RESUMO
Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.
Assuntos
Fator de Transcrição GATA4/metabolismo , Cardiopatias Congênitas , Proteínas Nucleares/metabolismo , Oxirredutases/metabolismo , Fatores de Transcrição , Animais , Cardiopatias Congênitas/genética , Camundongos , Mutação , Proteômica , Proteínas com Domínio T/genética , Fatores de Transcrição/genéticaRESUMO
Natural killer (NK) cells traffic through the blood and mount cytolytic and interferon-γ (IFNγ)-focused responses to intracellular pathogens and tumors. Type 1 innate lymphoid cells (ILC1s) also produce type 1 cytokines but reside in tissues and are not cytotoxic. Whether these differences reflect discrete lineages or distinct states of a common cell type is not understood. Using single-cell RNA sequencing and flow cytometry, we focused on populations of TCF7+ cells that contained precursors for NK cells and ILC1s and identified a subset of bone marrow lineage-negative NK receptor-negative cells that expressed the transcription factor Eomes, termed EomeshiNKneg cells. Transfer of EomeshiNKneg cells into Rag2-/-Il2rg-/- recipients generated functional NK cells capable of preventing metastatic disease. By contrast, transfer of PLZF+ ILC precursors generated a mixture of ILC1s, ILC2s and ILC3s that lacked cytotoxic potential. These findings identified EomeshiNKneg cells as the bone marrow precursor to classical NK cells and demonstrated that the NK and ILC1 lineages diverged early during development.
Assuntos
Células Matadoras Naturais , Proteínas com Domínio T , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Animais , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/genética , Camundongos , Camundongos Knockout , Linhagem da Célula/imunologia , Camundongos Endogâmicos C57BL , Imunidade Inata , Diferenciação Celular/imunologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Análise de Célula ÚnicaRESUMO
Group 1 innate lymphoid cells (ILC1s) are cytotoxic and interferon gamma-producing lymphocytes lacking antigen-specific receptors, which include ILC1s and natural killer (NK) cells. In mice, ILC1s differ from NK cells, as they develop independently of the NK-specifying transcription factor EOMES, while requiring the repressor ZFP683 (ZNF683 in humans) for tissue residency. Here we identify highly variable ILC1 subtypes across tissues through investigation of human ILC1 diversity by single-cell RNA sequencing and flow cytometry. The intestinal epithelium contained abundant mature EOMES- ILC1s expressing PRDM1 rather than ZNF683, alongside a few immature TCF7+PRDM1- ILC1s. Other tissues harbored NK cells expressing ZNF683 and EOMES transcripts; however, EOMES protein content was variable. These ZNF683+ NK cells are tissue-imprinted NK cells phenotypically resembling ILC1s. The tissue ILC1-NK spectrum also encompassed conventional NK cells and NK cells distinguished by PTGDS expression. These findings establish a foundation for evaluating phenotypic and functional changes within the NK-ILC1 spectrum in diseases.
Assuntos
Imunidade Inata , Células Matadoras Naturais , Linfócitos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas com Domínio T , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Linfócitos/imunologia , Linfócitos/metabolismo , Análise de Célula Única , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Animais , Camundongos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genéticaRESUMO
Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αß T and non-classic CD4+ αß TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Interferon gama/imunologia , Mycobacterium/imunologia , Proteínas com Domínio T/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Linhagem da Célula , Pré-Escolar , Cromatina/metabolismo , Ilhas de CpG/genética , Metilação de DNA/genética , Células Dendríticas/metabolismo , Epigênese Genética , Feminino , Homozigoto , Humanos , Mutação INDEL/genética , Lactente , Interferon gama/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Mutação com Perda de Função/genética , Masculino , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Linhagem , Proteínas com Domínio T/química , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma/genéticaRESUMO
During chronic viral infection, CD8+ T cells develop into three major phenotypically and functionally distinct subsets: Ly108+TCF-1+ progenitors, Ly108-CX3CR1- terminally exhausted cells and the recently identified CX3CR1+ cytotoxic effector cells. Nevertheless, how CX3CR1+ effector cell differentiation is transcriptionally and epigenetically regulated remains elusive. Here, we identify distinct gene regulatory networks and epigenetic landscapes underpinning the formation of these subsets. Notably, our data demonstrate that CX3CR1+ effector cells bear a striking similarity to short-lived effector cells during acute infection. Genetic deletion of Tbx21 significantly diminished formation of the CX3CR1+ subset. Importantly, we further identify a previously unappreciated role for the transcription factor BATF in maintaining a permissive chromatin structure that allows the transition from TCF-1+ progenitors to CX3CR1+ effector cells. BATF directly bound to regulatory regions near Tbx21 and Klf2, modulating their enhancer accessibility to facilitate the transition. These mechanistic insights can potentially be harnessed to overcome T cell exhaustion during chronic infection and cancer.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Proteínas com Domínio T/genética , Subpopulações de Linfócitos T/citologia , Animais , Antígenos Ly/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular , Feminino , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subpopulações de Linfócitos T/imunologiaRESUMO
