RESUMO
Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from the periphery to the CNS has been challenging with existing tools. Here, we develop and curate a mouse genetic toolkit that allows for interrogating the properties and functions of distinct cutaneous targeting DRG neuron subtypes. These tools have enabled a broad morphological analysis, which revealed distinct cutaneous axon arborization areas and branching patterns of the transcriptionally distinct DRG neuron subtypes. Moreover, in vivo physiological analysis revealed that each subtype has a distinct threshold and range of responses to mechanical and/or thermal stimuli. These findings support a model in which morphologically and physiologically distinct cutaneous DRG sensory neuron subtypes tile mechanical and thermal stimulus space to collectively encode a wide range of natural stimuli.
Assuntos
Gânglios Espinais , Células Receptoras Sensoriais , Análise da Expressão Gênica de Célula Única , Animais , Camundongos , Gânglios Espinais/citologia , Células Receptoras Sensoriais/citologia , Pele/inervaçãoRESUMO
Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues.
Assuntos
Colite Ulcerativa , Colite , Animais , Humanos , Camundongos , Colite/metabolismo , Colite/patologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Hibridização in Situ Fluorescente/métodos , Inflamação/metabolismo , Inflamação/patologia , Comunicação Celular , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologiaRESUMO
Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover substantial differences in the chromatin landscape of npTH17 and pTH17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTH17 cells share accessible chromatin configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Cromatina , Células Th17 , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Animais , Cromatina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/genética , Camundongos Knockout , Células Th1/imunologia , Humanos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Inflamação/imunologia , Inflamação/genética , Análise de Célula Única , Esclerose Múltipla/imunologia , Esclerose Múltipla/genética , FemininoRESUMO
While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.
Assuntos
Autoimunidade , Intestinos/imunologia , Células-Tronco/metabolismo , Células Th17/imunologia , Animais , Movimento Celular , Células Clonais , Encefalomielite Autoimune Experimental/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Homeostase , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , RNA/metabolismo , RNA-Seq , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CXCR6/metabolismo , Receptores de Interleucina/metabolismo , Reprodutibilidade dos Testes , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Análise de Célula Única , Baço/metabolismoRESUMO
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.
Assuntos
Linhagem da Célula , Poliaminas/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatina/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Colite/imunologia , Colite/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Epigenoma , Histonas/metabolismo , Inflamação/imunologia , Inflamação/patologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ornitina Descarboxilase/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fatores de Transcrição/metabolismoRESUMO
Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.
Assuntos
Autoimunidade/imunologia , Modelos Biológicos , Células Th17/imunologia , Acetiltransferases/metabolismo , Trifosfato de Adenosina/metabolismo , Aerobiose/efeitos dos fármacos , Algoritmos , Animais , Autoimunidade/efeitos dos fármacos , Cromatina/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Eflornitina/farmacologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Epigenoma , Ácidos Graxos/metabolismo , Glicólise/efeitos dos fármacos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos Endogâmicos C57BL , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Oxirredução/efeitos dos fármacos , Putrescina/metabolismo , Análise de Célula Única , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Transcriptoma/genéticaRESUMO
Since their discovery almost two decades ago, interleukin-17-producing CD4+ T cells (TH17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders. In addition, TH17 cells have been found to play an important role in tissue homeostasis, especially in the intestinal mucosa. Recently, the use of single-cell technologies, along with fate mapping and various mutant mouse models, has led to substantial progress in the understanding of TH17 cell heterogeneity in tissues and of TH17 cell plasticity leading to alternative T cell states and differing functions. In this Review, we discuss the heterogeneity of TH17 cells and the role of this heterogeneity in diverse functions of TH17 cells from homeostasis to tissue inflammation. In addition, we discuss TH17 cell plasticity and its incorporation into the current understanding of T cell subsets and alternative views on the role of TH17 cells in autoimmune and inflammatory diseases.
Assuntos
Inflamação , Células Th17 , Animais , Camundongos , Plasticidade Celular , Subpopulações de Linfócitos T/metabolismo , Modelos Animais de DoençasRESUMO
Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.
Assuntos
Encefalomielite Autoimune Experimental , Neoplasias , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/genética , Imunoterapia , Inflamação , Doenças Neuroinflamatórias , Microambiente TumoralRESUMO
Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut. Nociceptors regulate the density of microfold (M) cells in ileum Peyer's patch (PP) follicle-associated epithelia (FAE) to limit entry points for STm invasion. Downstream of M cells, nociceptors maintain levels of segmentous filamentous bacteria (SFB), a gut microbe residing on ileum villi and PP FAE that mediates resistance to STm infection. TRPV1+ nociceptors directly respond to STm by releasing calcitonin gene-related peptide (CGRP), a neuropeptide that modulates M cells and SFB levels to protect against Salmonella infection. These findings reveal a major role for nociceptor neurons in sensing and defending against enteric pathogens.
Assuntos
Microbioma Gastrointestinal/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Nociceptores/fisiologia , Animais , Epitélio/metabolismo , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/microbiologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/metabolismo , Nódulos Linfáticos Agregados/inervação , Nódulos Linfáticos Agregados/metabolismo , Infecções por Salmonella/metabolismo , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidade , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologiaRESUMO
Although inhibition of T cell coinhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. In the present study, we show that type 1 interferon (IFN-I) regulates coinhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses established the dynamic regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors (TFs) and TF footprint analysis revealed two regulator modules with different temporal kinetics that control expression of coinhibitory receptors and IFN-I response genes, with SP140 highlighted as one of the key regulators that differentiates LAG-3 and TIGIT expression. Finally, we found that the dynamic IFN-I response in vitro closely mirrored T cell features in acute SARS-CoV-2 infection. The identification of unique TFs controlling coinhibitory receptor expression under IFN-I response may provide targets for enhancement of immunotherapy in cancer, infectious diseases and autoimmunity.
