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1.
JCI Insight ; 7(21)2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36345939

RESUMO

Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis-associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis-associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications - TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Camundongos , Humanos , Animais , Macrófagos , Monócitos/patologia , Receptores de IgG/genética , Imunoglobulina G
2.
JCI Insight ; 7(13)2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35801586

RESUMO

IL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functionally inactive IRAK1 (IRAK1 kinase deficient, IRAK1KD), which also displayed reduced IRAK1 protein expression and cell type-specific deficiencies of TLR signaling. The serum transfer model of arthritis revealed a potentially novel role of IRAK1 for disease development and neutrophil chemoattraction exclusively via its activity in nonhematopoietic cells. Consistently, IRAK1KD synovial fibroblasts showed reduced secretion of neutrophil chemoattractant chemokines following stimulation with IL-1ß or human synovial fluids from patients with rheumatoid arthritis (RA) and gout. Together with patients with RA showing prominent IRAK1 expression in fibroblasts of the synovial lining, these data suggest that targeting IRAK1 may be therapeutically beneficial. As pharmacological inhibition of IRAK1 kinase activity had only mild effects on synovial fibroblasts from mice and patients with RA, targeted degradation of IRAK1 may be the preferred pharmacologic modality. Collectively, these data position IRAK1 as a central regulator of the IL-1ß-dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis.


Assuntos
Artrite Reumatoide , Quinases Associadas a Receptores de Interleucina-1 , Neutrófilos , Membrana Sinovial , Animais , Artrite Reumatoide/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-8/metabolismo , Camundongos , Neutrófilos/metabolismo , Membrana Sinovial/metabolismo
3.
Cell Rep ; 37(6): 109977, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34758308

RESUMO

Tumor necrosis factor (TNF) is a key driver of several inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, in which affected tissues show an interferon-stimulated gene signature. Here, we demonstrate that TNF triggers a type-I interferon response that is dependent on the cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. We show that TNF inhibits PINK1-mediated mitophagy and leads to altered mitochondrial function and to an increase in cytosolic mtDNA levels. Using cGAS-chromatin immunoprecipitation (ChIP), we demonstrate that cytosolic mtDNA binds to cGAS after TNF treatment. Furthermore, TNF induces a cGAS-STING-dependent transcriptional response that mimics that of macrophages from rheumatoid arthritis patients. Finally, in an inflammatory arthritis mouse model, cGAS deficiency blocked interferon responses and reduced inflammatory cell infiltration and joint swelling. These findings elucidate a molecular mechanism linking TNF to type-I interferon signaling and suggest a potential benefit for therapeutic targeting of cGAS/STING in TNF-driven diseases.


Assuntos
Artrite Experimental/imunologia , DNA Mitocondrial/metabolismo , Imunidade Inata , Inflamação/imunologia , Interferon Tipo I/farmacologia , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/genética , Artrite Experimental/metabolismo , DNA Mitocondrial/efeitos dos fármacos , Feminino , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Macrófagos/imunologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitofagia
4.
Oncogenesis ; 10(4): 32, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824280

RESUMO

CARD-CC complexes involving BCL10 and MALT1 are major cellular signaling hubs. They govern NF-κB activation through their scaffolding properties as well as MALT1 paracaspase function, which cleaves substrates involved in NF-κB regulation. In human lymphocytes, gain-of-function defects in this pathway lead to lymphoproliferative disorders. CARD10, the prototypical CARD-CC protein in non-hematopoietic cells, is overexpressed in several cancers and has been associated with poor prognosis. However, regulation of CARD10 remains poorly understood. Here, we identified CARD10 as the first MALT1 substrate in non-hematopoietic cells and showed that CARD10 cleavage by MALT1 at R587 dampens its capacity to activate NF-κB. Preventing CARD10 cleavage in the lung tumor A549 cell line increased basal levels of IL-6 and extracellular matrix components in vitro, and led to increased tumor growth in a mouse xenograft model, suggesting that CARD10 cleavage by MALT1 might be a built-in mechanism controlling tumorigenicity.

