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1.
Cell ; 184(13): 3361-3375, 2021 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-34171319

RESUMEN

Surface epithelia provide a critical barrier to the outside world. Upon a barrier breach, resident epithelial and immune cells coordinate efforts to control infections and heal tissue damage. Inflammation can etch lasting marks within tissues, altering features such as scope and quality of future responses. By remembering inflammatory experiences, tissues are better equipped to quickly and robustly respond to barrier breaches. Alarmingly, in disease states, memory may fuel the inflammatory fire. Here, we review the cellular communication networks in barrier tissues and the integration between tissue-resident and recruited immune cells and tissue stem cells underlying tissue adaptation to environmental stress.


Asunto(s)
Adaptación Fisiológica , Inflamación/patología , Especificidad de Órganos , Animales , Humanos , Linfocitos/metabolismo , Modelos Biológicos , Células Madre
2.
Cell ; 184(15): 3981-3997.e22, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34157301

RESUMEN

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.


Asunto(s)
Retroalimentación Fisiológica , Homeostasis/inmunología , Activación de Linfocitos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoantígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Proliferación Celular , Interleucina-2/metabolismo , Microdominios de Membrana/metabolismo , Ratones Endogámicos C57BL , Modelos Inmunológicos , Comunicación Paracrina , Transducción de Señal
3.
Nat Immunol ; 24(7): 1200-1210, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37277655

RESUMEN

Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1ß or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium.


Asunto(s)
Artritis Reumatoide , Humanos , Células Cultivadas , Artritis Reumatoide/genética , Membrana Sinovial , Citocinas/metabolismo , Fibroblastos
4.
Nat Immunol ; 24(6): 1020-1035, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37127830

RESUMEN

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.


Asunto(s)
Neoplasias , Linfocitos T Reguladores , Animales , Ratones , Humanos , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Microambiente Tumoral , Neoplasias/metabolismo
5.
Nat Immunol ; 23(1): 122-134, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34937932

RESUMEN

T cell activation, a key early event in the adaptive immune response, is subject to elaborate transcriptional control. In the present study, we examined how the activities of eight major transcription factor (TF) families are integrated to shape the epigenome of naive and activated CD4 and CD8 T cells. By leveraging extensive polymorphisms in evolutionarily divergent mice, we identified the 'heavy lifters' positively influencing chromatin accessibility. Members of Ets, Runx and TCF/Lef TF families occupied the vast majority of accessible chromatin regions, acting as 'housekeepers', 'universal amplifiers' and 'placeholders', respectively, at sites that maintained or gained accessibility upon T cell activation. In addition, a small subset of strongly induced immune response genes displayed a noncanonical TF recruitment pattern. Our study provides a key resource and foundation for the understanding of transcriptional and epigenetic regulation in T cells and offers a new perspective on the hierarchical interactions between critical TFs.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epigenoma/inmunología , Activación de Linfocitos/inmunología , Factores de Transcripción/inmunología , Inmunidad Adaptativa/inmunología , Animales , Cromatina/inmunología , Epigénesis Genética/inmunología , Regulación de la Expresión Génica/inmunología , Masculino , Ratones
6.
Annu Rev Immunol ; 30: 531-64, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22224781

RESUMEN

The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell-mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.


Asunto(s)
Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular , Citocinas/inmunología , Citocinas/metabolismo , Activación Enzimática , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Homeostasis/inmunología , Humanos , Tolerancia Inmunológica , MicroARNs/inmunología , MicroARNs/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Timo/inmunología , Timo/metabolismo , Transcripción Genética
7.
Cell ; 179(4): 846-863.e24, 2019 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-31668803

RESUMEN

Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.


Asunto(s)
Diferenciación Celular/genética , Linaje de la Célula/genética , Heterogeneidad Genética , Neoplasias/inmunología , Inmunidad Adaptativa/genética , Animales , Diferenciación Celular/inmunología , Cromatina/genética , Células Dendríticas/inmunología , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunidad Innata/genética , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Ratones , Neoplasias/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transcripción Genética/inmunología
8.
Nat Immunol ; 22(9): 1163-1174, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34426690

RESUMEN

The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Factores de Transcripción Forkhead/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/genética , Diferenciación Celular/inmunología , Femenino , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/genética , Homeostasis/inmunología , Mediadores de Inflamación/metabolismo , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Síndrome de Respuesta Inflamatoria Sistémica/patología
9.
Immunity ; 57(5): 1071-1086.e7, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38677291

RESUMEN

Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.


Asunto(s)
Antígeno B7-1 , Folículo Piloso , Inflamación , Piel , Células Madre , Linfocitos T Reguladores , Cicatrización de Heridas , Animales , Linfocitos T Reguladores/inmunología , Ratones , Cicatrización de Heridas/inmunología , Piel/inmunología , Piel/lesiones , Piel/patología , Células Madre/inmunología , Células Madre/metabolismo , Inflamación/inmunología , Folículo Piloso/inmunología , Antígeno B7-1/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Repitelización/inmunología , Movimiento Celular/inmunología , Proliferación Celular
10.
Cell ; 174(5): 1293-1308.e36, 2018 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-29961579

RESUMEN

Knowledge of immune cell phenotypes in the tumor microenvironment is essential for understanding mechanisms of cancer progression and immunotherapy response. We profiled 45,000 immune cells from eight breast carcinomas, as well as matched normal breast tissue, blood, and lymph nodes, using single-cell RNA-seq. We developed a preprocessing pipeline, SEQC, and a Bayesian clustering and normalization method, Biscuit, to address computational challenges inherent to single-cell data. Despite significant similarity between normal and tumor tissue-resident immune cells, we observed continuous phenotypic expansions specific to the tumor microenvironment. Analysis of paired single-cell RNA and T cell receptor (TCR) sequencing data from 27,000 additional T cells revealed the combinatorial impact of TCR utilization on phenotypic diversity. Our results support a model of continuous activation in T cells and do not comport with the macrophage polarization model in cancer. Our results have important implications for characterizing tumor-infiltrating immune cells.


Asunto(s)
Neoplasias de la Mama/inmunología , Regulación Neoplásica de la Expresión Génica , Receptores de Antígenos de Linfocitos T/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Microambiente Tumoral/inmunología , Teorema de Bayes , Neoplasias de la Mama/patología , Análisis por Conglomerados , Biología Computacional , Femenino , Perfilación de la Expresión Génica , Humanos , Sistema Inmunológico , Inmunoterapia/métodos , Ganglios Linfáticos , Linfocitos Infiltrantes de Tumor , Macrófagos/metabolismo , Fenotipo , Transcriptoma
11.
Immunity ; 56(2): 240-255, 2023 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-36792571

RESUMEN

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.


Asunto(s)
Autoinmunidad , Linfocitos T Reguladores , Humanos , Sistema Inmunológico , Inflamación , Homeostasis
12.
Nat Immunol ; 20(2): 232-242, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30643266

RESUMEN

Regulatory T cells (Treg cells), whose differentiation and function are controlled by transcription factor Foxp3, express the closely related family member Foxp1. Here we explored Foxp1 function in Treg cells. We found that a large number of Foxp3-bound genomic sites in Treg cells were occupied by Foxp1 in both Treg cells and conventional T cells (Tconv cells). In Treg cells, Foxp1 markedly increased Foxp3 binding to these sites. Foxp1 deficiency in Treg cells resulted in their impaired function and competitive fitness, associated with markedly reduced CD25 expression and interleukin-2 (IL-2) responsiveness, diminished CTLA-4 expression and increased SATB1 expression. The characteristic expression patterns of CD25, Foxp3 and CTLA-4 in Treg cells were fully or partially rescued by strong IL-2 signaling. Our studies suggest that Foxp1 serves an essential non-redundant function in Treg cells by enforcing Foxp3-mediated regulation of gene expression and enabling efficient IL-2 signaling in these cells.


Asunto(s)
Cromatina/metabolismo , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/inmunología , Proteínas Represoras/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Células Cultivadas , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Interleucina-2/inmunología , Interleucina-2/metabolismo , Masculino , Ratones , Ratones Transgénicos , Cultivo Primario de Células , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología
13.
Immunity ; 55(8): 1354-1369.e8, 2022 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-35926508

RESUMEN

FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Linfocitos T Reguladores , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , ADN , Dimerización , Factores de Transcripción Forkhead/metabolismo , Homeostasis
14.
Immunity ; 55(7): 1173-1184.e7, 2022 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-35700740

RESUMEN

Regulatory T (Treg) cells expressing the transcription factor Foxp3 are an essential suppressive T cell lineage of dual origin: Foxp3 induction in thymocytes and mature CD4+ T cells gives rise to thymic (tTreg) and peripheral (pTreg) Treg cells, respectively. While tTreg cells suppress autoimmunity, pTreg cells enforce tolerance to food and commensal microbiota. However, the role of Foxp3 in pTreg cells and the mechanisms supporting their differentiation remain poorly understood. Here, we used genetic tracing to identify microbiota-induced pTreg cells and found that many of their distinguishing features were Foxp3 independent. Lineage-committed, microbiota-dependent pTreg-like cells persisted in the colon in the absence of Foxp3. While Foxp3 was critical for the suppression of a Th17 cell program, colitis, and mastocytosis, pTreg cells suppressed colonic effector T cell expansion in a Foxp3-independent manner. Thus, Foxp3 and the tolerogenic signals that precede and promote its expression independently confer distinct facets of pTreg functionality.


Asunto(s)
Factores de Transcripción Forkhead , Linfocitos T Reguladores , Factores de Transcripción Forkhead/metabolismo , Tolerancia Inmunológica , Células Th17/metabolismo , Timocitos/metabolismo
15.
Cell ; 164(6): 1198-1211, 2016 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-26967286

RESUMEN

Although they are classically viewed as continuously recirculating through the lymphoid organs and blood, lymphocytes also establish residency in non-lymphoid tissues, most prominently at barrier sites, including the mucosal surfaces and skin. These specialized tissue-resident lymphocyte subsets span the innate-adaptive continuum and include innate lymphoid cells (ILCs), unconventional T cells (e.g., NKT, MAIT, γδ T cells, and CD8αα(+) IELs), and tissue-resident memory T (T(RM)) cells. Although these diverse cell types differ in the particulars of their biology, they nonetheless exhibit important shared features, including a role in the preservation of tissue integrity and function during homeostasis, infection, and non-infectious perturbations. In this Review, we discuss the hallmarks of tissue-resident innate, innate-like, and adaptive lymphocytes, as well as their potential functions in non-lymphoid organs.


Asunto(s)
Linfocitos/citología , Linfocitos/inmunología , Inmunidad Adaptativa , Animales , Humanos , Inmunidad Innata , Memoria Inmunológica , Infecciones/inmunología , Linfocitos/clasificación , Linfocitos T/citología , Linfocitos T/inmunología
16.
Cell ; 166(4): 977-990, 2016 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-27499023

RESUMEN

Eukaryotic cells can "remember" transient encounters with a wide range of stimuli, inducing lasting states of altered responsiveness. Regulatory T (Treg) cells are a specialized lineage of suppressive CD4 T cells that act as critical negative regulators of inflammation in various biological contexts. Treg cells exposed to inflammatory conditions acquire strongly enhanced suppressive function. Using inducible genetic tracing, we analyzed the long-term stability of activation-induced transcriptional, epigenomic, and functional changes in Treg cells. We found that the inflammation-experienced Treg cell population reversed many activation-induced changes and lost its enhanced suppressive function over time. The "memory-less" potentiation of Treg suppressor function may help avoid a state of generalized immunosuppression that could otherwise result from repeated activation.


Asunto(s)
Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular , Cromatina/metabolismo , Memoria Inmunológica , Inflamación/metabolismo , Activación de Linfocitos , Ratones , Organismos Libres de Patógenos Específicos , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Transcripción Genética
17.
Nat Immunol ; 19(10): 1137-1145, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30224821

RESUMEN

Numerous microRNAs and their target mRNAs are coexpressed across diverse cell types. However, it is unknown whether they are regulated in a manner independent of or dependent on cellular context. Here, we explored transcriptome-wide targeting and gene regulation by miR-155, whose activation-induced expression plays important roles in innate and adaptive immunity. Through mapping of miR-155 targets through differential iCLIP, mRNA quantification with RNA-seq, and 3' untranslated region (UTR)-usage analysis with poly(A)-seq in macrophages, dendritic cells, and T and B lymphocytes either sufficient or deficient in activated miR-155, we identified numerous targets differentially bound by miR-155. Whereas alternative cleavage and polyadenylation (ApA) contributed to differential miR-155 binding to some transcripts, in most cases, identical 3'-UTR isoforms were differentially regulated across cell types, thus suggesting ApA-independent and cellular-context-dependent miR-155-mediated gene regulation. Our study provides comprehensive maps of miR-155 regulatory networks and offers a valuable resource for dissecting context-dependent and context-independent miRNA-mediated gene regulation in key immune cell types.


Asunto(s)
Linfocitos B/inmunología , Células Dendríticas/inmunología , Regulación de la Expresión Génica/inmunología , Macrófagos/inmunología , MicroARNs/inmunología , Linfocitos T/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
18.
Immunity ; 54(5): 931-946.e11, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33838102

RESUMEN

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.


Asunto(s)
Linaje de la Célula/inmunología , Factores de Transcripción Forkhead/inmunología , Tolerancia Inmunológica/inmunología , Interleucina-2/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/inmunología , Diferenciación Celular/inmunología , Elementos de Facilitación Genéticos/inmunología , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , Ratones , Receptores de Interleucina-2/inmunología , Factor de Transcripción STAT5/inmunología , Transducción de Señal/inmunología
19.
Cell ; 162(5): 1078-89, 2015 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-26317471

RESUMEN

Regulatory T (Treg) cells suppress immune responses to a broad range of non-microbial and microbial antigens and indirectly limit immune inflammation-inflicted tissue damage by employing multiple mechanisms of suppression. Here, we demonstrate that selective Treg cell deficiency in amphiregulin leads to severe acute lung damage and decreased blood oxygen concentration during influenza virus infection without any measureable alterations in Treg cell suppressor function, antiviral immune responses, or viral load. This tissue repair modality is mobilized in Treg cells in response to inflammatory mediator IL-18 or alarmin IL-33, but not by TCR signaling that is required for suppressor function. These results suggest that, during infectious lung injury, Treg cells have a major direct and non-redundant role in tissue repair and maintenance-distinct from their role in suppression of immune responses and inflammation-and that these two essential Treg cell functions are invoked by separable cues.


Asunto(s)
Gripe Humana/inmunología , Pulmón/citología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Anfirregulina/genética , Animales , Autoinmunidad , Modelos Animales de Enfermedad , Humanos , Gripe Humana/patología , Pulmón/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Factores Supresores Inmunológicos/análisis , Linfocitos T Reguladores/química
20.
Immunity ; 53(5): 971-984.e5, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33176163

RESUMEN

Regulatory T (Treg) cell identity is defined by the lineage-specifying transcription factor (TF) Foxp3. Here we examined mechanisms of Foxp3 function by leveraging naturally occurring genetic variation in wild-derived inbred mice, which enables the identification of DNA sequence motifs driving epigenetic features. Chromatin accessibility, TF binding, and gene expression patterns in resting and activated subsets of Treg cells, conventional CD4 T cells, and cells expressing a Foxp3 reporter null allele revealed that the majority of Foxp3-dependent changes occurred at sites not bound by Foxp3. Chromatin accessibility of these indirect Foxp3 targets depended on the presence of DNA binding motifs for other TFs, including TCF1. Foxp3 expression correlated with decreased TCF1 and reduced accessibility of TCF1-bound chromatin regions. Deleting one copy of the Tcf7 gene recapitulated Foxp3-dependent negative regulation of chromatin accessibility. Thus, Foxp3 defines Treg cell identity in a largely indirect manner by fine-tuning the activity of other major chromatin remodeling TFs such as TCF1.


Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Autoinmunidad/genética , Sitios de Unión , Ensamble y Desensamble de Cromatina , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Inmunohistoquímica , Masculino , Ratones , Motivos de Nucleótidos , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Unión Proteica , Transactivadores/metabolismo
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