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1.
Nat Immunol ; 17(2): 179-86, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26595889

RESUMEN

Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet-dependent differentiation of NCR(-) ILC3 cells into NCR(+) ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR(+) ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR(+) ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis.


Asunto(s)
Inmunidad Innata , Interleucinas/biosíntesis , Linfocitos/inmunología , Linfocitos/metabolismo , Animales , Citrobacter rodentium/inmunología , Análisis por Conglomerados , Modelos Animales de Enfermedad , Infecciones por Enterobacteriaceae/genética , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/metabolismo , Infecciones por Enterobacteriaceae/mortalidad , Infecciones por Enterobacteriaceae/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Homeostasis , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/deficiencia , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Transducción de Señal , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Transcriptoma , Interleucina-22
2.
Semin Immunol ; 36: 31-44, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29503124

RESUMEN

Biological redundancy ensures robustness in living organisms at several levels, from genes to organs. In this review, we explore the concept of redundancy and robustness through an analysis of the caecal appendix, an organ that is often considered to be a redundant remnant of evolution. However, phylogenic data show that the Appendix was selected during evolution and is unlikely to disappear once it appeared. In humans, it is highly conserved and malformations are extremely rare, suggesting a role for that structure. The Appendix could perform a dual role. First, it is a concentrate of lymphoid tissue resembling Peyer's patches and is the primary site for immunoglobulin A production which is crucial to regulate the density and quality of the intestinal flora. Second, given its shape and position, the Appendix could be a unique niche for commensal bacteria in the body. It is extremely rich in biofilms that continuously shed bacteria into the intestinal lumen. The Appendix contains a microbiota as diverse as that found in the colon and could replenish the large intestine with healthy flora after a diarrhea episode. In conditions of modern medicine hygiene, and people live healthy without their appendix. However, several reports suggest that the effects of appendectomy could be subtler and associated with the development of inflammatory conditions such as inflammatory bowel disease (IBD), heart disease but also in less expected disorders such as Parkinson's disease. Lack of an Appendix also predicts a worsen outcome for recurrent Clostridium difficile infection, which is the first nosocomial infection in hospitals. Here, we review the literature and in combination with our own data, we suggest that the Appendix might be redundant in its immunological function but unique as a reservoir of microbiota.


Asunto(s)
Apéndice/inmunología , Microbioma Gastrointestinal/inmunología , Cardiopatías/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Tejido Linfoide/inmunología , Enfermedad de Parkinson/inmunología , Complicaciones Posoperatorias/inmunología , Animales , Apendicectomía , Biopelículas , Evolución Biológica , Cardiopatías/etiología , Humanos , Inmunoglobulina A/biosíntesis , Enfermedades Inflamatorias del Intestino/etiología , Enfermedad de Parkinson/etiología , Ganglios Linfáticos Agregados/inmunología , Filogenia
3.
PLoS Pathog ; 8(8): e1002846, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22876184

RESUMEN

IL-10 is an anti-inflammatory cytokine that regulates the extent of host immunity to infection by exerting suppressive effects on different cell types. Herpes viruses induce IL-10 to modulate the virus-host balance towards their own benefit, resulting in prolonged virus persistence. To define the cellular and molecular players involved in IL-10 modulation of herpes virus-specific immunity, we studied mouse cytomegalovirus (MCMV) infection. Here we demonstrate that IL-10 specifically curtails the MCMV-specific CD4 T cell response by suppressing the bidirectional crosstalk between NK cells and myeloid dendritic cells (DCs). In absence of IL-10, NK cells licensed DCs to effectively prime MCMV-specific CD4 T cells and we defined the pro-inflammatory cytokines IL-12, IFN-γ and TNF-α as well as NK cell activating receptors NKG2D and NCR-1 to regulate this bidirectional NK/DC interplay. Consequently, markedly enhanced priming of MCMV-specific CD4 T cells in Il10(-/-) mice led to faster control of lytic viral replication, but this came at the expense of TNF-α mediated immunopathology. Taken together, our data show that early induction of IL-10 during MCMV infection critically regulates the strength of the innate-adaptive immune cell crosstalk, thereby impacting beneficially on the ensuing virus-host balance for both the virus and the host.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Infecciones por Herpesviridae/inmunología , Interleucina-10/inmunología , Células Asesinas Naturales/inmunología , Muromegalovirus/fisiología , Replicación Viral/inmunología , Animales , Linfocitos T CD4-Positivos/patología , Citocinas/genética , Citocinas/inmunología , Células Dendríticas/patología , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/patología , Interleucina-10/genética , Células Asesinas Naturales/metabolismo , Ratones , Ratones Noqueados
4.
J Allergy Clin Immunol ; 129(1): 143-50.e1-10, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21975175

RESUMEN

BACKGROUND: IL-10 is a pleiotropic cytokine and potent negative regulator of both innate and adaptive immune responses. Consequently, IL-10-deficient (IL-10(-/-)) mice have enhanced contact hypersensitivity (CHS) to topical hapten. OBJECTIVE: Although the importance of IL-10 production by (regulatory) T cells and Langerhans cells in regulating CHS has been established by cell type-specific il-10 gene targeting, it remains elusive to what extent IL-10 controls dendritic cell (DC) function in vivo. METHODS: To this aim, we generated mice with a DC-specific deletion of the IL-10 receptor (IL-10R). RESULTS: Despite the ability of IL-10 to inhibit DC maturation in vitro, DCs of resting DC-IL10R(-/-) mice retained their immature phenotype in vivo. In contrast, IL-10R(-/-) DCs produced increased levels of proinflammatory cytokines and IL-10 after in vitro stimulation. Induction of CHS was indistinguishable from that seen in control mice at 24 hours after hapten challenge but resulted in increased ear swelling at 48 hours and delayed resolution of the inflammatory reaction. Adoptive T-cell transfer experiments revealed that only T-cell reactivation and not sensitization by IL-10R(-/-) DCs leads to enhanced CHS. Accordingly, the expression of proinflammatory cytokines and IL-10 was augmented in the skin of DC-IL10R(-/-) mice after hapten challenge. CONCLUSION: Our data demonstrate that IL-10 signaling in DCs is dispensable during naive T-cell priming but is critical to prevent an exaggerated effector T-cell response in the skin.


Asunto(s)
Células Dendríticas/inmunología , Dermatitis por Contacto/inmunología , Interleucina-10/fisiología , Activación de Linfocitos/inmunología , Piel/inmunología , Linfocitos T/inmunología , Animales , Citocinas/biosíntesis , Células Dendríticas/metabolismo , Dermatitis por Contacto/genética , Eliminación de Gen , Inmunidad Innata , Ratones , Ratones Noqueados , Fenotipo , Receptores de Interleucina-10/genética , Transducción de Señal , Piel/metabolismo
5.
J Immunol ; 185(6): 3248-55, 2010 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-20713882

RESUMEN

The pivotal role of TGF-beta in Langerhans cell (LC) development has been previously established in TGF-beta-deficient mice, which lack epidermal LCs. As to whether TGF-beta also governs LC homeostasis and function remains elusive. To assess the role of TGF-beta-mediated control of cutaneous dendritic cells (DCs) in vivo, we generated mice with a conditional knockout of the TGF-beta receptor 1 (TbetaR1) under a DC-specific promoter (DC-TbetaR1(del) mice). While initial LC seeding occurred in DC-TbetaR1(del) mice, the cells disappeared from the epidermis during the first week of life. TbetaR1-deficient LCs demonstrated spontaneous maturation and gained migratory potential based on increased surface expression of MHC class II, costimulatory molecules, and CCR7 and downregulation of E-cadherin. In parallel to their early loss from the epidermis, migrating LCs were reduced in the dermis and skin-draining lymph nodes of adult DC-TbetaR1(del) mice, whereas the number of Langerin(+) dermal DCs was similar to wild-type. In the absence of LCs, low-dose contact hypersensitivity in DC-TbetaR1(del) mice was significantly diminished. In contrast, ear swelling was restored to wild-type levels when a higher hapten dose was applied to efficiently target TbetaR1-deficient dermal DCs. In conclusion, TGF-beta inhibits in vivo LC maturation and migratory phenotype, identifying TGF-beta as a critical factor controlling LC homeostasis in the steady state.


Asunto(s)
Diferenciación Celular/inmunología , Células Epidérmicas , Epidermis/inmunología , Células de Langerhans/citología , Células de Langerhans/inmunología , Factor de Crecimiento Transformador beta1/fisiología , Animales , Diferenciación Celular/genética , Movimiento Celular/genética , Movimiento Celular/inmunología , Células Cultivadas , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/metabolismo , Dermatitis por Contacto/patología , Epidermis/patología , Homeostasis/genética , Homeostasis/inmunología , Células de Langerhans/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/deficiencia , Receptores de Factores de Crecimiento Transformadores beta/genética
6.
Front Immunol ; 11: 563414, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33329525

RESUMEN

Since their discovery, innate lymphoid cells (ILCs) have gradually been gaining greater relevance in the field of immunology due to their multiple functions in the innate immune response. They can mainly be found in mucosal and barrier organs like skin, gut, and lungs, and have been classified into five main types (NKs, ILC1s, ILC2s, ILC3s, and Lti cells) according to their function and development. They all play major roles in functions such as tissue homeostasis, early pathogen defense, regulation of inflammation, or tissue remodeling. ILCs are mostly tissue-resident cells tightly bound to the tissue structure, a fact that requires long and complex protocols that do not always provide sufficient yield for analysis. This suggests the need for optimized approaches aimed at ensuring that enriched and viable ILC samples are obtained, in order to furnish quality results. Herein a detailed protocol is established for obtaining a single-cell suspension highly enriched in lymphoid cells from mouse gut in order to identify the different subsets of ILCs by means of flow cytometry. The cell marker panel and flow cytometry gating strategies for identification and quantification of all the different ILC populations are provided for simultaneous analysis. Moreover, the protocol described includes a procedure for studying the different cytokines produced by ILC3s involved in maintaining the integrity of the gut barrier and defending against extracellular pathogens. As a result, herein an efficient method is presented for studying mouse ILCs within the lamina propria of the small intestine and colon; this can constitute a useful tool for future investigations in the field.