5.
Nat Commun ; 11(1): 5086, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033248

RESUMO

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients die significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Linfócitos T CD8-Positivos/imunologia , COVID-19 , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Interferons/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , SARS-CoV-2 , Carga Viral
6.
Proc Natl Acad Sci U S A ; 117(14): 7905-7916, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32193341

RESUMO

Transposable elements (TEs) compose nearly half of mammalian genomes and provide building blocks for cis-regulatory elements. Using high-throughput sequencing, we show that 84 TE subfamilies are overrepresented, and distributed in a lineage-specific fashion in core and boundary domains of CD8+ T cell enhancers. Endogenous retroviruses are most significantly enriched in core domains with accessible chromatin, and bear recognition motifs for immune-related transcription factors. In contrast, short interspersed elements (SINEs) are preferentially overrepresented in nucleosome-containing boundaries. A substantial proportion of these SINEs harbor a high density of the enhancer-specific histone mark H3K4me1 and carry sequences that match enhancer boundary nucleotide composition. Motifs with regulatory features are better preserved within enhancer-enriched TE copies compared to their subfamily equivalents located in gene deserts. TE-rich and TE-poor enhancers associate with both shared and unique gene groups and are enriched in overlapping functions related to lymphocyte and leukocyte biology. The majority of T cell enhancers are shared with other immune lineages and are accessible in common hematopoietic progenitors. A higher proportion of immune tissue-specific enhancers are TE-rich compared to enhancers specific to other tissues, correlating with higher TE occurrence in immune gene-associated genomic regions. Our results suggest that during evolution, TEs abundant in these regions and carrying motifs potentially beneficial for enhancer architecture and immune functions were particularly frequently incorporated by evolving enhancers. Their putative selection and regulatory cooption may have accelerated the evolution of immune regulatory networks.


Assuntos
Elementos de DNA Transponíveis/genética , Elementos Facilitadores Genéticos/genética , Evolução Molecular , Linfócitos T/imunologia , Animais , Cromatina/genética , Cromatina/imunologia , Elementos de DNA Transponíveis/imunologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/imunologia , Elementos Facilitadores Genéticos/imunologia , Redes Reguladoras de Genes/genética , Genoma Humano/genética , Genoma Humano/imunologia , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Elementos Nucleotídeos Curtos e Dispersos/genética , Elementos Nucleotídeos Curtos e Dispersos/imunologia
7.
Proc Natl Acad Sci U S A ; 116(51): 25839-25849, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31776254

RESUMO

Naive CD4+ T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4+ T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 ß and γ isoforms (HP1ß/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K-AKT-mTOR axis and switch to glycolysis. While differentiation of naive TRIM28-/- T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28-/- regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1ß/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes.


Assuntos
Diferenciação Celular/fisiologia , Reprogramação Celular/fisiologia , Proteínas Cromossômicas não Histona/metabolismo , Epigênese Genética/fisiologia , Linfócitos T/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Animais , Autoimunidade/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Plasticidade Celular/fisiologia , Reprogramação Celular/genética , Homólogo 5 da Proteína Cromobox , Colo/patologia , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Histonas/metabolismo , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transcriptoma , Proteína 28 com Motivo Tripartido/genética
9.
Cell ; 157(2): 340-356, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24725403

RESUMO

Innate lymphoid cells (ILCs) are a recently recognized group of lymphocytes that have important functions in protecting epithelial barriers against infections and in maintaining organ homeostasis. ILCs have been categorized into three distinct groups, transcriptional circuitry and effector functions of which strikingly resemble the various T helper cell subsets. Here, we identify a common, Id2-expressing progenitor to all interleukin 7 receptor-expressing, "helper-like" ILC lineages, the CHILP. Interestingly, the CHILP differentiated into ILC2 and ILC3 lineages, but not into conventional natural killer (cNK) cells that have been considered an ILC1 subset. Instead, the CHILP gave rise to a peculiar NKp46(+) IL-7Rα(+) ILC lineage that required T-bet for specification and was distinct of cNK cells or other ILC lineages. Such ILC1s coproduced high levels of IFN-γ and TNF and protected against infections with the intracellular parasite Toxoplasma gondii. Our data significantly advance our understanding of ILC differentiation and presents evidence for a new ILC lineage that protects barrier surfaces against intracellular infections.


