RESUMO
While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg cell 'connectivity' to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Treg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Treg cell deprivation in either setting, as well as in Treg cell-poor versus Treg cell-rich human lung adenocarcinomas. Accordingly, punctual Treg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers.
Assuntos
Neoplasias , Linfócitos T Reguladores , Animais , Camundongos , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Microambiente Tumoral , Neoplasias/metabolismoRESUMO
Regulatory T (Treg) cells represent a distinct lineage of cells of the adaptive immune system indispensable for forestalling fatal autoimmune and inflammatory pathologies. The role of Treg cells as principal guardians of the immune system can be attributed to their ability to restrain all currently recognized major types of inflammatory responses through modulating the activity of a wide range of cells of the innate and adaptive immune system. This broad purview over immunity and inflammation is afforded by the multiple modes of action Treg cells exert upon their diverse molecular and cellular targets. Beyond the suppression of autoimmunity for which they were originally recognized, Treg cells have been implicated in tissue maintenance, repair, and regeneration under physiologic and pathologic conditions. Herein, we discuss the current and emerging understanding of Treg cell effector mechanisms in the context of the basic properties of Treg cells that endow them with such functional versatility.
Assuntos
Autoimunidade , Linfócitos T Reguladores , Humanos , Sistema Imunitário , Inflamação , HomeostaseRESUMO
Activation of the STAT5 transcription factor downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic effects of IL-2R signaling, it is unclear how STAT5 acts directly on the Foxp3 locus to promote its expression. Here, we report that IL-2 - STAT5 signaling converged on an enhancer (CNS0) during Foxp3 induction. CNS0 facilitated the IL-2 dependent CD25+Foxp3- precursor to Treg cell transition in the thymus. Its deficiency resulted in impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS0 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS0 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms minimizes autoimmunity.
Assuntos
Linhagem da Célula/imunologia , Fatores de Transcrição Forkhead/imunologia , Tolerância Imunológica/imunologia , Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Elementos Facilitadores Genéticos/imunologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos , Receptores de Interleucina-2/imunologia , Fator de Transcrição STAT5/imunologia , Transdução de Sinais/imunologiaRESUMO
In this issue of Immunity, Chisolm et al. (2019) issue a "three-alarm fire" warning to the immunology research community of unexpectedly widespread genetic variation in widely used congenic mouse strains and provide a simple method to identify such a variation through a re-analysis of existing RNA-seq and ChIP-seq datasets.
Assuntos
Variação Genética , Animais , Imunoprecipitação da Cromatina , Análise Mutacional de DNA , CamundongosRESUMO
The mammalian gut microbiota provides essential metabolites to the host and promotes the differentiation and accumulation of extrathymically generated regulatory T (pTreg) cells. To explore the impact of these cells on intestinal microbial communities, we assessed the composition of the microbiota in pTreg cell-deficient and -sufficient mice. pTreg cell deficiency led to heightened type 2 immune responses triggered by microbial exposure, which disrupted the niche of border-dwelling bacteria early during colonization. Moreover, impaired pTreg cell generation led to pervasive changes in metabolite profiles, altered features of the intestinal epithelium, and reduced body weight in the presence of commensal microbes. Absence of a single species of bacteria depleted in pTreg cell-deficient animals, Mucispirillum schaedleri, partially accounted for the sequelae of pTreg cell deficiency. These observations suggest that pTreg cells modulate the metabolic function of the intestinal microbiota by restraining immune defense mechanisms that may disrupt a particular bacterial niche.
Assuntos
Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , CamundongosRESUMO
Select humans and animals control persistent viral infections via adaptive immune responses that include production of neutralizing antibodies. The precise genetic basis for the control remains enigmatic. Here, we report positional cloning of the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical major histocompatibility complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJ H2-Ob allele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homolog, HLA-DOB, revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with human hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.
Assuntos
Anticorpos Neutralizantes , Antígenos HLA-D/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunidade Humoral , Vírus do Tumor Mamário do Camundongo/imunologia , Vírus Rauscher/imunologia , Infecções por Retroviridae/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Apresentação de Antígeno/genética , Biologia Computacional , Feminino , Predisposição Genética para Doença , Antígenos HLA-D/genética , Células HeLa , Hepatite B/imunologia , Hepatite B/transmissão , Hepatite C/imunologia , Hepatite C/transmissão , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Imunidade Humoral/genética , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Mutação/genética , Polimorfismo Genético , Infecções por Retroviridae/transmissãoRESUMO
Deletion of self-antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self-antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all. For pancreatic self antigen, this resulted in an absence of steady-state tolerance, while for the lung and intestine, tolerance was maintained by the enhanced presence of thymically-derived antigen-specific Foxp3+ regulatory T (Treg) cells. Unlike deletional tolerance, Treg cell-mediated tolerance was broken by successive antigen challenges. These findings reveal that for some tissue-restricted self antigens, tolerance relies entirely on nondeletional mechanisms that are less durable than T cell deletion. This might explain why autoimmunity is often tissue-specific, and it offers a rationale for cancer vaccine strategies targeting tissue-restricted tumor antigens.
