonical roles in tissue repair and metabolism. This review highlights recent works in the following two streams: non-immune cells of the intestine performing immunological functions; and traditional immune cells exhibiting non-immune functions in the gut.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Inmunidad Innata , Mucosa IntestinalRESUMEN
Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, many patients fail to respond to this therapy or experience side effects. Recently, gut microbiota have emerged as a key determinant of ICB efficacy and toxicity, making manipulation of the microbiome a novel therapeutic strategy with which to improve ICB outcomes.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Inmunoterapia/efectos adversosRESUMEN
This commentary article highlights two recently published studies, which for the first time revealed the immunological underpinnings of sex-bias in cancer incidence and mortality. These studies showed that the androgen receptor restrains anti-tumour immunity in males by repressing cytotoxic genes in CD8+ T cells.
RESUMEN
Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism. Adipose tissue consists of an array of different cell types, including specialized adipocytes and stromal and endothelial cells. In addition, adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function. These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue, which is directly linked to insulin sensitivity and signaling. Furthermore, these cells affect the control of thermogenesis. While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10, obesity tips the balance in favor of a proinflammatory milieu, leading to the development of insulin resistance and the dysregulation of systemic metabolism. Notably, anti-inflammatory immune cells, including regulatory T cells and innate lymphocytes, protect against insulin resistance and have the characteristics of tissue-resident cells, while proinflammatory immune cells are recruited from the circulation to obese adipose tissue. Here, we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.
Asunto(s)
Células Endoteliales , Resistencia a la Insulina , Adipocitos , Tejido Adiposo , Animales , Metabolismo Energético/fisiología , Mamíferos , Termogénesis/fisiologíaAsunto(s)
Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Biomarcadores , Plasticidad de la Célula/inmunología , Susceptibilidad a Enfermedades/inmunología , Homeostasis , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , FenotipoRESUMEN
CD8+ T cells responding to chronic infections or tumors acquire an 'exhausted' state associated with elevated expression of inhibitory receptors, including PD-1, and impaired cytokine production. Exhausted T cells are continuously replenished by T cells with precursor characteristics that self-renew and depend on the transcription factor TCF1; however, their developmental requirements are poorly understood. In the present study, we demonstrate that high antigen load promoted the differentiation of precursor T cells, which acquired hallmarks of exhaustion within days of infection, whereas early effector cells retained polyfunctional features. Early precursor T cells showed epigenetic imprinting characteristic of T cell receptor-dependent transcription factor binding and were restricted to the generation of cells displaying exhaustion characteristics. Transcription factors BACH2 and BATF were key regulators with opposing functions in the generation of early precursor T cells. Overall, we demonstrate that exhaustion manifests first in TCF1+ precursor T cells and is propagated subsequently to the pool of antigen-specific T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Células Precursoras de Linfocitos T/inmunología , Animales , Diferenciación Celular , Autorrenovación de las Células , Células Cultivadas , Enfermedad Crónica , Anergia Clonal , Epigénesis Genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Tolerancia Inmunológica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos TRESUMEN
The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ Tregs in tumors are not well known. High-dimensional single-cell profiling of T cells from chemotherapy-naive individuals with non-small-cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4- counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespective of the tumor type.
Asunto(s)
Diferenciación Celular/inmunología , Factores Reguladores del Interferón/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología , Anciano , Anciano de 80 o más Años , Animales , Humanos , Masculino , Ratones , Persona de Mediana Edad , Neoplasias/patología , Linfocitos T Reguladores/patologíaRESUMEN
Adipose tissue is an energy store and a dynamic endocrine organ1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism3,4. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes5,6. Regulatory T (Treg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT7-9. Here we uncover pronounced sexual dimorphism in Treg cells in the VAT. Male VAT was enriched for Treg cells compared with female VAT, and Treg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of Treg cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of Treg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident Treg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.
Asunto(s)
Hormonas Esteroides Gonadales/metabolismo , Grasa Intraabdominal/inmunología , Caracteres Sexuales , Linfocitos T Reguladores/inmunología , Andrógenos/metabolismo , Animales , Quimiocina CCL2/inmunología , Cromatina/genética , Femenino , Regulación de la Expresión Génica , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-33/inmunología , Grasa Intraabdominal/metabolismo , Masculino , Ratones , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , RNA-Seq , Receptores CCR2/metabolismo , Células del Estroma/citología , Células del Estroma/inmunología , Células del Estroma/metabolismo , Linfocitos T Reguladores/metabolismo , Transcripción GenéticaRESUMEN
Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Diferenciación Celular/inmunología , Cromatina/metabolismo , Colitis/inmunología , Modelos Animales de Enfermedad , Epigénesis Genética/inmunología , Factores de Transcripción Forkhead/metabolismo , Tracto Gastrointestinal/inmunología , Regulación de la Expresión Génica/inmunología , Homeostasis/inmunología , Factores Reguladores del Interferón/deficiencia , Factores Reguladores del Interferón/metabolismo , Interleucina-10/biosíntesis , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
A wide array of chemokine receptors, including CCR2, are known to control Treg migration. Here, we report that CCR2 regulates Tregs beyond chemotaxis. We found that CCR2 deficiency reduced CD25 expression by FoxP3+ Treg cells. Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type (WT) and CCR2-/- strains. Thus, CCR2 deficiency resulted in profound loss of CD25hi FoxP3+ Tregs in secondary lymphoid organs as well as in peripheral tissues. CCR2-/- Treg cells were also functionally inferior to WT cells. Interestingly, these changes to Treg cells did not depend on CCR2+ monocytes/moDCs (the cells where CCR2 receptors are most abundant). Rather, we demonstrated that CCR2 was required for TLR-stimulated, but not TCR- or IL-2-stimulated, CD25 upregulation on Treg cells. Thus, we propose that CCR2 signaling can increase the fitness of FoxP3+ Treg cells and provide negative feedback to counter the proinflammatory effects of CCR2 on myeloid cells.
Asunto(s)
Quimiotaxis/genética , Factores de Transcripción Forkhead/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Monocitos/inmunología , Receptores CCR2/deficiencia , Transducción de Señal/genética , Linfocitos T Reguladores/inmunología , Animales , Células Dendríticas/inmunología , Retroalimentación Fisiológica , Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CCR2/genética , Receptores Toll-Like/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Foxp3+ regulatory T cells (Treg cells) are crucial for the maintenance of immune homeostasis both in lymphoid tissues and in non-lymphoid tissues. Here we demonstrate that the ability of intestinal Treg cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (TH17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal Treg cell populations, including RORγt+ Treg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled Treg cell-derived IL-10 production and prevented excessive signaling via the kinases PI(3)K (phosphatidylinositol-3-OH kinase) and Akt and the metabolic checkpoint kinase complex mTORC1 (mammalian target of rapamycin) and expression of inflammatory cytokines in intestinal Treg cells. c-Maf deficiency in Treg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal TH17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal Treg cells, which is essential for the establishment of host-microbe symbiosis.
Asunto(s)
Inmunoglobulina A/biosíntesis , Intestinos/inmunología , Microbiota , Proteínas Proto-Oncogénicas c-maf/fisiología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Células Cultivadas , Colitis/inmunología , Citocinas/metabolismo , Disbiosis , Regulación de la Expresión Génica , Homeostasis , Interleucina-10/biosíntesis , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-maf/genética , Proteínas Proto-Oncogénicas c-maf/metabolismo , Linfocitos T Reguladores/enzimologíaRESUMEN
Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
Asunto(s)
Metilación de ADN , Encefalomielitis Autoinmune Experimental/inmunología , Factores de Transcripción Forkhead/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/inmunología , Linfocitos T Reguladores/inmunología , Animales , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasas/inmunología , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Epigénesis Genética , Femenino , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/inmunología , Impresión Genómica , Interleucina-6/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/metabolismoRESUMEN
Cytokines play an integral role in shaping innate and adaptive immune responses. Members of the interleukin (IL)-1 family regulate a plethora of immune-cell-mediated processes, which include pathogen defense and tissue homeostasis. Notably, the IL-1 family cytokine IL-33 promotes adaptive and innate type 2 immune responses, confers viral protection and facilitates glucose metabolism and tissue repair. At the cellular level, IL-33 stimulates differentiation, maintenance, and function of various immune cell types, including regulatory T cells, effector CD4+ and CD8+ T cells, macrophages, and type 2 innate lymphoid cells (ILC2s). Other IL-1 family members, such as IL-1ß and IL-18 promote type 1 responses, while IL-37 limits immune activation. Although IL-1 cytokines play critical roles in immunity and tissue repair, their deregulated expression is often linked to autoimmune and inflammatory diseases. Therefore, IL-1 cytokines are regulated tightly by posttranscriptional mechanisms and decoy receptors. In this review, we discuss the biology and function of IL-1 family cytokines, with a specific focus on regulation and function of IL-33 in immune and tissue homeostasis.