Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Assunto da revista
Intervalo de ano de publicação
1.
Cell ; 187(4): 897-913.e18, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38280374

RESUMO

Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein, we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization and is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host's specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as an innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.


Assuntos
Complemento C3 , Mucosa Intestinal , Microbiota , Animais , Humanos , Camundongos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Neutrófilos , Complemento C3/metabolismo , Células Estromais/metabolismo
2.
Immunity ; 57(6): 1345-1359.e5, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38692280

RESUMO

Regulatory T (Treg) cells in epidydimal visceral adipose tissue (eVAT) of lean mice and humans regulate metabolic homeostasis. We found that constitutive or punctual depletion of eVAT-Treg cells reined in the differentiation of stromal adipocyte precursors. Co-culture of these precursors with conditional medium from eVAT-Treg cells limited their differentiation in vitro, suggesting a direct effect. Transcriptional comparison of adipocyte precursors, matured in the presence or absence of the eVAT-Treg-conditioned medium, identified the oncostatin-M (OSM) signaling pathway as a key distinction. Addition of OSM to in vitro cultures blocked the differentiation of adipocyte precursors, while co-addition of anti-OSM antibodies reversed the ability of the eVAT-Treg-conditioned medium to inhibit in vitro adipogenesis. Genetic depletion of OSM (specifically in Treg) cells or of the OSM receptor (specifically on stromal cells) strongly impaired insulin sensitivity and related metabolic indices. Thus, Treg-cell-mediated control of local progenitor cells maintains adipose tissue and metabolic homeostasis, a regulatory axis seemingly conserved in humans.


Assuntos
Adipócitos , Diferenciação Celular , Homeostase , Resistência à Insulina , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Humanos , Camundongos , Adipócitos/metabolismo , Diferenciação Celular/imunologia , Oncostatina M/metabolismo , Transdução de Sinais , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/imunologia , Células Estromais/metabolismo , Camundongos Endogâmicos C57BL , Técnicas de Cocultura , Adipogenia , Células Cultivadas , Masculino , Tecido Adiposo/metabolismo , Tecido Adiposo/citologia , Meios de Cultivo Condicionados/farmacologia
3.
Nature ; 628(8007): 400-407, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480882

RESUMO

AIRE is an unconventional transcription factor that enhances the expression of thousands of genes in medullary thymic epithelial cells and promotes clonal deletion or phenotypic diversion of self-reactive T cells1-4. The biological logic of AIRE's target specificity remains largely unclear as, in contrast to many transcription factors, it does not bind to a particular DNA sequence motif. Here we implemented two orthogonal approaches to investigate AIRE's cis-regulatory mechanisms: construction of a convolutional neural network and leveraging natural genetic variation through analysis of F1 hybrid mice5. Both approaches nominated Z-DNA and NFE2-MAF as putative positive influences on AIRE's target choices. Genome-wide mapping studies revealed that Z-DNA-forming and NFE2L2-binding motifs were positively associated with the inherent ability of a gene's promoter to generate DNA double-stranded breaks, and promoters showing strong double-stranded break generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, AIRE preferentially targets genes with poised promoters. We propose a model in which Z-DNA anchors the AIRE-mediated transcriptional program by enhancing double-stranded break generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest routes for manipulating T cell tolerance.


Assuntos
Proteína AIRE , DNA Forma Z , Tolerância Imunológica , Linfócitos T , Timo , Animais , Camundongos , Proteína AIRE/metabolismo , Cromatina/genética , Cromatina/metabolismo , Quebras de DNA de Cadeia Dupla , DNA Forma Z/química , DNA Forma Z/genética , DNA Forma Z/metabolismo , Células Epiteliais/metabolismo , Variação Genética , Redes Neurais de Computação , Fator 2 Relacionado a NF-E2/metabolismo , Regiões Promotoras Genéticas , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/citologia , Transcrição Gênica , Feminino
4.
Proc Natl Acad Sci U S A ; 121(4): e2320602121, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38227656

RESUMO

Foxp3+CD4+ regulatory T (Treg) cells found within tissues regulate local immunity, inflammation, and homeostasis. Tregs in epididymal visceral adipose tissue (eVAT) are critical regulators of local and systemic inflammation and metabolism. During aging and under obesogenic conditions, eVAT Tregs undergo transcriptional and phenotypic changes and are important for containing inflammation and normalizing metabolic indices. We have employed single-cell RNA sequencing, single-cell Tra and Trb sequencing, adoptive transfers, photoconvertible mice, cellular interaction analyses, and in vitro cultures to dissect the evolving heterogeneity of eVAT Tregs with aging and obesity. Distinct Treg subtypes with distinguishable gene expression profiles and functional roles were enriched at differing ages and with differing diets. Like those in lean mice, eVAT Tregs in obese mice were not primarily recruited from the circulation but instead underwent local expansion and had a distinct and diversified T cell receptor repertoire. The different eVAT-Treg subtypes were specialized in different functions; for example, the subtypes enriched in lean, but not obese, mice suppressed adipogenesis. The existence of functionally divergent eVAT-Treg subtypes in response to obesogenic conditions presents possibilities for precision therapeutics in the context of obesity.


Assuntos
Tecido Adiposo , Linfócitos T Reguladores , Camundongos , Animais , Tecido Adiposo/metabolismo , Dieta , Obesidade/metabolismo , Camundongos Obesos , Inflamação/metabolismo
5.
J Immunol ; 213(1): 96-104, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38775402

RESUMO

The response to type I IFNs involves the rapid induction of prototypical IFN signature genes (ISGs). It is not known whether the tightly controlled ISG expression observed at the cell population level correctly represents the coherent responses of individual cells or whether it masks some heterogeneity in gene modules and/or responding cells. We performed a time-resolved single-cell analysis of the first 3 h after in vivo IFN stimulation in macrophages and CD4+ T and B lymphocytes from mice. All ISGs were generally induced in concert, with no clear cluster of faster- or slower-responding ISGs. Response kinetics differed between cell types: mostly homogeneous for macrophages, but with far more kinetic diversity among B and T lymphocytes, which included a distinct subset of nonresponsive cells. Velocity analysis confirmed the differences between macrophages in which the response progressed throughout the full 3 h, versus B and T lymphocytes in which it was rapidly curtailed by negative feedback and revealed differences in transcription rates between the lineages. In all cell types, female cells responded faster than their male counterparts. The ISG response thus seems to proceed as a homogeneous gene block, but with kinetics that vary between immune cell types and with sex differences that might underlie differential outcomes of viral infections.


Assuntos
Linfócitos B , Interferon Tipo I , Macrófagos , Camundongos Endogâmicos C57BL , Animais , Camundongos , Feminino , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Masculino , Linfócitos B/imunologia , Macrófagos/imunologia , Cinética , Linfócitos T CD4-Positivos/imunologia , Fatores Sexuais , Análise de Célula Única
6.
Sci Immunol ; 9(91): eadi0672, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38181094

RESUMO

Dysbiosis in the gut microbiota affects several systemic diseases, possibly by driving the migration of perturbed intestinal immunocytes to extraintestinal tissues. Combining Kaede photoconvertible mice and single-cell genomics, we generated a detailed map of migratory trajectories from the colon, at baseline, and in several models of intestinal and extraintestinal inflammation. All lineages emigrated from the colon in an S1P-dependent manner. B lymphocytes represented the largest contingent, with the unexpected circulation of nonexperienced follicular B cells, which carried a gut-imprinted transcriptomic signature. T cell emigration included distinct groups of RORγ+ and IEL-like CD160+ subsets. Gut inflammation curtailed emigration, except for dendritic cells disseminating to lymph nodes. Colon-emigrating cells distributed differentially to distinct sites of extraintestinal models of inflammation (psoriasis-like skin, arthritic synovium, and tumors). Thus, specific cellular trails originating in the gut and influenced by microbiota may shape peripheral immunity in varied ways.


Assuntos
Linfócitos B , Microbioma Gastrointestinal , Animais , Camundongos , Disbiose , Perfilação da Expressão Gênica , Inflamação
7.
bioRxiv ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38948783

RESUMO

Our knowledge about the meningeal immune system has recently burgeoned, particularly our understanding of how innate and adaptive effector cells are mobilized to meet brain challenges. However, information on how meningeal immunocytes guard brain homeostasis in healthy individuals remains sparse. This study highlights the heterogeneous and polyfunctional regulatory-T (Treg) cell compartment in the meninges. A Treg subtype specialized in controlling Th1-cell responses and another known to control responses in B-cell follicles were substantial components of this compartment, foretelling that punctual Treg-cell ablation rapidly unleashed interferon-gamma production by meningeal lymphocytes, unlocked their access to the brain parenchyma, and altered meningeal B-cell profiles. Distally, the hippocampus assumed a reactive state, with morphological and transcriptional changes in multiple glial-cell types; within the dentate gyrus, neural stem cells showed exacerbated death and desisted from further differentiation, associated with inhibition of spatial-reference memory. Thus, meningeal Treg cells are a multifaceted bulwark to brain homeostasis at steady-state. One sentence summary: A distinct population of regulatory T cells in the murine meninges safeguards homeostasis by keeping local interferon-γ-producing lymphocytes in check, thereby preventing their invasion of the parenchyma, activation of hippocampal glial cells, death of neural stem cells, and memory decay.

8.
bioRxiv ; 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39026711

RESUMO

Pregnancy brings about profound changes to the mammary gland in preparation for lactation. Changes in immunocyte populations that accompany this rapid remodeling are incompletely understood. We comprehensively analyzed mammary T cells through all parous stages, revealing a marked increase in CD4+ and CD8+ T effector cells in late pregnancy and lactation. T cell expansion was partly dependent on microbial signals and included an increase in TCRαß+CD8αα+ cells with strong cytotoxic markers, located in the epithelium, that resemble intraepithelial lymphocytes of mucosal tissues. This relationship was substantiated by demonstrating T cell migration from gut to mammary gland in late pregnancy, by TCR clonotypes shared by intestine and mammary tissue in the same mouse, including intriguing gut TCR families. Putative counterparts of CD8αα+ IELs were found in human milk. Mammary T cells are thus poised to manage the transition from a non-mucosal tissue to a mucosal barrier during lactogenesis.

9.
Science ; 385(6708): eadk1679, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39088603

RESUMO

Neuroimmune cross-talk participates in intestinal tissue homeostasis and host defense. However, the matrix of interactions between arrays of molecularly defined neuron subsets and of immunocyte lineages remains unclear. We used a chemogenetic approach to activate eight distinct neuronal subsets, assessing effects by deep immunophenotyping, microbiome profiling, and immunocyte transcriptomics in intestinal organs. Distinct immune perturbations followed neuronal activation: Nitrergic neurons regulated T helper 17 (TH17)-like cells, and cholinergic neurons regulated neutrophils. Nociceptor neurons, expressing Trpv1, elicited the broadest immunomodulation, inducing changes in innate lymphocytes, macrophages, and RORγ+ regulatory T (Treg) cells. Neuroanatomical, genetic, and pharmacological follow-up showed that Trpv1+ neurons in dorsal root ganglia decreased Treg cell numbers via the neuropeptide calcitonin gene-related peptide (CGRP). Given the role of these neurons in nociception, these data potentially link pain signaling with gut Treg cell function.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Gânglios Espinais , Neuroimunomodulação , Nociceptores , Linfócitos T Reguladores , Canais de Cátion TRPV , Células Th17 , Animais , Camundongos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/genética , Neurônios Colinérgicos/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/citologia , Microbioma Gastrointestinal , Intestinos/imunologia , Intestinos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Nociceptividade , Nociceptores/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA