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1.
Cell ; 186(3): 607-620.e17, 2023 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-36640762

RESUMEN

Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.


Asunto(s)
Interleucina-17 , Microbiota , Regeneración Nerviosa , Células Th17 , Axones , Regeneración Nerviosa/fisiología , Células Receptoras Sensoriales , Animales , Ratones , Células Th17/citología
2.
Cell ; 184(14): 3794-3811.e19, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34166614

RESUMEN

The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratinocyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the microbiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for heightened ERV- expression in response to commensal colonization, leading to increased immune responses and tissue inflammation. Together, our results support the idea that the host may have co-opted its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-kingdom dialog that controls both tissue homeostasis and inflammation.


Asunto(s)
Retrovirus Endógenos/fisiología , Homeostasis , Inflamación/microbiología , Inflamación/patología , Microbiota , Animales , Bacterias/metabolismo , Cromosomas Bacterianos/genética , Dieta Alta en Grasa , Inflamación/inmunología , Inflamación/virología , Interferón Tipo I/metabolismo , Queratinocitos/metabolismo , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Nucleotidiltransferasas/metabolismo , Retroelementos/genética , Transducción de Señal , Piel/inmunología , Piel/microbiología , Linfocitos T/inmunología , Transcripción Genética
3.
Nat Immunol ; 24(8): 1331-1344, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37443284

RESUMEN

CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host's ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Ratones , Diferenciación Celular , Sistema Nervioso Central , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias , Células TH1 , Células Th17 , Factores de Transcripción , Virulencia , Humanos
4.
Immunity ; 57(5): 1019-1036.e9, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38677292

RESUMEN

Group 3 innate lymphoid cells (ILC3) are the major subset of gut-resident ILC with essential roles in infections and tissue repair, but how they adapt to the gut environment to maintain tissue residency is unclear. We report that Tox2 is critical for gut ILC3 maintenance and function. Gut ILC3 highly expressed Tox2, and depletion of Tox2 markedly decreased ILC3 in gut but not at central sites, resulting in defective control of Citrobacter rodentium infection. Single-cell transcriptional profiling revealed decreased expression of Hexokinase-2 in Tox2-deficient gut ILC3. Consistent with the requirement for hexokinases in glycolysis, Tox2-/- ILC3 displayed decreased ability to utilize glycolysis for protein translation. Ectopic expression of Hexokinase-2 rescued Tox2-/- gut ILC3 defects. Hypoxia and interleukin (IL)-17A each induced Tox2 expression in ILC3, suggesting a mechanism by which ILC3 adjusts to fluctuating environments by programming glycolytic metabolism. Our results reveal the requirement for Tox2 to support the metabolic adaptation of ILC3 within the gastrointestinal tract.


Asunto(s)
Citrobacter rodentium , Infecciones por Enterobacteriaceae , Glucólisis , Proteínas HMGB , Inmunidad Innata , Linfocitos , Ratones Noqueados , Animales , Ratones , Adaptación Fisiológica/inmunología , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/metabolismo , Hexoquinasa/metabolismo , Hexoquinasa/genética , Interleucina-17/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Transactivadores/metabolismo , Transactivadores/genética , Proteínas HMGB/genética , Proteínas HMGB/inmunología , Proteínas HMGB/metabolismo
5.
Immunity ; 57(4): 859-875.e11, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38513665

RESUMEN

At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.


Asunto(s)
Interleucina-23 , Periodontitis , Humanos , Células Epiteliales , Inflamación , Receptor Toll-Like 5/metabolismo
6.
Cell ; 172(4): 784-796.e18, 2018 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-29358051

RESUMEN

Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.


Asunto(s)
Inmunidad Adaptativa , Bacterias/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Microbiota/inmunología , Piel/inmunología , Linfocitos T/inmunología , Animales , Regulación de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Ratones , Ratones Transgénicos
7.
Proc Natl Acad Sci U S A ; 121(11): e2322574121, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38451947

RESUMEN

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. The neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Neuroinmunomodulación , Péptido Relacionado con Gen de Calcitonina/genética , Proteína 1 Modificadora de la Actividad de Receptores/genética , Receptores de Péptido Relacionado con el Gen de Calcitonina , Inmunidad Adaptativa
8.
Nat Immunol ; 15(10): 947-56, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25129370

RESUMEN

The transcription factor ThPOK promotes CD4(+) T cell differentiation in the thymus. Here, using a mouse strain that allows post-thymic gene deletion, we show that ThPOK maintains CD4(+) T lineage integrity and couples effector differentiation to environmental cues after antigenic stimulation. ThPOK preserved the integrity and amplitude of effector responses and was required for proper differentiation of types 1 and 2 helper T cells in vivo by restraining the expression and function of Runx3, a nuclear factor crucial for cytotoxic T cell differentiation. The transcription factor LRF acts redundantly with ThPOK to prevent the transdifferentiation of mature CD4(+) T cells into CD8(+) T cells. As such, the ThPOK-LRF transcriptional module was essential for CD4(+) T cell integrity and responses.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Proteínas de Unión al ADN/inmunología , Timo/inmunología , Factores de Transcripción/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/inmunología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/inmunología , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Timo/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcriptoma/inmunología
9.
Immunity ; 47(6): 1154-1168.e6, 2017 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-29221731

RESUMEN

White adipose tissue bridges body organs and plays a fundamental role in host metabolism. To what extent adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we have shown that at steady state, white adipose tissue contained abundant memory lymphocyte populations. After infection, white adipose tissue accumulated large numbers of pathogen-specific memory T cells, including tissue-resident cells. Memory T cells in white adipose tissue expressed a distinct metabolic profile, and white adipose tissue from previously infected mice was sufficient to protect uninfected mice from lethal pathogen challenge. Induction of recall responses within white adipose tissue was associated with the collapse of lipid metabolism in favor of antimicrobial responses. Our results suggest that white adipose tissue represents a memory T cell reservoir that provides potent and rapid effector memory responses, positioning this compartment as a potential major contributor to immunological memory.


Asunto(s)
Tejido Adiposo Blanco/trasplante , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Toxoplasmosis/inmunología , Infecciones por Yersinia pseudotuberculosis/inmunología , Tejido Adiposo Blanco/inmunología , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/parasitología , Linfocitos T CD8-positivos/microbiología , Linfocitos T CD8-positivos/parasitología , Expresión Génica , Genes Reporteros , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-5/genética , Interleucina-5/inmunología , Metabolismo de los Lípidos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis de Supervivencia , Trasplante de Tejidos , Toxoplasma/inmunología , Toxoplasmosis/genética , Toxoplasmosis/mortalidad , Toxoplasmosis/parasitología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Yersinia pseudotuberculosis/inmunología , Infecciones por Yersinia pseudotuberculosis/genética , Infecciones por Yersinia pseudotuberculosis/microbiología , Infecciones por Yersinia pseudotuberculosis/mortalidad
10.
Immunity ; 46(1): 133-147, 2017 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-28087239

RESUMEN

Immuno-surveillance networks operating at barrier sites are tuned by local tissue cues to ensure effective immunity. Site-specific commensal bacteria provide key signals ensuring host defense in the skin and gut. However, how the oral microbiome and tissue-specific signals balance immunity and regulation at the gingiva, a key oral barrier, remains minimally explored. In contrast to the skin and gut, we demonstrate that gingiva-resident T helper 17 (Th17) cells developed via a commensal colonization-independent mechanism. Accumulation of Th17 cells at the gingiva was driven in response to the physiological barrier damage that occurs during mastication. Physiological mechanical damage, via induction of interleukin 6 (IL-6) from epithelial cells, tailored effector T cell function, promoting increases in gingival Th17 cell numbers. These data highlight that diverse tissue-specific mechanisms govern education of Th17 cell responses and demonstrate that mechanical damage helps define the immune tone of this important oral barrier.


Asunto(s)
Encía/inmunología , Inmunidad Mucosa/inmunología , Vigilancia Inmunológica/inmunología , Mucosa Bucal/inmunología , Células Th17/inmunología , Animales , Citometría de Flujo , Encía/microbiología , Humanos , Masticación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microbiota , Mucosa Bucal/microbiología , Reacción en Cadena en Tiempo Real de la Polimerasa
11.
Nature ; 587(7834): 472-476, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33149302

RESUMEN

The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells1. So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain2. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA+ cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.


Asunto(s)
Senos Craneales/inmunología , Microbioma Gastrointestinal/inmunología , Inmunoglobulina A Secretora/inmunología , Intestinos/inmunología , Meninges/inmunología , Células Plasmáticas/inmunología , Anciano , Envejecimiento/inmunología , Animales , Barrera Hematoencefálica/inmunología , Femenino , Hongos/inmunología , Vida Libre de Gérmenes , Humanos , Intestinos/citología , Intestinos/microbiología , Masculino , Meninges/irrigación sanguínea , Meninges/citología , Ratones , Ratones Endogámicos C57BL , Células Plasmáticas/citología
12.
Proc Natl Acad Sci U S A ; 120(49): e2304905120, 2023 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-38011570

RESUMEN

Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. However, the factors and mechanisms involved remain to be elucidated. Here, we propose that DR-induced optimization of immunological memory requires a complex cascade of events involving memory T cells, the intestinal microbiota, and myeloid cells. Our findings suggest that DR enhances the ability of memory T cells to recruit and activate myeloid cells in the context of a secondary infection. Concomitantly, DR promotes the expansion of commensal Bifidobacteria within the large intestine, which produce the short-chain fatty acid acetate. Acetate conditioning of the myeloid compartment during DR enhances the capacity of these cells to kill pathogens. Enhanced host protection during DR is compromised when Bifidobacteria expansion is prevented, indicating that microbiota configuration and function play an important role in determining immune responsiveness to this dietary intervention. Altogether, our study supports the idea that DR induces both memory T cells and the gut microbiota to produce distinct factors that converge on myeloid cells to promote optimal pathogen control. These findings suggest that nutritional cues can promote adaptation and co-operation between multiple immune cells and the gut microbiota, which synergize to optimize immunity and protect the collective metaorganism.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Ácidos Grasos Volátiles , Acetatos
13.
Proc Natl Acad Sci U S A ; 119(26): e2200348119, 2022 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-35727974

RESUMEN

Immune checkpoint inhibitors (ICIs) are essential components of the cancer therapeutic armamentarium. While ICIs have demonstrated remarkable clinical responses, they can be accompanied by immune-related adverse events (irAEs). These inflammatory side effects are of unclear etiology and impact virtually all organ systems, with the most common being sites colonized by the microbiota such as the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint inhibition unleashes commensal-specific inflammatory T cell responses. These aberrant responses were dependent on production of IL-17 by commensal-specific T cells and induced pathology that recapitulated the cutaneous inflammation seen in patients treated with ICIs. Importantly, aberrant T cell responses unleashed by ICIs were sufficient to perpetuate inflammatory memory responses to the microbiota months following the cessation of treatment. Altogether, we have established a mouse model of skin irAEs and reveal that ICIs unleash aberrant immune responses against skin commensals, with long-lasting inflammatory consequences.


Asunto(s)
Dermatitis , Inhibidores de Puntos de Control Inmunológico , Microbiota , Animales , Dermatitis/inmunología , Dermatitis/microbiología , Modelos Animales de Enfermedad , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunidad/efectos de los fármacos , Interleucina-17/metabolismo , Ratones , Microbiota/efectos de los fármacos , Microbiota/inmunología , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus epidermidis/inmunología , Simbiosis/efectos de los fármacos , Linfocitos T/inmunología
14.
Immunity ; 42(6): 1130-42, 2015 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-26070484

RESUMEN

Tissue-infiltrating Ly6C(hi) monocytes play diverse roles in immunity, ranging from pathogen killing to immune regulation. How and where this diversity of function is imposed remains poorly understood. Here we show that during acute gastrointestinal infection, priming of monocytes for regulatory function preceded systemic inflammation and was initiated prior to bone marrow egress. Notably, natural killer (NK) cell-derived IFN-γ promoted a regulatory program in monocyte progenitors during development. Early bone marrow NK cell activation was controlled by systemic interleukin-12 (IL-12) produced by Batf3-dependent dendritic cells (DCs) in the mucosal-associated lymphoid tissue (MALT). This work challenges the paradigm that monocyte function is dominantly imposed by local signals after tissue recruitment, and instead proposes a sequential model of differentiation in which monocytes are pre-emptively educated during development in the bone marrow to promote their tissue-specific function.


Asunto(s)
Células de la Médula Ósea/inmunología , Células Dendríticas/inmunología , Mucosa Intestinal/inmunología , Células Asesinas Naturales/inmunología , Leucocitos Mononucleares/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Antígenos Ly/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Células de la Médula Ósea/parasitología , Diferenciación Celular , Células Cultivadas , Interferón gamma/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Mucosa Intestinal/parasitología , Células Asesinas Naturales/parasitología , Leucocitos Mononucleares/parasitología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Inmunológicos , Especificidad de Órganos/inmunología , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
15.
Nature ; 554(7691): 255-259, 2018 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-29364878

RESUMEN

The mammalian gut is colonized by numerous microorganisms collectively termed the microbiota, which have a mutually beneficial relationship with their host. Normally, the gut microbiota matures during ontogeny to a state of balanced commensalism marked by the absence of adverse inflammation. Subsets of innate lymphoid cells (ILCs) and conventional T cells are considered to have redundant functions in containment and clearance of microbial pathogens, but how these two major lymphoid-cell populations each contribute to shaping the mature commensal microbiome and help to maintain tissue homeostasis has not been determined. Here we identify, using advanced multiplex quantitative imaging methods, an extensive and persistent phosphorylated-STAT3 signature in group 3 ILCs and intestinal epithelial cells that is induced by interleukin (IL)-23 and IL-22 in mice that lack CD4+ T cells. By contrast, in immune-competent mice, phosphorylated-STAT3 activation is induced only transiently by microbial colonization at weaning. This early signature is extinguished as CD4+ T cell immunity develops in response to the expanding commensal burden. Physiologically, the persistent IL-22 production from group 3 ILCs that occurs in the absence of adaptive CD4+ T-cell activity results in impaired host lipid metabolism by decreasing lipid transporter expression in the small bowel. These findings provide new insights into how innate and adaptive lymphocytes operate sequentially and in distinct ways during normal development to establish steady-state commensalism and tissue metabolic homeostasis.


Asunto(s)
Inmunidad Adaptativa , Microbioma Gastrointestinal/inmunología , Inmunidad Innata , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Metabolismo de los Lípidos , Linfocitos/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Células Epiteliales/citología , Células Epiteliales/inmunología , Proteínas de Homeodominio/genética , Homeostasis , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Interleucina-23/inmunología , Interleucinas/biosíntesis , Interleucinas/inmunología , Intestino Delgado/metabolismo , Activación de Linfocitos , Masculino , Ratones , Monocitos/metabolismo , Fosforilación , Receptores CCR2/metabolismo , Factor de Transcripción STAT3/metabolismo , Simbiosis , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Destete , Interleucina-22
16.
Immunity ; 40(3): 378-88, 2014 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-24631153

RESUMEN

Innate lymphoid cells (ILCs) are critical in innate immune responses to pathogens and lymphoid organ development. Similar to CD4(+) T helper (Th) cell subsets, ILC subsets positive for interleukin-7 receptor α (IL-7Rα) produce distinct sets of effector cytokines. However, the molecular control of IL-7Rα(+) ILC development and maintenance is unclear. Here, we report that GATA3 was indispensable for the development of all IL-7Rα(+) ILC subsets and T cells but was not required for the development of classical natural killer cells. Conditionally Gata3-deficient mice had no lymph nodes and were susceptible to Citrobactor rodentium infection. After the ILCs had fully developed, GATA3 remained important for the maintenance and functions of ILC2s. Genome-wide gene expression analyses indicated that GATA3 regulated a similar set of cytokines and receptors in Th2 cells and ILC2s, but not in ILC3s. Thus, GATA3 plays parallel roles in regulating the development and functions of CD4(+) T cells and IL-7Rα(+) ILCs.


Asunto(s)
Factor de Transcripción GATA3/metabolismo , Regulación de la Expresión Génica , Inmunidad Innata/genética , Subgrupos Linfocitarios/metabolismo , Receptores de Interleucina-7/genética , Animales , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/genética , Infecciones por Enterobacteriaceae/inmunología , Factor de Transcripción GATA3/genética , Predisposición Genética a la Enfermedad , Subgrupos Linfocitarios/inmunología , Ratones , Ratones Noqueados , Modelos Inmunológicos , Proteínas Proto-Oncogénicas c-vav/genética , Proteínas Proto-Oncogénicas c-vav/metabolismo , Receptores de Interleucina-7/metabolismo
17.
Proc Natl Acad Sci U S A ; 117(28): 16465-16474, 2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-32601220

RESUMEN

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.