Non-coding regions comprise most of the human genome and harbor a significant fraction of risk alleles for neuropsychiatric diseases, yet their functions remain poorly defined. We created a high-resolution map of non-coding elements involved in human cortical neurogenesis by contrasting chromatin accessibility and gene expression in the germinal zone and cortical plate of the developing cerebral cortex. We link distal regulatory elements (DREs) to their cognate gene(s) together with chromatin interaction data and show that target genes of human-gained enhancers (HGEs) regulate cortical neurogenesis and are enriched in outer radial glia, a cell type linked to human cortical evolution. We experimentally validate the regulatory effects of predicted enhancers for FGFR2 and EOMES. We observe that common genetic variants associated with educational attainment, risk for neuropsychiatric disease, and intracranial volume are enriched within regulatory elements involved in cortical neurogenesis, demonstrating the importance of this early developmental process for adult human cognitive function.
Assuntos
Córtex Cerebral/metabolismo , Montagem e Desmontagem da Cromatina , Regulação da Expressão Gênica no Desenvolvimento , Neurogênese , Neurônios/metabolismo , Linhagem Celular , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Cromatina/genética , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Feminino , Humanos , Masculino , Neurônios/citologia , Polimorfismo Genético , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismoRESUMO
Unprimed mice harbor a substantial population of 'memory-phenotype' CD8+ T cells (CD8-MP cells) that exhibit hallmarks of activation and innate-like functional properties. Due to the lack of faithful markers to distinguish CD8-MP cells from bona fide CD8+ memory T cells, the developmental origins and antigen specificities of CD8-MP cells remain incompletely defined. Using deep T cell antigen receptor (TCR) sequencing, we found that the TCRs expressed by CD8-MP cells are highly recurrent and distinct from the TCRs expressed by naive-phenotype CD8+ T cells. CD8-MP clones exhibited reactivity to widely expressed self-ligands. T cell precursors expressing CD8-MP TCRs showed upregulation of the transcription factor Eomes during maturation in the thymus, prior to induction of the full memory phenotype, which is suggestive of a unique program triggered by recognition of self-ligands. Moreover, CD8-MP cells infiltrate oncogene-driven prostate tumors and express high densities of PD-1, which suggests potential roles in antitumor immunity and the response to immunotherapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias da Próstata/imunologia , Receptores de Antígenos de Linfócitos T/genética , Proteínas com Domínio T/metabolismo , Timo/fisiologia , Animais , Autoantígenos/imunologia , Diferenciação Celular , Seleção Clonal Mediada por Antígeno , Células Clonais , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/metabolismo , Proteínas com Domínio T/genética , Regulação para CimaRESUMO
Tissue-resident memory T (TRM) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of TRM cells are incompletely understood. Here we show that type 1 regulatory T (Treg) cells, which express the transcription factor T-bet, promote the generation of CD8+ TRM cells. The absence of T-bet-expressing type 1 Treg cells reduces the presence of TRM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 Treg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8+ T cells and Treg cell expression of integrin-ß8 endows the bioavailability of transforming growth factor-ß in the microenvironment, thereby promoting the generation of CD8+ TRM cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Memória Imunológica , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/transplante , Coccidiose/imunologia , Coccidiose/parasitologia , Modelos Animais de Doenças , Eimeria/imunologia , Feminino , Humanos , Cadeias beta de Integrinas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Receptores CXCR3/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante , Fator de Crescimento Transformador beta/metabolismoRESUMO
Cardiac lymphatics cooperate with the reparative immune response in myocardial healing after infarction. In this issue of Immunity, Wang and colleagues discover a mechanism underlying this cooperation, dependent on the transcription factor Tbx1 and responsible for the creation of an immunosuppressive niche that mitigates autoimmunity.