Assuntos
Diferenciação Celular , Linfócitos/citologia , Linfócitos/imunologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Fator de Transcrição GATA3/metabolismo , Imunidade Inata , Proteína 2 Inibidora de Diferenciação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-7/metabolismo , Células-Tronco/citologia , Toxoplasma , Toxoplasmose/imunologia
10.
Nat Immunol ; 14(8): 867-75, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23812095

RESUMO

The transcription factors EBF1 and Pax5 have been linked to activation of the B cell lineage program and irreversible loss of alternative lineage potential (commitment), respectively. Here we conditionally deleted Ebf1 in committed pro-B cells after transfer into alymphoid mice. We found that those cells converted into innate lymphoid cells (ILCs) and T cells with variable-diversity-joining (VDJ) rearrangements of loci encoding both B cell and T cell antigen receptors. As intermediates in lineage conversion, Ebf1-deficient CD19(+) cells expressing Pax5 and transcriptional regulators of the ILC and T cell fates were detectable. In particular, genes encoding the transcription factors Id2 and TCF-1 were bound and repressed by EBF1. Thus, both EBF1 and Pax5 are required for B lineage commitment by repressing distinct and common determinants of alternative cell fates.


Assuntos
Linfócitos B/imunologia , Transativadores/imunologia , Transferência Adotiva , Animais , Linfócitos B/citologia , Diferenciação Celular/imunologia , Linhagem da Célula , DNA/química , DNA/genética , Regulação da Expressão Gênica , Linfopoese/imunologia , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Transativadores/genética , Recombinação V(D)J/genética , Recombinação V(D)J/imunologia
11.
Curr Opin Immunol ; 25(2): 139-47, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23490163

RESUMO

Innate lymphoid cells (ILCs) are an emerging group of innate lymphocytes that share functional and transcriptional attributes with the various T helper cell effector fates (e.g. Th1, Th2, Th17). ILCs are substantially represented in the intestinal mucosa but are rare in secondary lymphoid organs. They play important roles in epithelial homeostasis, tissue repair and in immunity to intestinal infections. They are also involved in immune-mediated pathology. Here, we will review the emerging roles of the transcription factors T-bet and Gata3 in the development, lineage specification and function of distinct ILC lineages. We will also highlight the requirement of these transcriptional programs for the control of infections and the pathogenesis of inflammatory diseases.


Assuntos
Fator de Transcrição GATA3/metabolismo , Imunidade Inata/imunologia , Proteínas com Domínio T/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Animais , Humanos , Imunidade Inata/genética , Células Th1/metabolismo , Células Th2/metabolismo
12.
Nature ; 494(7436): 261-5, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23334414

RESUMO

At mucosal surfaces, the immune system should not initiate inflammatory immune responses to the plethora of antigens constantly present in the environment, but should remain poised to unleash a potent assault on intestinal pathogens. The transcriptional programs and regulatory factors required for immune cells to switch from homeostatic (often tissue-protective) function to potent antimicrobial immunity are poorly defined. Mucosal retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections. Various subsets of RORγt(+) ILCs have been described but the transcriptional programs controlling their specification and fate remain largely unknown. Here we provide evidence that the transcription factor T-bet determines the fate of a distinct lineage of CCR6(-)RORγt(+) ILCs. Postnatally emerging CCR6(-)RORγt(+) ILCs upregulated T-bet and this was controlled by cues from the commensal microbiota and interleukin-23 (IL-23). In contrast, CCR6(+)RORγt(+) ILCs, which arise earlier during ontogeny, did not express T-bet. T-bet instructed the expression of T-bet target genes such as interferon-γ (IFN-γ) and of the natural cytotoxicity receptor NKp46. Mice genetically lacking T-bet showed normal development of CCR6(-)RORγt(+) ILCs, but they could not differentiate into NKp46-expressing RORγt(+) ILCs (that is, IL-22-producing natural killer (NK-22) cells) and failed to produce IFN-γ. The production of IFN-γ by T-bet-expressing CCR6(-)RORγt(+) ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier during Salmonella enterica infection. Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-γ. Mice deficient for T-bet or depleted of ILCs developed only mild enterocolitis. Thus, graded expression of T-bet in CCR6(-)RORγt(+) ILCs facilitates the differentiation of IFN-γ-producing CCR6(-)RORγt(+) ILCs required to protect the epithelial barrier against Salmonella infections. Co-expression of T-bet and RORγt, which is also found in subsets of IL-17-producing T-helper (T(H)17) cells, may be an evolutionarily conserved transcriptional program that originally developed as part of the innate defence against infections but that also confers an increased risk of immune-mediated pathology.