Asunto(s)
Arthrodermataceae/fisiología , Microbiota , Psoriasis/inmunología , Piel/microbiología , Animales , Arthrodermataceae/clasificación , Arthrodermataceae/genética , Arthrodermataceae/aislamiento & purificación , Trampas Extracelulares/inmunología , Trampas Extracelulares/microbiología , Femenino , Humanos , Inmunidad , Masculino , Ratones , Ratones Endogámicos C57BL , Psoriasis/microbiología , Psoriasis/patología , Piel/inmunología , Piel/patología , Simbiosis , Células Th17/inmunología
18.
Immunity ; 38(6): 1198-210, 2013 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-23809163

RESUMEN

Differences in gut commensal flora can dramatically influence autoimmune responses, but the mechanisms behind this are still unclear. We report, in a Th1-cell-driven murine model of autoimmune arthritis, that specific gut commensals, such as segmented filamentous bacteria, have the ability to modulate the activation threshold of self-reactive T cells. In the local microenvironment of gut-associated lymphoid tissues, inflammatory cytokines elicited by the commensal flora dynamically enhanced the antigen responsiveness of T cells that were otherwise tuned down to a systemic self-antigen. Together with subtle differences in early lineage differentiation, this ultimately led to an enhanced recruitment of pathogenic Th1 cells and the development of a more severe form of autoimmune arthritis. These findings define a key role for the gut commensal flora in sustaining ongoing autoimmune responses through the local fine tuning of T-cell-receptor-proximal activation events in autoreactive T cells.


Asunto(s)
Artritis Experimental/inmunología , Enfermedades Autoinmunes/inmunología , Clostridium/inmunología , Intestinos/inmunología , Células TH1/inmunología , Animales , Artritis Experimental/microbiología , Autoantígenos/inmunología , Enfermedades Autoinmunes/microbiología , Complejo CD3/genética , Células Cultivadas , Selección Clonal Mediada por Antígenos , Modelos Animales de Enfermedad , Humanos , Intestinos/microbiología , Activación de Linfocitos , Metagenoma , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células TH1/microbiología
19.
Proc Natl Acad Sci U S A ; 116(47): 23643-23652, 2019 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-31672911

RESUMEN

The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22-mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A-producing CD4+ T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissue-specific rules governing the dialogue between a host and its microbiota.


Asunto(s)
Epidermis/microbiología , Antígenos de Histocompatibilidad Clase II/biosíntesis , Interacciones Microbiota-Huesped/inmunología , Queratinocitos/inmunología , Microbiota/inmunología , Células TH1/inmunología , Animales , Presentación de Antígeno , Candida albicans/inmunología , Epidermis/inmunología , Genes MHC Clase II , Interferón gamma/biosíntesis , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Quimera por Radiación , Organismos Libres de Patógenos Específicos , Staphylococcus aureus/inmunología , Staphylococcus epidermidis/inmunología , Simbiosis , Células TH1/metabolismo
20.
Immunity ; 37(3): 511-23, 2012 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-22981537

RESUMEN

Interferon-γ (IFN-γ) promotes a population of T-bet(+) CXCR3(+) regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii, a similar population emerged that limited T cell responses and was dependent on IFN-γ in the periphery but on IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27(-/-) mice, and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-γ or IL-27 have distinct transcriptional profiles. Thus, IFN-γ and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.


Asunto(s)
Interferón gamma/farmacología , Interleucina-17/farmacología , Salmonelosis Animal/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Toxoplasmosis Animal/inmunología , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Células Cultivadas , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Receptores CXCR3/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , Salmonelosis Animal/microbiología , Salmonelosis Animal/patología , Salmonella typhimurium/inmunología , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Proteínas de Dominio T Box/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Toxoplasma/inmunología , Toxoplasmosis Animal/parasitología , Toxoplasmosis Animal/patología
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