Assuntos
Coração , Proteínas com Domínio T , Proteínas com Domínio T/genética , Coração/fisiologia , Miocárdio , Fatores de TranscriçãoRESUMO
Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.
Assuntos
Fator de Transcrição GATA4/genética , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Cromatina , Elementos Facilitadores Genéticos , Feminino , Coração/crescimento & desenvolvimento , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Mutação de Sentido Incorreto , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Proteínas com Domínio T/genéticaRESUMO
Transcription factors (TFs) are thought to function with partners to achieve specificity and precise quantitative outputs. In the developing heart, heterotypic TF interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5, have been proposed as a mechanism for human congenital heart defects. We report extensive and complex interdependent genomic occupancy of TBX5, NKX2-5, and the zinc finger TF GATA4 coordinately controlling cardiac gene expression, differentiation, and morphogenesis. Interdependent binding serves not only to co-regulate gene expression but also to prevent TFs from distributing to ectopic loci and activate lineage-inappropriate genes. We define preferential motif arrangements for TBX5 and NKX2-5 cooperative binding sites, supported at the atomic level by their co-crystal structure bound to DNA, revealing a direct interaction between the two factors and induced DNA bending. Complex interdependent binding mechanisms reveal tightly regulated TF genomic distribution and define a combinatorial logic for heterotypic TF regulation of differentiation.
Assuntos
Fator de Transcrição GATA4/metabolismo , Proteínas de Homeodomínio/metabolismo , Miocárdio/citologia , Organogênese , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Cristalografia por Raios X , Embrião de Mamíferos/metabolismo , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Miocárdio/metabolismo , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas , Proteínas com Domínio T/genética , Fatores de Transcrição/genéticaRESUMO
Most vertebrate oocytes contain a Balbiani body, a large, non-membrane-bound compartment packed with RNA, mitochondria, and other organelles. Little is known about this compartment, though it specifies germline identity in many non-mammalian vertebrates. We show Xvelo, a disordered protein with an N-terminal prion-like domain, is an abundant constituent of Xenopus Balbiani bodies. Disruption of the prion-like domain of Xvelo, or substitution with a prion-like domain from an unrelated protein, interferes with its incorporation into Balbiani bodies in vivo. Recombinant Xvelo forms amyloid-like networks in vitro. Amyloid-like assemblies of Xvelo recruit both RNA and mitochondria in binding assays. We propose that Xenopus Balbiani bodies form by amyloid-like assembly of Xvelo, accompanied by co-recruitment of mitochondria and RNA. Prion-like domains are found in germ plasm organizing proteins in other species, suggesting that Balbiani body formation by amyloid-like assembly could be a conserved mechanism that helps oocytes function as long-lived germ cells.
Assuntos
Amiloide/metabolismo , Biogênese de Organelas , Proteínas com Domínio T/metabolismo , Proteínas de Xenopus/metabolismo , Animais , Benzotiazóis , Feminino , Corantes Fluorescentes , Mitocôndrias/metabolismo , Oócitos/citologia , Organelas/metabolismo , Príons/química , Domínios Proteicos , Transporte Proteico , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Células Sf9 , Proteínas com Domínio T/química , Proteínas com Domínio T/genética , Tiazóis , Proteínas de Xenopus/química , Proteínas de Xenopus/genética , Xenopus laevis , Peixe-ZebraRESUMO
The oropharyngeal mucosa serves as a perpetual pathogen entry point and a critical site for viral replication and spread. Here, we demonstrate that type 1 innate lymphoid cells (ILC1s) were the major immune force providing early protection during acute oral mucosal viral infection. Using intravital microscopy, we show that ILC1s populated and patrolled the uninfected labial mucosa. ILC1s produced interferon-γ (IFN-γ) in the absence of infection, leading to the upregulation of key antiviral genes, which were downregulated in uninfected animals upon genetic ablation of ILC1s or antibody-based neutralization of IFN-γ. Thus, tonic IFN-γ production generates increased oral mucosal viral resistance even before infection. Our results demonstrate barrier-tissue protection through tissue surveillance in the absence of rearranged-antigen receptors and the induction of an antiviral state during homeostasis. This aspect of ILC1 biology raises the possibility that these cells do not share true functional redundancy with other tissue-resident lymphocytes.
Assuntos
Interferon gama/metabolismo , Linfócitos/imunologia , Orofaringe/imunologia , Mucosa Respiratória/imunologia , Vaccinia virus/fisiologia , Vacínia/imunologia , Animais , Células Cultivadas , Resistência à Doença , Humanos , Imunidade Inata , Interferon gama/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas com Domínio T/genética , Células Th1/imunologiaRESUMO
The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3, with a proposed role in contributing to human bipedalism4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.
Assuntos
Processamento Alternativo , Evolução Molecular , Hominidae , Proteínas com Domínio T , Cauda , Animais , Humanos , Camundongos , Processamento Alternativo/genética , Elementos Alu/genética , Modelos Animais de Doenças , Genoma/genética , Hominidae/anatomia & histologia , Hominidae/genética , Íntrons/genética , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Fenótipo , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Cauda/anatomia & histologia , Cauda/embriologia , Éxons/genéticaRESUMO
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.
Assuntos
Células Epiteliais/imunologia , Redes Reguladoras de Genes , Linfócitos T/fisiologia , Timo/imunologia , Fatores de Transcrição/metabolismo , Animais , Apresentação de Antígeno/genética , Autoantígenos/metabolismo , Fator de Ligação a CCCTC , Diferenciação Celular , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Metilação de DNA , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Especificidade de Órgãos/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Timo/citologia , Fatores de Transcrição/genética , Proteína AIRERESUMO
TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR).
Assuntos
Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Células T Matadoras Naturais/fisiologia , Células Precursoras de Linfócitos T/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Linhagem da Célula , Proliferação de Células , Células Cultivadas , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Dioxigenases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Memory B cells (MBCs) expressing the transcription factor T-bet have been described in normal and dysregulated immune responses. In this issue of Immunity, Johnson et al. report that T-bet+ MBCs, formed in response to a primary influenza infection, contribute to protective antibody titers and persist mainly in the spleen with restricted trafficking between tissues.
Assuntos
Subpopulações de Linfócitos B , Animais , Especificidade de Anticorpos , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Humanos , Memória Imunológica , Camundongos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Distribuição TecidualRESUMO
B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet+ and T-bet- memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet- and T-bet+ hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet- and T-bet+ MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet+ MBCs could be subdivided into recirculating T-betlo MBCs and spleen-resident T-bethi MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.
Assuntos
Especificidade de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Memória Imunológica/imunologia , Especificidade de Órgãos/imunologia , Proteínas com Domínio T/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Anticorpos Anti-HIV/imunologia , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismoRESUMO
CD8+ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8+ T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1+ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Transcrição Gênica/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Epigênese Genética/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/terapia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcrição Gênica/genéticaRESUMO
Senescence shapes embryonic development, plays a key role in aging, and is a critical barrier to cancer initiation, yet how senescence is regulated remains incompletely understood. TBX2 is an antisenescence T-box family transcription repressor implicated in embryonic development and cancer. However, the repertoire of TBX2 target genes, its cooperating partners, and how TBX2 promotes proliferation and senescence bypass are poorly understood. Here, using melanoma as a model, we show that TBX2 lies downstream from PI3K signaling and that TBX2 binds and is required for expression of E2F1, a key antisenescence cell cycle regulator. Remarkably, TBX2 binding in vivo is associated with CACGTG E-boxes, present in genes down-regulated by TBX2 depletion, more frequently than the consensus T-element DNA binding motif that is restricted to Tbx2 repressed genes. TBX2 is revealed to interact with a wide range of transcription factors and cofactors, including key components of the BCOR/PRC1.1 complex that are recruited by TBX2 to the E2F1 locus. Our results provide key insights into how PI3K signaling modulates TBX2 function in cancer to drive proliferation.