Assuntos
Linhagem da Célula , Imunidade Inata/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores CCR6/deficiência , Proteínas com Domínio T/metabolismo , Animais , Antígenos Ly/genética , Diferenciação Celular , Células Cultivadas , Enterocolite/imunologia , Enterocolite/metabolismo , Enterocolite/patologia , Epitélio/imunologia , Epitélio/metabolismo , Epitélio/microbiologia , Interferon gama/biossíntese , Interferon gama/genética , Interferon gama/imunologia , Interleucina-23/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Muco/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptores CCR6/metabolismo , Infecções por Salmonella/imunologia , Infecções por Salmonella/metabolismo , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade
13.
Immunity ; 37(4): 634-48, 2012 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-23063333

RESUMO

Innate lymphoid cells (ILCs) reside at mucosal surfaces and control immunity to intestinal infections. Type 2 innate lymphoid cells (ILC2s) produce cytokines such as IL-5 and IL-13, are required for immune defense against helminth infections, and are involved in the pathogenesis of airway hyperreactivity. Here, we have investigated the role of the transcription factor GATA-3 for ILC2 differentiation and maintenance. We showed that ILC2s and their lineage-specified bone marrow precursors (ILC2Ps), as identified here, were characterized by continuous high expression of GATA-3. Analysis of mice with temporary deletion of GATA-3 in all ILCs showed that GATA-3 was required for the differentiation and maintenance of ILC2s but not for RORγt(+) ILCs. Thus, our data demonstrate that GATA-3 is essential for ILC2 fate decisions and reveal similarities between the transcriptional programs controlling ILC and T helper cell fates.


Assuntos
Linhagem da Célula , Fator de Transcrição GATA3/imunologia , Imunidade Inata , Linfócitos/imunologia , Animais , Células da Medula Óssea/imunologia , Movimento Celular , Estudo de Associação Genômica Ampla , Intestinos/citologia , Intestinos/imunologia , Lectinas Tipo C , Linfócitos/citologia , Camundongos , Receptores Imunológicos/imunologia
14.
Curr Opin Immunol ; 24(3): 290-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22595694

RESUMO

It has recently emerged that innate lymphocytes are more diverse than previously appreciated. In addition to natural killer cells, various subsets of innate lymphoid cells are now being characterized. It has become apparent that the transcriptional programs underlying lineage specification and cell fate decisions of innate lymphocytes strikingly resemble those of T cell subsets, suggesting that such transcriptional circuitry was already pre-formed in the evolutionary older innate immune system. Here, we will review recent advances in our understanding of the core transcriptional programs driving development and cell fate decisions of innate lymphocytes. We will also discuss whether these transcriptional programs are stable or flexible, thereby allowing for plastic adaptation of immune responses.


Assuntos
Linhagem da Célula , Imunidade Inata , Linfócitos/imunologia , Transcrição Gênica , Animais , Humanos , Células Matadoras Naturais/imunologia , Linfócitos/citologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia
15.
Immunity ; 33(5): 736-51, 2010 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-21093318

RESUMO

Whether the recently identified innate lymphocyte population coexpressing natural killer cell receptors (NKRs) and the nuclear receptor RORγt is part of the NK or lymphoid tissue inducer (LTi) cell lineage remains unclear. By using adoptive transfer of genetically tagged LTi-like cells, we demonstrate that NKR⁻RORγt(+) innate lymphocytes but not NK cells were direct progenitors to NKR(+)RORγt(+) cells in vivo. Genetic lineage tracing revealed that the differentiation of LTi-like cells was characterized by the stable upregulation of NKRs and a progressive loss of RORγt expression. Whereas interleukin-7 (IL-7) and intestinal microbiota stabilized RORγt expression within such NKR-LTi cells, IL-12 and IL-15 accelerated RORγt loss. RORγt(+) NKR-LTi cells produced IL-22, whereas RORγt⁻ NKR-LTi cells released IFN-γ and were potent inducers of colitis. Thus, the RORγt gradient in NKR-LTi cells serves as a tunable rheostat for their functional program. Our data also define a previously unappreciated role of RORγt⁻ NKR-LTi cells for the onset or maintenance of inflammatory bowel diseases.


Assuntos
Células Matadoras Naturais/imunologia , Tecido Linfoide/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Animais , Linhagem da Célula/imunologia , Regulação para Baixo , Doenças Inflamatórias Intestinais/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-7/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Intestinos/imunologia , Intestinos/microbiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Regulação para Cima , Interleucina 22
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