Assuntos
Autoantígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/imunologia , Vacinas Anticâncer/imunologia , Fatores de Transcrição Forkhead/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Adaptive immune responses are tailored to different types of pathogens through differentiation of naive CD4 T cells into functionally distinct subsets of effector T cells (T helper 1 (TH1), TH2, and TH17) defined by expression of the key transcription factors T-bet, GATA3, and RORγt, respectively. Regulatory T (Treg) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2, 3). Paradoxically, some activated Treg cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide Treg cells with enhanced suppressive capacity. Whether expression of these factors in Treg cells-as in effector T cells-is indicative of heterogeneity of functionally discrete and stable differentiation states, or conversely may be readily reversible, is unknown. Here we demonstrate that expression of the TH1-associated transcription factor T-bet in mouse Treg cells, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss of function or elimination of T-bet-expressing Treg cells-but not of T-bet expression in Treg cells-resulted in severe TH1 autoimmunity. Conversely, following depletion of T-bet- Treg cells, the remaining T-bet+ cells specifically inhibited TH1 and CD8 T cell activation consistent with their co-localization with T-bet+ effector T cells. These results suggest that T-bet+ Treg cells have an essential immunosuppressive function and indicate that Treg cell functional heterogeneity is a critical feature of immunological tolerance.
Assuntos
Tolerância Imunológica/imunologia , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Animais , Autoimunidade/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Separação Celular , Feminino , Ativação Linfocitária , Masculino , Camundongos , Linfócitos T Reguladores/citologia , Células Th1/citologia , Células Th17/citologia , Células Th17/imunologia , Células Th2/citologia , Células Th2/imunologiaRESUMO
This corrects the article DOI: 10.1038/nature22360.
RESUMO
Viruses, including retroviruses, can be passed from mothers to their progeny during birth and breastfeeding. It is assumed that newborns may develop immune tolerance to milk-transmitted pathogens similarly to food antigens. I/LnJ mice are uniquely resistant to retroviruses acquired as newborns or as adults as they produce virus-neutralizing antibodies (Abs). A loss-of-function allele of H2-Ob (Ob), originally mapped within the virus infectivity controller 1 (vic1) locus, is responsible for production of antiretrovirus Abs in I/LnJ mice. Importantly, Ob-deficient and vic1 I/LnJ congenic mice on other genetic backgrounds produce antivirus Abs when infected as adults, but not as newborns. We report here that I/LnJ mice carry an additional genetic locus, virus infectivity controller 2 (vic2), that abrogates neonatal immune tolerance to retroviruses. Further genetic analysis mapped the vic2 locus to the telomeric end of chromosome 15. Identification of the vic2 gene and understanding of the related signaling pathways would make blocking of neonatal immune tolerance to retroviruses an achievable goal.IMPORTANCE This work describes a previously unknown genetic mechanism that allows neonates to respond to infections as efficiently as adults.
Assuntos
Tolerância Imunológica/genética , Infecções por Retroviridae/imunologia , Retroviridae/imunologia , Animais , Anticorpos Neutralizantes , Mapeamento Cromossômico , Feminino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Infecções por Retroviridae/virologiaRESUMO
T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for 'self' are either eliminated through TCR-agonist-induced apoptosis (negative selection) or restrained by regulatory T (Treg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist-driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to Treg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs. Here we explore in mice whether a specialized mechanism enables agonist-driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.
Assuntos
Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Sequência Conservada/genética , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Feminino , Fatores de Transcrição Forkhead/genética , Íntrons/genética , Masculino , Camundongos , Regiões Promotoras Genéticas/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Interleucina-2/imunologia , Receptores de Interleucina-2/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/deficiência , Proteína AIRERESUMO
Innate immune sensors are required for induction of pathogen-specific immune responses. Retroviruses are notorious for their ability to evade immune defenses and establish long-term persistence in susceptible hosts. However, some infected animals are able to develop efficient virus-specific immune responses, and thus can be employed for identification of critical innate virus-sensing mechanisms. With mice from two inbred strains that control retroviruses via adaptive immune mechanisms, we found that of all steps in viral replication, the ability to enter the host cell was sufficient to induce antivirus humoral immune responses. Virus sensing occurred in endosomes via a MyD88-Toll-like receptor 7-dependent mechanism and stimulated virus-neutralizing immunity independently of type I interferons. Thus, efficient adaptive immunity to retroviruses is induced in vivo by innate sensing of the early stages of retroviral infection.
Assuntos
Glicoproteínas de Membrana/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Infecções por Retroviridae/imunologia , Retroviridae/fisiologia , Receptor 7 Toll-Like/metabolismo , Internalização do Vírus , Imunidade Adaptativa , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Células Cultivadas , Suscetibilidade a Doenças , Endossomos/metabolismo , Interações Hospedeiro-Patógeno , Imunidade Inata , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos , Infecções por Retroviridae/virologia , Transdução de SinaisRESUMO
Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
Assuntos
Butiratos/metabolismo , Diferenciação Celular , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Simbiose , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Acetilação , Animais , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Elementos Facilitadores Genéticos/genética , Fermentação , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Histona Desacetilases/metabolismo , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestinos/citologia , Intestinos/imunologia , Íntrons/genética , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Amido/metabolismo , Linfócitos T Reguladores/imunologiaRESUMO
The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we questioned whether regulatory T cells (Treg cells), a T cell subset that suppresses systemic and local inflammation, can modulate activation of peripheral neurons. Short-term ablation of Treg cells increased neuronal activation to noxious stimuli independently from immunosuppressive function. We find that a population of skin Treg cells is highly enriched for Penk expression, a precursor for endogenous opioid enkephalins. Acute depletion of Penk-expressing Treg cells, or cell-specific ablation of Penk in Treg cells increases neuronal activation in response to noxious stimuli and associated inflammation. Our study indicates that a population of Treg cells exhibits neuromodulatory activity to restrain inflammation.
RESUMO
Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease worldwide. Although the mechanisms underlying this important disease are poorly understood, the glomerular podocyte clearly plays a central role in disease pathogenesis. In the current work, we demonstrate that the homophilic adhesion molecule sidekick-1 (sdk-1) is up-regulated in podocytes in FSGS both in rodent models and in human kidney biopsy samples. Transgenic mice that have podocyte-specific overexpression of sdk-1 develop gradually progressive heavy proteinuria and severe FSGS. We also show that sdk-1 associates with the slit diaphragm linker protein MAGI-1, which is already known to interact with several critical podocyte proteins including synaptopodin, alpha-actinin-4, nephrin, JAM4, and beta-catenin. This interaction is mediated through a direct interaction between the carboxyl terminus of sdk-1 and specific PDZ domains of MAGI-1. In vitro expression of sdk-1 enables a dramatic recruitment of MAGI-1 to the cell membrane. Furthermore, a truncated version of sdk-1 that is unable to bind to MAGI-1 does not induce podocyte dysfunction when overexpressed. We conclude that the up-regulation of sdk-1 in podocytes is an important pathogenic factor in FSGS and that the mechanism involves disruption of the actin cytoskeleton possibly via alterations in MAGI-1 function.
Assuntos
Moléculas de Adesão Celular/metabolismo , Glomerulosclerose Segmentar e Focal/etiologia , Glomerulosclerose Segmentar e Focal/metabolismo , Imunoglobulina G/metabolismo , Proteínas de Membrana/metabolismo , Podócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Células Cultivadas , Glomerulosclerose Segmentar e Focal/genética , Guanilato Quinases , Humanos , Imunoglobulina G/genética , Imunoprecipitação , Técnicas In Vitro , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase , Ligação ProteicaRESUMO
Regulatory T (T reg) cells, a specialized subset of CD4+ T cells, are essential to prevent fatal autoimmunity. Expression of the T reg lineage-defining transcription factor Foxp3, and therefore their differentiation in the thymus, is dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that the majority of IL-2-producing cells in the thymus are mature CD4 single-positive (CD4SP) thymocytes and that continuous IL-2 production sustained thymic T reg cell generation and control of systemic immune activation. Furthermore, single-cell RNA sequencing analysis of CD4 thymocyte subsets revealed that IL-2 was expressed in self-reactive CD4SP thymocytes, which also contain T reg precursor cells. Thus, our results suggest that the thymic T reg cell pool size is scaled by a key niche factor, IL-2, produced by self-reactive CD4SP thymocytes. This IL-2-dependent scaling of thymic T reg cell generation by overall self-reactivity of a mature post-selection thymic precursor pool may likely ensure adequate control of autoimmunity.
Assuntos
Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Expressão Gênica/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/citologia , Timo/metabolismoRESUMO
Innate lymphoid cells (ILCs) contribute to barrier immunity, tissue homeostasis, and immune regulation at various anatomical sites throughout the body. How ILCs maintain their presence in lymphoid and peripheral tissues thus far has been unclear. We found that in the lymphoid and nonlymphoid organs of adult mice, ILCs are tissue-resident cells that were maintained and expanded locally under physiologic conditions, upon systemic perturbation of immune homeostasis and during acute helminth infection. However, at later time points after infection, cells from hematogenous sources helped to partially replenish the pool of resident ILCs. Thus, ILCs are maintained by self-renewal in broadly different microenvironments and physiological settings. Such an extreme "sedentary" lifestyle is consistent with the proposed roles of ILCs as sentinels and local keepers of tissue function.