RESUMEN
Tissue adaptation is required for regulatory T (Treg) cell function within organs. Whether this program shares aspects with other tissue-localized immune populations is unclear. Here, we analyzed single-cell chromatin accessibility data, including the transposable element (TE) landscape of CD45+ immune cells from colon, skin, adipose tissue, and spleen. We identified features of organ-specific tissue adaptation across different immune cells. Focusing on tissue Treg cells, we found conservation of the Treg tissue adaptation program in other tissue-localized immune cells, such as amphiregulin-producing T helper (Th)17 cells. Accessible TEs can act as regulatory elements, but their contribution to tissue adaptation is not understood. TE landscape analysis revealed an enrichment of specific transcription factor binding motifs in TE regions within accessible chromatin peaks. TEs, specifically from the LTR family, were located in enhancer regions and associated with tissue adaptation. These findings broaden our understanding of immune tissue residency and provide an important step toward organ-specific immune interventions.
Asunto(s)
Cromatina , Elementos Transponibles de ADN , Análisis de la Célula Individual , Linfocitos T Reguladores , Animales , Cromatina/metabolismo , Cromatina/genética , Linfocitos T Reguladores/inmunología , Elementos Transponibles de ADN/genética , Ratones , Especificidad de Órganos/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Ratones Endogámicos C57BL , HumanosRESUMEN
T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Here, we explored the microenvironmental signals regulating T cell exhaustion using a model of chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset of PD-1hi, functionally impaired CD8+ T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1int subset. Frequencies of PD-1int TCF-1+ CD8+ T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1hi cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and disrupted cooperativity between the transcription factors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequencies of exhausted CD8+ T cells and poor survival in CLL and in breast cancer patients. Thus, balance between PD-1hi, exhausted CD8+ T cells and functional PD-1int TCF-1+ CD8+ T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunoterapia/métodos , Leucemia Linfocítica Crónica de Células B/inmunología , Receptores de Interleucina-10/metabolismo , Subgrupos de Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Células Cultivadas , Microambiente Celular , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Inmunidad , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Interleucina-10/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/metabolismoRESUMEN
Murine regulatory T (Treg) cells in tissues promote tissue homeostasis and regeneration. We sought to identify features that characterize human Treg cells with these functions in healthy tissues. Single-cell chromatin accessibility profiles of murine and human tissue Treg cells defined a conserved, microbiota-independent tissue-repair Treg signature with a prevailing footprint of the transcription factor BATF. This signature, combined with gene expression profiling and TCR fate mapping, identified a population of tissue-like Treg cells in human peripheral blood that expressed BATF, chemokine receptor CCR8 and HLA-DR. Human BATF+CCR8+ Treg cells from normal skin and adipose tissue shared features with nonlymphoid T follicular helper-like (Tfh-like) cells, and induction of a Tfh-like differentiation program in naive human Treg cells partially recapitulated tissue Treg regenerative characteristics, including wound healing potential. Human BATF+CCR8+ Treg cells from healthy tissue share features with tumor-resident Treg cells, highlighting the importance of understanding the context-specific functions of these cells.
Asunto(s)
Cromatina/inmunología , Linfocitos T Reguladores/inmunología , Cicatrización de Heridas/inmunología , Adulto , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Diferenciación Celular/inmunología , Línea Celular , Femenino , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/inmunología , Células HaCaT , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptores CCR8/inmunología , Células T Auxiliares Foliculares/inmunologíaRESUMEN
Regulatory T cells (Treg cells) perform two distinct functions: they maintain self-tolerance, and they support organ homeostasis by differentiating into specialized tissue Treg cells. We found that epigenetic modifications defined the molecular characteristics of tissue Treg cells. Tagmentation-based whole-genome bisulfite sequencing revealed more than 11,000 regions that were methylated differentially in pairwise comparisons of tissue Treg cell populations and lymphoid T cells. Similarities in the epigenetic landscape led to the identification of a common tissue Treg cell population that was present in many organs and was characterized by gain and loss of DNA methylation that included many gene sites associated with the TH2 subset of helper T cells, such as the gene encoding cytokine IL-33 receptor ST2, as well as the production of tissue-regenerative factors. Furthermore, the ST2-expressing population was dependent on the transcriptional regulator BATF and could be expanded by IL-33. Thus, tissue Treg cells integrate multiple waves of epigenetic reprogramming that define their tissue-restricted specialization.
Asunto(s)
Metilación de ADN , Estudio de Asociación del Genoma Completo , Linfocitos T Reguladores/metabolismo , Animales , Biomarcadores , Análisis por Conglomerados , Biología Computacional/métodos , Islas de CpG , Epigénesis Genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Inmunofenotipificación , Ratones , Ratones Transgénicos , Anotación de Secuencia Molecular , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Regiones Promotoras Genéticas , Células Th2/metabolismo , Sitio de Iniciación de la Transcripción , TranscriptomaRESUMEN
This corrects the article DOI: 10.1038/ni.3799.
RESUMEN
Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-acting and trans-acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.
Asunto(s)
Células Epiteliales/inmunología , Redes Reguladoras de Genes , Linfocitos T/fisiología , Timo/inmunología , Factores de Transcripción/metabolismo , Animales , Presentación de Antígeno/genética , Autoantígenos/metabolismo , Factor de Unión a CCCTC , Diferenciación Celular , Células Cultivadas , Selección Clonal Mediada por Antígenos , Metilación de ADN , Regulación de la Expresión Génica , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Especificidad de Órganos/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Timo/citología , Factores de Transcripción/genética , Proteína AIRERESUMEN
Specialized regulatory T (Treg) cells accumulate and perform homeostatic and regenerative functions in nonlymphoid tissues. Whether common precursors for nonlymphoid-tissue Treg cells exist and how they differentiate remain elusive. Using transcription factor nuclear factor, interleukin 3 regulated (Nfil3) reporter mice and single-cell RNA-sequencing (scRNA-seq), we identified two precursor stages of interleukin 33 (IL-33) receptor ST2-expressing nonlymphoid tissue Treg cells, which resided in the spleen and lymph nodes. Global chromatin profiling of nonlymphoid tissue Treg cells and the two precursor stages revealed a stepwise acquisition of chromatin accessibility and reprogramming toward the nonlymphoid-tissue Treg cell phenotype. Mechanistically, we identified and validated the transcription factor Batf as the driver of the molecular tissue program in the precursors. Understanding this tissue development program will help to harness regenerative properties of tissue Treg cells for therapy.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Ganglios Linfáticos/inmunología , Bazo/inmunología , Linfocitos T Reguladores/citología , Traslado Adoptivo , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Diferenciación Celular/genética , Cromatina/metabolismo , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ratones , Especificidad de Órganos/inmunología , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
Regulatory T (Treg) cells ensure tolerance against self-antigens, limit excessive inflammation, and support tissue repair processes. Therefore, Treg cells are currently attractive candidates for the treatment of certain inflammatory diseases, autoimmune disorders, or transplant rejection. Early clinical trials have proved the safety and efficacy of certain Treg cell therapies in inflammatory diseases. We summarize recent advances in engineering Treg cells, including the concept of biosensors for inflammation. We assess Treg cell engineering possibilities for novel functional units, including Treg cell modifications influencing stability, migration, and tissue adaptation. Finally, we outline perspectives of engineered Treg cells going beyond inflammatory diseases by using custom-designed receptors and read-out systems, aiming to use Treg cells as in vivo diagnostic tools and drug delivery vehicles.
Asunto(s)
Enfermedades Autoinmunes , Linfocitos T Reguladores , Humanos , Enfermedades Autoinmunes/terapia , Tolerancia Inmunológica , Inmunoterapia Adoptiva , Inflamación/terapiaRESUMEN
Monocytes, macrophages and dendritic cells (DCs) are developmentally related regulators of the immune system that share the monocyte-macrophage DC progenitor (MDP) as a common precursor. Unlike differentiation into DCs, the distal pathways for differentiation into monocytes and monocyte-derived macrophages are not fully elucidated. We have now demonstrated the existence of a clonogenic, monocyte- and macrophage-restricted progenitor cell derived from the MDP. This progenitor was a Ly6C(+) proliferating cell present in the bone marrow and spleen that generated the major monocyte subsets and macrophages, but not DCs or neutrophils. By in-depth quantitative proteomics, we characterized changes in the proteome during monocyte differentiation, which provided insight into the molecular principles of developing monocytes, such as their functional maturation. Thus, we found that monocytes and macrophages were renewed independently of DCs from a committed progenitor.
Asunto(s)
Médula Ósea/inmunología , Células Precursoras de Monocitos y Macrófagos/inmunología , Proteómica/métodos , Bazo/inmunología , Animales , Diferenciación Celular/inmunología , Cromatografía Liquida , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Células Precursoras de Monocitos y Macrófagos/citología , Organismos Libres de Patógenos Específicos , Espectrometría de Masa por Ionización de Electrospray , Bazo/citología , Espectrometría de Masas en TándemRESUMEN
Tertiary lymphoid structures (TLS) are highly organized ectopic structures found in nonlymphoid organs under chronic inflammatory conditions, including cancer. A recent study by Chaurio et al. reports that repression of Satb1 in CD4+ T cells can lead to increased Tfh cell differentiation, driving intratumoral TLS formation, resulting in reduced tumor growth in mice.
Asunto(s)
Proteínas de Unión a la Región de Fijación a la Matriz , Neoplasias , Estructuras Linfoides Terciarias , Animales , Diferenciación Celular , Humanos , Ratones , Células T Auxiliares Foliculares , Estructuras Linfoides Terciarias/patologíaRESUMEN
Engineered regulatory T cell (Treg cell) therapy is a promising strategy to treat patients suffering from inflammatory diseases, autoimmunity, and transplant rejection. However, in many cases, disease-related antigens that can be targeted by Treg cells are not available. In this study, we introduce a class of synthetic biosensors, named artificial immune receptors (AIRs), for murine and human Treg cells. AIRs consist of three domains: (a) extracellular binding domain of a tumor necrosis factor (TNF)-receptor superfamily member, (b) intracellular costimulatory signaling domain of CD28, and (c) T cell receptor signaling domain of CD3-ζ chain. These AIR receptors equip Treg cells with an inflammation-sensing machinery and translate this environmental information into a CD3-ζ chain-dependent TCR-activation program. Different AIRs were generated, recognizing the inflammatory ligands of the TNF-receptor superfamily, including LIGHT, TNFα, and TNF-like ligand 1A (TL1A), leading to activation, differentiation, and proliferation of AIR-Treg cells. In a graft-versus-host disease model, Treg cells expressing lymphotoxin ß receptor-AIR, which can be activated by the ligand LIGHT, protect significantly better than control Treg cells. Expression and signaling of the corresponding human AIR in human Treg cells prove that this concept can be translated. Engineering Treg cells that target inflammatory ligands leading to TCR signaling and activation might be used as a Treg cell-based therapy approach for a broad range of inflammation-driven diseases.
Asunto(s)
Técnicas Biosensibles , Ingeniería Celular , Tratamiento Basado en Trasplante de Células y Tejidos , Inflamación , Linfocitos T Reguladores , Animales , Antígenos CD28/metabolismo , Humanos , Inflamación/terapia , Ligandos , Receptor beta de Linfotoxina/metabolismo , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Linfocitos T Reguladores/trasplante , Factor de Necrosis Tumoral alfaRESUMEN
Self-tolerance imposition requires the presentation of self-antigens by a variety of thymic antigen-presenting cells. In this issue of Immunity, Perry et al. (2014) reveal unidirectional self-antigen transfer from medullary thymic epithelial cells to dendritic cells as an essential aspect.
Asunto(s)
Células de la Médula Ósea/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Autotolerancia/inmunología , Timo/inmunología , Factores de Transcripción/genética , Animales , Proteína AIRERESUMEN
Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy.
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Lactato Deshidrogenasas/metabolismo , Ácido Láctico , Neoplasias , Línea Celular Tumoral , Citocinas/metabolismo , Glucólisis , Humanos , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Neoplasias/metabolismo , Linfocitos T/metabolismoRESUMEN
Regulatory T cells (T(reg) cells) characterized by expression of the transcription factor Foxp3 play a key role in immune homeostasis. Rather than a monomorphic population strictly determined by Foxp3 as a 'master regulator', the emerging view is one of T(reg) cells as a population with many levels of complexity. Several regulatory factors partake in the control of their transcriptional 'signature', with Foxp3 being a key regulator but insufficient and unnecessary to specify all aspects of the lineage. Distinct subphenotypes of Foxp3+ T(reg) cells are found in different anatomical locations. Some subphenotypes specifically control different facets of effector T cell function and, perhaps surprisingly, share transcriptional control elements with the very cells they regulate. This review will focus on these novel aspects of T(reg) cell diversity.
Asunto(s)
Factores de Transcripción Forkhead/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/inmunología , Factores de Transcripción Forkhead/genética , Perfilación de la Expresión Génica , Humanos , Modelos Inmunológicos , FN-kappa B/inmunología , Transducción de Señal/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismoRESUMEN
The macroscopic and microscopic anatomy of the oral cavity is complex and unique in the human body. Soft-tissue structures are in close interaction with mineralized bone, but also dentine, cementum and enamel of our teeth. These are exposed to intense mechanical and chemical stress as well as to dense microbiologic colonization. Teeth are susceptible to damage, most commonly to caries, where microorganisms from the oral cavity degrade the mineralized tissues of enamel and dentine and invade the soft connective tissue at the core, the dental pulp. However, the pulp is well-equipped to sense and fend off bacteria and their products and mounts various and intricate defense mechanisms. The front rank is formed by a layer of odontoblasts, which line the pulp chamber towards the dentine. These highly specialized cells not only form mineralized tissue but exert important functions as barrier cells. They recognize pathogens early in the process, secrete antibacterial compounds and neutralize bacterial toxins, initiate the immune response and alert other key players of the host defense. As bacteria get closer to the pulp, additional cell types of the pulp, including fibroblasts, stem and immune cells, but also vascular and neuronal networks, contribute with a variety of distinct defense mechanisms, and inflammatory response mechanisms are critical for tissue homeostasis. Still, without therapeutic intervention, a deep carious lesion may lead to tissue necrosis, which allows bacteria to populate the root canal system and invade the periradicular bone via the apical foramen at the root tip. The periodontal tissues and alveolar bone react to the insult with an inflammatory response, most commonly by the formation of an apical granuloma. Healing can occur after pathogen removal, which is achieved by disinfection and obturation of the pulp space by root canal treatment. This review highlights the various mechanisms of pathogen recognition and defense of dental pulp cells and periradicular tissues, explains the different cell types involved in the immune response and discusses the mechanisms of healing and repair, pointing out the close links between inflammation and regeneration as well as between inflammation and potential malignant transformation.
Asunto(s)
Pulpa Dental/patología , Periodontitis Periapical/patología , Tejido Periapical/patología , Pulpitis/patología , Animales , Antígenos de Neoplasias/inmunología , Carcinogénesis/inmunología , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/fisiopatología , Quimiocinas/metabolismo , Proteínas del Sistema Complemento/metabolismo , Caries Dental/fisiopatología , Pulpa Dental/microbiología , Dentina/irrigación sanguínea , Dentina/inervación , Dentina/metabolismo , Fibroblastos/inmunología , Fibroblastos/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Células Madre Mesenquimatosas/fisiología , Neoplasias de la Boca/etiología , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/fisiopatología , Red Nerviosa/fisiología , Neuropéptidos/metabolismo , Óxido Nítrico/fisiología , Odontoblastos/fisiología , Granuloma Periapical/etiología , Granuloma Periapical/patología , Tejido Periapical/microbiología , Quiste Radicular/etiología , Quiste Radicular/fisiopatologíaRESUMEN
The transcription factor FOXP3 is essential for the suppressive function of regulatory T cells that are required for maintaining self-tolerance. We have solved the crystal structure of the FOXP3 forkhead domain as a ternary complex with the DNA-binding domain of the transcription factor NFAT1 and a DNA oligonucleotide from the interleukin-2 promoter. A striking feature of this structure is that FOXP3 forms a domain-swapped dimer that bridges two molecules of DNA. Structure-guided or autoimmune disease (IPEX)-associated mutations in the domain-swap interface diminished dimer formation by the FOXP3 forkhead domain without compromising FOXP3 DNA binding. These mutations also eliminated T cell-suppressive activity conferred by FOXP3, both in vitro and in a murine model of autoimmune diabetes in vivo. We conclude that FOXP3-mediated suppressor function requires dimerization through the forkhead domain and that mutations in the dimer interface can lead to the systemic autoimmunity observed in IPEX patients.
Asunto(s)
Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/inmunología , Linfocitos T Reguladores/química , Linfocitos T Reguladores/inmunología , Secuencia de Aminoácidos , Animales , Humanos , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Factores de Transcripción NFATC/química , Factores de Transcripción NFATC/inmunología , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Alineación de SecuenciaRESUMEN
BACKGROUND: NY-BR-1 has been described as a breast cancer associated differentiation antigen with intrinsic immunogenicity giving rise to endogenous T and B cell responses. The current study presents the first murine tumor model allowing functional investigation of NY-BR-1-specific immune responses in vivo. METHODS: A NY-BR-1 expressing tumor model was established in DR4tg mice based on heterotopic transplantation of stable transfectant clones derived from the murine H2 compatible breast cancer cell line EO771. Composition and phenotype of tumor infiltrating immune cells were analyzed by qPCR and FACS. MHC I binding affinity of candidate CTL epitopes predicted in silico was determined by FACS using the mutant cell line RMA-S. Frequencies of NY-BR-1 specific CTLs among splenocytes of immunized mice were quantified by FACS with an epitope loaded Db-dextramer. Functional CTL activity was determined by IFNγ catch or IFNγ ELISpot assays and statistical analysis was done applying the Mann Whitney test. Tumor protection experiments were performed by immunization of DR4tg mice with replication deficient recombinant adenovirus followed by s.c. challenge with NY-BR-1 expressing breast cancer cells. RESULTS: Our results show spontaneous accumulation of CD8+ T cells and F4/80+ myeloid cells preferentially in NY-BR-1 expressing tumors. Upon NY-BR-1-specific immunization experiments combined with in silico prediction and in vitro binding assays, the first NY-BR-1-specific H2-Db-restricted T cell epitope could be identified. Consequently, flow cytometric analysis with fluorochrome conjugated multimers showed enhanced frequencies of CD8+ T cells specific for the newly identified epitope in spleens of immunized mice. Moreover, immunization with Ad.NY-BR-1 resulted in partial protection against outgrowth of NY-BR-1 expressing tumors and promoted intratumoral accumulation of macrophages. CONCLUSION: This study introduces the first H2-Db-resctricted CD8+ T cell epitope-specific for the human breast cancer associated tumor antigen NY-BR-1. Our novel, partially humanized tumor model enables investigation of the interplay between HLA-DR4-restricted T cell responses and CTLs within their joint attack of NY-BR-1 expressing tumors.
Asunto(s)
Antígenos de Neoplasias/inmunología , Epítopos de Linfocito T/inmunología , Cadenas HLA-DRB1/genética , Neoplasias/etiología , Neoplasias/patología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Antígenos de Neoplasias/genética , Biomarcadores , Línea Celular Tumoral , Modelos Animales de Enfermedad , Cadenas HLA-DRB1/inmunología , Xenoinjertos , Humanos , Inmunización , Inmunofenotipificación , Leucocitos/inmunología , Leucocitos/metabolismo , Ratones , Ratones Transgénicos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Recent studies have leveraged MHC tetramer and TCR sequencing approaches towards a more precise characterization of the peripheral T cell repertoire, providing important insight into both the contribution of self-reactive T cells to the overall repertoire and their function. The peripheral T cell repertoire of healthy individuals contains a high frequency of diverse, self-reactive T cells. Furthermore, self-reactive T cells can perform essential beneficial physiological functions. We review these recent findings here, and discuss their implications to the current understanding of peripheral tolerance and the role of self-reactive T cells in autoimmune disease. We outline gaps in understanding, and argue that an important step forward is to revise the definition of self-reactive T cells to incorporate new concepts regarding the nature and physiological functions of different populations of T cells capable of recognizing self-antigens.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos T/fisiología , Linfocitos T/fisiología , Animales , Autoantígenos/inmunología , Humanos , Tolerancia Periférica , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
During the last decade, advances in sequencing technologies allowed production of a wealth of information on epigenetic modifications in T cells. Epigenome maps, in combination with mechanistic studies, have demonstrated that T cells undergo extensive epigenome remodeling in response to signals, which has a strong effect on phenotypic stability and function of lymphocytes. In this review we focus on DNA methylation, histone modifications, and chromatin structure as important epigenetic mechanisms involved in controlling T-cell responses. In particular, we discuss epigenetic processes in light of the development, activation, and differentiation of CD4+ T helper (TH), regulatory T, and CD8+ T cells. As central aspects of the adaptive immune system, we review mechanisms that ensure molecular memory, stability, plasticity, and exhaustion of T cells. We further discuss the effect of the tissue environment on imprinting T-cell epigenomes with potential implications for immunotherapy.
Asunto(s)
Epigénesis Genética , Linfocitos T/citología , Animales , Diferenciación Celular , Humanos , Timo/citologíaRESUMEN
CD4(+)Foxp3(+) regulatory T cells (Treg cells) are known to control the progression of autoimmune diabetes, but when, where, and how they exert their influence in this context are questions still under vigorous debate. Exploiting a transgene encoding the human diphtheria toxin receptor, we punctually and specifically ablated Foxp3(+) cells in the BCD2.5/NOD mouse model of autoimmune diabetes. Strikingly, overt disease developed within 3 days. The earliest detectable event was the activation of natural killer (NK) cells directly within the insulitic lesion, particularly the induction of Ifng gene expression within 7 hours of Treg cell ablation. Interferon-gamma had a strong impact on the gene-expression program of the local CD4(+) T effector cell population, unleashing it to aggressively attack the islets, which was required for the development of diabetes. Thus, Treg cells regulate pancreatic autoimmunity in situ through control of a central innate immune system player, NK cells.