Asunto(s)
Separación Celular/métodos , Colon/inmunología , Inmunidad Innata , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Intestino Delgado/inmunología , Linfocitos/inmunología , Animales , Citocinas/metabolismo , Citometría de Flujo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL
7.
Sci Signal ; 9(426): ra46, 2016 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-27141930

RESUMEN

Group 3 innate lymphoid cells (ILC3s) are composed of subsets that are either positive or negative for the natural cytotoxicity receptor (NCR) NKp46 (encoded by Ncr1). ILC3s are located at mucosal sites, such as in the intestine and lung, where they are exposed to billions of commensal microbes and potentially harmful pathogens. Together with T cells, the various ILC3 subsets maintain the balance between homeostasis and immune activation. Through genetic mapping, we identified a previously uncharacterized subset of NCR(-) ILC3s in mice that transiently express Ncr1, demonstrating previously undescribed heterogeneity within the ILC3 population. In addition, we showed that sustained Notch signaling was required for the maintenance of the NCR(+) phenotype and that the cytokine transforming growth factor-ß (TGF-ß) impaired the development of NCR(+) ILC3s. Thus, the plasticity of ILC3s is regulated by the balance between the opposing effects of Notch and TGF-ß signaling, maintaining homeostasis in the face of continual challenges.


Asunto(s)
Linfocitos/citología , Receptor Notch1/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Antígenos Ly/metabolismo , Diferenciación Celular , Citocinas/metabolismo , Femenino , Inmunidad Innata , Mucosa Intestinal/metabolismo , Ligandos , Pulmón/metabolismo , Masculino , Ratones , Ratones Transgénicos , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Transducción de Señal , Linfocitos T/citología , Transcripción Genética
8.
Oncotarget ; 7(22): 32015-30, 2016 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-27027442

RESUMEN

Although IL-10 promotes a regulatory phenotype of CD11c+ dendritic cells and macrophages in vitro, the role of IL-10 signaling in CD11c+ cells to maintain intestinal tolerance in vivo remains elusive. To this aim, we generated mice with a CD11c-specific deletion of the IL-10 receptor alpha (Cd11ccreIl10rafl/fl). In contrast to the colon, the small intestine of Cd11ccreIl10rafl/fl mice exhibited spontaneous crypt hyperplasia, increased numbers of intraepithelial lymphocytes and lamina propria T cells, associated with elevated levels of T cell-derived IFNγ and IL-17A. Whereas naive mucosal T-cell priming was not affected and oral tolerance to ovalbumin was intact, augmented T-cell function in the lamina propria was associated with elevated numbers of locally dividing T cells, expression of T-cell attracting chemokines and reduced T-cell apoptosis. Upon stimulation, intestinal IL-10Rα deficient CD11c+ cells exhibited increased activation associated with enhanced IL-6 and TNFα production. Following colonization with Helicobacter hepaticus Cd11ccreIl10rafl/fl mice developed severe large intestinal inflammation characterized by infiltrating T cells and increased levels of Il17a, Ifng, and Il12p40. Altogether these findings demonstrate a critical role of IL-10 signaling in CD11c+ cells to control small intestinal immune homeostasis by limiting reactivation of local memory T cells and to protect against Helicobacter hepaticus-induced colitis.


Asunto(s)
Antígeno CD11c/metabolismo , Colitis/prevención & control , Infecciones por Helicobacter/prevención & control , Inmunidad Mucosa , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Intestino Grueso/metabolismo , Intestino Delgado/metabolismo , Linfocitos T/metabolismo , Animales , Antígeno CD11c/deficiencia , Antígeno CD11c/genética , Antígeno CD11c/inmunología , Colitis/inmunología , Colitis/metabolismo , Colitis/microbiología , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Helicobacter hepaticus/inmunología , Helicobacter hepaticus/patogenicidad , Homeostasis , Memoria Inmunológica , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-10/inmunología , Subunidad alfa del Receptor de Interleucina-10/genética , Subunidad alfa del Receptor de Interleucina-10/inmunología , Subunidad alfa del Receptor de Interleucina-10/metabolismo , Interleucina-17/inmunología , Interleucina-17/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Intestino Grueso/inmunología , Intestino Grueso/microbiología , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/microbiología
9.
Oncoimmunology ; 2(3): e23186, 2013 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-23802070

RESUMEN

Interleukin-10 (IL-10) is a potent immunomodulatory cytokine, whose cellular targets have not yet been precisely identified. Dendritic cell (DC)-specific IL-10 receptor knockout mice exhibit exaggerated T-cell reactivation in the skin, highlighting a key role of DCs in the maintenance of local immune homeostasis, beyond their classical function as regulators of T-cell priming in lymph nodes.

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