Assuntos
COVID-19 , Interferon Tipo I , Redes Reguladoras de Genes , Humanos , Interferon Tipo I/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores Imunológicos/genética , SARS-CoV-2 , Linfócitos TRESUMO
LAG-3, TIM-3, and TIGIT comprise the next generation of immune checkpoint receptors being harnessed in the clinic. Although initially studied for their roles in restraining T cell responses, intense investigation over the last several years has started to pinpoint the unique functions of these molecules in other immune cell types. Understanding the distinct processes that these receptors regulate across immune cells and tissues will inform the clinical development and application of therapies that either antagonize or agonize these receptors, as well as the profile of potential tissue toxicity associated with their targeting. Here, we discuss the distinct functions of LAG-3, TIM-3, and TIGIT, including their contributions to the regulation of immune cells beyond T cells, their roles in disease, and the implications for their targeting in the clinic.
Assuntos
Receptor Celular 2 do Vírus da Hepatite A , Receptores Imunológicos , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptores Imunológicos/metabolismo , Linfócitos TRESUMO
In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5+ ISCs. We show that MHCII+ Lgr5+ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4+ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5+ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5+ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5+ ISCs, thus, orchestrate tissue-wide responses to external signals.
Assuntos
Diferenciação Celular , Autorrenovação Celular , Interleucina-10/metabolismo , Células-Tronco/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Citocinas/farmacologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Sistema Imunitário/metabolismo , Intestinos/citologia , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Salmonella enterica/patogenicidade , Células-Tronco/metabolismo , Linfócitos T Auxiliares-Indutores/citologiaRESUMO
Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.
Assuntos
Estresse do Retículo Endoplasmático , Mucosa Intestinal , Células Th17 , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Diferenciação Celular , Humanos , Animais , Camundongos , Camundongos Transgênicos , Antibacterianos/farmacologiaRESUMO
In the version of this article initially published, in the legend to Fig. 1b, the description of the frequency of TH17-IL-10+ clones was incomplete for the first group; this should read as follows: "...13 experiments with clones isolated from CCR6+CCR4+CXCR3- T cells...". Also, the label along the vertical axis of the bottom right plot in Figure 5b was incomplete; the correct label is 'IFN-γ+ cells (%)'. Finally, in the first sentence of the final paragraph of the final Results subsection, the description of the regions analyzed was incorrect; that sentence should begin: "DNA motif-enrichment analysis of the subset-specific H3K27ac-positive regions...". The errors have been corrected in the HTML and PDF versions of the article.
RESUMO
Follicular regulatory T (TFR) cells have specialized roles in modulating follicular helper T (TFH) cell activation of B cells. However, the precise role of TFR cells in controlling antibody responses to foreign antigens and autoantigens in vivo is still unclear due to a lack of specific tools. A TFR cell-deleter mouse was developed that selectively deletes TFR cells, facilitating temporal studies. TFR cells were found to regulate early, but not late, germinal center (GC) responses to control antigen-specific antibody and B cell memory. Deletion of TFR cells also resulted in increased self-reactive immunoglobulin (Ig) G and IgE. The increased IgE levels led us to interrogate the role of TFR cells in house dust mite models. TFR cells were found to control TFH13 cell-induced IgE. In vivo, loss of TFR cells increased house-dust-mite-specific IgE and lung inflammation. Thus, TFR cells control IgG and IgE responses to vaccines, allergens and autoantigens, and exert critical immunoregulatory functions before GC formation.
Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Hipersensibilidade/imunologia , Pneumonia/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Autoantígenos/imunologia , Deleção Clonal/genética , Modelos Animais de Doenças , Humanos , Tolerância Imunológica , Imunidade Humoral , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Memória Imunológica , Interleucina-13/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pyroglyphidae/imunologiaRESUMO
Epstein-Barr virus (EBV) is a putative trigger for multiple sclerosis (MS), but clear causality is lacking. In a recent issue of Science, Bjornevik and Cortese et al. utilize longitudinal evaluation of over 10 million adults to demonstrate increased MS risk after EBV infection.
Assuntos
Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Adulto , Herpesvirus Humano 4 , Humanos , Esclerose Múltipla/etiologiaRESUMO
To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders.
Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Microglia/metabolismo , Mitocôndrias/metabolismo , Convulsões/imunologia , Animais , Comportamento Animal , Suscetibilidade a Doenças , Sinapses Elétricas/metabolismo , Metabolismo Energético , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Camundongos , Camundongos Knockout , Microglia/patologia , Neurogênese/genética , Proteína Oncogênica v-akt/metabolismo , Fagocitose , Transdução de SinaisRESUMO
Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.
Assuntos
Colite , Receptores de Interleucina , Animais , Inflamação/metabolismo , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Células Th1 , Células Th17RESUMO
IL-17A both directly induces and synergizes with other cytokines to promote autoimmune tissue inflammation. Secukinumab and ixekizumab are monoclonal antibodies (mAb) that inhibit interleukin-17A. These two agents were recently approved for treatment of psoriasis, and secukinumab is also approved for treatment of two spondyloarthropathies, psoriatic arthritis and ankylosing spondylitis.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , HumanosRESUMO
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8(+) tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8(+) TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact.