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1.
bioRxiv ; 2023 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-37503101

RESUMO

Genetic variants associated with human autoimmune diseases commonly map to non-coding control regions, particularly enhancers that function selectively in immune cells and fine-tune gene expression within a relatively narrow range of values. How such modest, cell-type-selective changes can meaningfully shape organismal disease risk remains unclear. To explore this issue, we experimentally manipulated species-conserved enhancers within the disease-associated IL2RA locus and studied accompanying changes in the progression of autoimmunity. Perturbing distinct enhancers with restricted activity in conventional T cells (Tconvs) or regulatory T cells (Tregs)-two functionally antagonistic T cell subsets-caused only modest, cell-type-selective decreases in IL2ra expression parameters. However, these same perturbations had striking and opposing effects in vivo , completely preventing or severely accelerating disease in a murine model of type 1 diabetes. Quantitative tissue imaging and computational modelling revealed that each enhancer manipulation impinged on distinct IL-2-dependent feedback circuits. These imbalances altered the intracellular signaling and intercellular communication dynamics of activated Tregs and Tconvs, producing opposing spatial domains that amplified or constrained ongoing autoimmune responses. These findings demonstrate how subtle changes in gene regulation stemming from non-coding variation can propagate across biological scales due to non-linearities in intra- and intercellular feedback circuitry, dramatically shaping disease risk at the organismal level.

3.
Trends Immunol ; 42(10): 865-875, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34493455

RESUMO

Mature T cells must distinguish between foreign and self-antigens to promote host defense while limiting autoimmunity. How such discrimination occurs reproducibly has been explored extensively regarding mechanisms regulating initial T cell activation at short time and length scales. Here, we suggest that T cells encounter a higher-level discriminatory boundary post-activation, empowering or constraining their responses over greater spatiotemporal scales. This boundary emerges from coordinated communication among at least three cell types, forming a control system governed by intercellular circuits, including negative feedback from regulatory T cells (Tregs). We propose that the nonlinearities inherent to this system can amplify subtle baseline imbalances in a single cell type's functional state, altering the threshold for productive T cell responses and autoimmune disease risk.


Assuntos
Autoimunidade , Ativação Linfocitária , Autoantígenos , Retroalimentação , Linfócitos T Reguladores
4.
5.
Cell ; 184(15): 3981-3997.e22, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34157301

RESUMO

A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death ("pruning"). Computational simulations and experimental manipulations revealed the feedback machinery's quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.


Assuntos
Retroalimentação Fisiológica , Homeostase/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoantígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Interleucina-2/metabolismo , Microdomínios da Membrana/metabolismo , Camundongos Endogâmicos C57BL , Modelos Imunológicos , Comunicação Parácrina , Transdução de Sinais
6.
Elife ; 102021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33533717

RESUMO

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103+ gut dendritic cells (DCs), yet their role in commensal-reactive pTreg development is unclear. Using two Helicobacter-specific T cell receptor (TCR) transgenic mouse lines, we found that both CD103+ and CD103- migratory, but not resident, DCs from the colon-draining mesenteric lymph node presented Helicobacter antigens to T cells ex vivo. Loss of most CD103+ migratory DCs in vivo using murine genetic models did not affect the frequency of Helicobacter-specific pTreg cell generation or induce compensatory tolerogenic changes in the remaining CD103- DCs. By contrast, activation in a Th1-promoting niche in vivo blocked Helicobacter-specific pTreg generation. Thus, these data suggest a model where DC-mediated effector T cell differentiation is 'dominant', necessitating that all DC subsets presenting antigen are permissive for pTreg cell induction to maintain gut tolerance.


Assuntos
Células Dendríticas/microbiologia , Helicobacter/fisiologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular , Movimento Celular , Colo/microbiologia , Linfonodos/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos
7.
Nature ; 589(7840): 131-136, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33239787

RESUMO

The liver connects the intestinal portal vasculature with the general circulation, using a diverse array of immune cells to protect from pathogens that translocate from the gut1. In liver lobules, blood flows from portal triads that are situated in periportal lobular regions to the central vein via a polarized sinusoidal network. Despite this asymmetry, resident immune cells in the liver are considered to be broadly dispersed across the lobule. This differs from lymphoid organs, in which immune cells adopt spatially biased positions to promote effective host defence2,3. Here we used quantitative multiplex imaging, genetic perturbations, transcriptomics, infection-based assays and mathematical modelling to reassess the relationship between the localization of immune cells in the liver and host protection. We found that myeloid and lymphoid resident immune cells concentrate around periportal regions. This asymmetric localization was not developmentally controlled, but resulted from sustained MYD88-dependent signalling induced by commensal bacteria in liver sinusoidal endothelial cells, which in turn regulated the composition of the pericellular matrix involved in the formation of chemokine gradients. In vivo experiments and modelling showed that this immune spatial polarization was more efficient than a uniform distribution in protecting against systemic bacterial dissemination. Together, these data reveal that liver sinusoidal endothelial cells sense the microbiome, actively orchestrating the localization of immune cells, to optimize host defence.


Assuntos
Microbioma Gastrointestinal/imunologia , Fígado/imunologia , Fígado/microbiologia , Simbiose/imunologia , Animais , Bactérias/imunologia , Bactérias/isolamento & purificação , Separação Celular , Quimiocina CXCL9/imunologia , Células Endoteliais/citologia , Células Endoteliais/imunologia , Feminino , Humanos , Células de Kupffer/citologia , Células de Kupffer/imunologia , Células de Kupffer/metabolismo , Fígado/irrigação sanguínea , Fígado/citologia , Linfócitos/imunologia , Masculino , Camundongos , Modelos Imunológicos , Imagem Molecular , Células Mieloides/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Simbiose/genética , Transcriptoma
8.
Semin Immunol ; 36: 17-27, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29290544

RESUMO

The adaptive immune system continually faces unpredictable circumstances yet reproducibly counteracts invading pathogens while limiting damage to self. However, the system is dynamic in nature: many of its internal components are not fixed, but rather, fluctuate over time. This concept is exemplified by αß T lymphocytes, which vary significantly from cell-to-cell in their spatiotemporal dynamics, antigen-binding receptors, and subcellular protein concentrations. How are reproducible immune functions achieved in the face of such variability? This design principle is known as robustness and requires the system to employ layered control schemes that both buffer and exploit different facets of cellular variation. In this article, we discuss these schemes and their applications to individual αß T cell responses as well as integrated population level behaviours.


Assuntos
Imunidade Adaptativa , Interações Hospedeiro-Patógeno , Linfócitos T/imunologia , Animais , Variação Biológica da População , Plasticidade Celular , Humanos , Sistema Imunitário , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Análise de Sistemas
9.
Cell Rep ; 14(12): 2859-71, 2016 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-26997267

RESUMO

Excessive uptake of oxidized low-density lipoproteins (oxLDL) by macrophages is a fundamental characteristic of atherosclerosis. However, signals regulating the engagement of these ligands remain elusive. Using single-molecule imaging, we discovered a mechanism whereby chemokine signaling enhanced binding of oxLDL to the scavenger receptor, CD36. By activating the Rap1-GTPase, chemokines promoted integrin-mediated adhesion of macrophages to the substratum. As a result, cells exhibited pronounced remodeling of the cortical actin cytoskeleton that increased CD36 clustering. Remarkably, CD36 clusters formed predominantly within actin-poor regions of the cortex, and these regions were primed to engage oxLDL. In accordance with enhanced ligand engagement, prolonged exposure of macrophages to chemokines amplified the accumulation of esterified cholesterol, thereby accentuating the foam cell phenotype. These findings imply that the activation of integrins by chemokine signaling exerts feedforward control over receptor clustering and effectively alters the threshold for cells to engage ligands.


Assuntos
Antígenos CD36/metabolismo , Quimiocinas/metabolismo , Lipoproteínas LDL/toxicidade , Transdução de Sinais/efeitos dos fármacos , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Antígenos CD36/deficiência , Antígenos CD36/genética , Quimiocina CCL2/metabolismo , Quimiocina CX3CL1/metabolismo , Quimiocina CXCL12/metabolismo , Células Espumosas/citologia , Células Espumosas/metabolismo , Células HeLa , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Microscopia Confocal , Ligação Proteica , Células RAW 264.7 , Transfecção
11.
Nat Commun ; 6: 6168, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25644899

RESUMO

Integrating signals from multiple receptors allows cells to interpret the physiological context in which a signal is received. Here we describe a mechanism for receptor crosstalk in which receptor-induced increases in actin dynamics lower the threshold for signalling by another receptor. We show that the Toll-like receptor ligands lipopolysaccharide and CpG DNA, which are conserved microbial molecules, enhance signalling by the B-cell antigen receptor (BCR) by activating the actin-severing protein cofilin. Single-particle tracking reveals that increased severing of actin filaments reduces the spatial confinement of the BCR within the plasma membrane and increases BCR mobility. This allows more frequent collisions between BCRs and greater signalling in response to low densities of membrane-bound antigen. These findings implicate actin dynamics as a means of tuning receptor signalling and as a mechanism by which B cells distinguish inert antigens from those that are accompanied by indicators of microbial infection.


Assuntos
Actinas/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Animais , Immunoblotting , Ligantes , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo
12.
Mol Biol Cell ; 25(24): 3884-99, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25253723

RESUMO

CX3CL1 is a unique chemokine that acts both as a transmembrane endothelial adhesion molecule and, upon proteolytic cleavage, a soluble chemoattractant for circulating leukocytes. The constitutive release of soluble CX3CL1 requires the interaction of its transmembrane species with the integral membrane metalloprotease ADAM10, yet the mechanisms governing this process remain elusive. Using single-particle tracking and subdiffraction imaging, we studied how ADAM10 interacts with CX3CL1. We observed that the majority of cell surface CX3CL1 diffused within restricted confinement regions structured by the cortical actin cytoskeleton. These confinement regions sequestered CX3CL1 from ADAM10, precluding their association. Disruption of the actin cytoskeleton reduced CX3CL1 confinement and increased CX3CL1-ADAM10 interactions, promoting the release of soluble chemokine. Our results demonstrate a novel role for the cytoskeleton in limiting membrane protein proteolysis, thereby regulating both cell surface levels and the release of soluble ligand.


Assuntos
Proteínas ADAM/metabolismo , Citoesqueleto de Actina/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Membrana Celular/metabolismo , Quimiocina CX3CL1/metabolismo , Proteínas de Membrana/metabolismo , Proteína ADAM10 , Células Cultivadas , Quimiocina CX3CL1/genética , Endocitose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Microscopia de Fluorescência , Ligação Proteica , Proteólise , Fator de Necrose Tumoral alfa/farmacologia , Gravação de Videoteipe
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