RESUMEN
Rapid activation of memory CD4(+) T helper 2 (TH2) cells during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid (ILC2) cells have a crucial role in memory TH2 cell responses, with targeted depletion of ILC2 cells profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin 13 (IL-13) is critical for eliciting production of the TH2 cell-attracting chemokine CCL17 by IRF4(+)CD11b(+)CD103(-) dendritic cells (DCs). Consequently, the sentinel function of DCs is contingent on ILC2 cells for the generation of an efficient memory TH2 cell response. These results elucidate a key innate mechanism in the regulation of the immune memory response to allergens.
Asunto(s)
Células Dendríticas/inmunología , Hipersensibilidad/inmunología , Memoria Inmunológica/inmunología , Activación de Linfocitos/inmunología , Linfocitos/inmunología , Células Th2/inmunología , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Inmunidad Innata/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Early thymic progenitors (ETPs) are bone marrow-derived hematopoietic stem cells that remain multipotent and give rise to a variety of lineage-specific cells. Recently, we discovered a subset of murine ETPs that expresses the IL-4Rα/IL-13Rα1 heteroreceptor (HR) and commits only to the myeloid lineage. This is because IL-4/IL-13 signaling through the HR inhibits their T cell potential and enacts commitment of HR+ETPs to thymic resident CD11c+CD8α+ dendritic cells (DCs). In this study, we discovered that HR+-ETP-derived DCs function as APCs in the thymus and promote deletion of myelin-reactive T cells. Furthermore, this negative T cell selection function of HR+-ETP-derived DCs sustains protection against experimental allergic encephalomyelitis, a mouse model for human multiple sclerosis. These findings, while shedding light on the intricacies underlying ETP lineage commitment, reveal a novel, to our knowledge, function by which IL-4 and IL-13 cytokines condition thymic microenvironment to rheostat T cell selection and fine-tune central tolerance.
Asunto(s)
Células Dendríticas/inmunología , Interleucina-13/inmunología , Interleucina-4/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T/inmunología , Timo/inmunología , Animales , Microambiente Celular/genética , Microambiente Celular/inmunología , Células Dendríticas/patología , Modelos Animales de Enfermedad , Interleucina-13/genética , Interleucina-4/genética , Ratones , Ratones Noqueados , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Linfocitos T/patología , Timo/patologíaRESUMEN
Ig-GAD2, an antigen-specific immune modulator, requires bone marrow (BM) cell transfer in order to restore beta (ß)-cell formation and induce recovery from established type 1 diabetes (T1D). The BM cells provide endothelial precursor cells (EPCs) that give rise to islet resident endothelial cells (ECs). This study shows that, during development of T1D, the immune attack causes collateral damage to the islet vascular network. The EPC-derived ECs repair and restore islet blood vessel integrity. In addition, ß-cell genetic tracing indicates that the newly formed ß-cells originate from residual ß-cells that escaped the immune attack and, unexpectedly, from ß-cell precursors. This indicates that the rejuvenated islet microenvironment invigorates formation of new ß-cells not only from residual ß-cells but also from precursor cells. This is twofold significant from the perspective of precursor cells as a safe reserve for restoration of ß-cell mass and its promise for therapy of T1D long after diagnosis.
Asunto(s)
Células de la Médula Ósea/fisiología , Diabetes Mellitus Tipo 1/terapia , Células Progenitoras Endoteliales/fisiología , Factores Inmunológicos/uso terapéutico , Células Secretoras de Insulina/fisiología , Proteínas Recombinantes de Fusión/uso terapéutico , Animales , Diferenciación Celular , Autorrenovación de las Células , Células Cultivadas , Diabetes Mellitus Tipo 1/inmunología , Modelos Animales de Enfermedad , Glutamato Descarboxilasa/genética , Humanos , Inmunoglobulinas/genética , Factores Inmunológicos/genética , Ratones , Ratones Endogámicos NOD , Proteínas Recombinantes de Fusión/genética , Regeneración , Flujo Sanguíneo RegionalRESUMEN
This brief review is written in memory of Eli Sercarz, a colleague who among many achievements, pioneered and revitalized early-life immunity, a field that is of high relevance to child health. For a long time, the neonatal stage was viewed as a window during which exposure to antigen (Ag) induces immune tolerance. In early 1990, however, it was discovered that the newborn mouse given Ag on the day of birth develops immunity when challenged later with the same Ag. But, these secondary responses displayed a deficit in T-helper (Th)1 cells and excess Th2 lymphocytes. Such discoveries explain the perceived tolerance of Ags given at the neonatal stage and correlate the paucity of effective neonatal vaccines and vulnerability to allergic reactions. Analyzing the mechanisms underlying neonatal Th1 cell deficits revealed a complex developmental interaction between Ag-presenting cells and the cytokines that they produced. This culminated into limited interleukin (IL)-12 in the environment and up-regulation of IL-13Rα1 expression and its association with IL-4Rα on the surface of Th1 cells. After Ag re-exposure, Th2 cells produce IL-4 and -13. Both bind to the heteroreceptor on Th1 cell surfaces and trigger their death. Usually, cytokines promote growth of T cells, but in this case IL-4 and -13 stimulate production of interferon regulatory factor 1 (IRF-1). IRF-1 translocates from nucleus to cytoplasm and stimulates apoptotic machinery that terminates Th1 cells. This suggests that vaccine formulations that could elevate IL-12 production are likely to counter IL-13Rα1 expression, preserve Th1 cells, and potentiate vaccine efficacy in neonates.
Asunto(s)
Células TH1 , Vacunas , Animales , Citocinas , Humanos , Tolerancia Inmunológica , Ratones , Células Th2RESUMEN
Early life immune responses are deficient in Th1 lymphocytes that compromise neonatal vaccination. We found that IL-4 and IL-13 engage a developmentally expressed IL-4Rα/IL-13Rα1 heteroreceptor to endow IFN regulatory factor 1 (IRF-1) with apoptotic functions, which redirect murine neonatal Th1 reactivation to cell death. IL-4/IL-13-induced STAT6 phosphorylation serves to enhance IRF-1 transcription and promotes its egress from the nucleus. In the cytoplasm, IRF-1 can no longer serve as an anti-viral transcription factor but, instead, colocalizes with Bim and instigates the mitochondrial, or intrinsic, death pathway. The new pivotal function of IRF-1 in the death of neonatal Th1 cells stems from the ability of its gene to bind STAT6 for enhanced transcription and the proficiency of its protein to precipitate Bim-driven apoptosis. This cytokine-induced, IRF-1-mediated developmental death network weakens neonatal Th1 responses during early life vaccination and increases susceptibility to viral infection.
Asunto(s)
Factor 1 Regulador del Interferón/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Células TH1/inmunología , Vacunas Virales/inmunología , Virosis/inmunología , Animales , Animales Recién Nacidos , Apoptosis , Proteína 11 Similar a Bcl2/metabolismo , Resistencia a la Enfermedad , Humanos , Inmunidad , Recién Nacido , Factor 1 Regulador del Interferón/genética , Subunidad alfa1 del Receptor de Interleucina-13/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT6/metabolismo , Transducción de SeñalRESUMEN
Recently we reported that IL-4 and IL-13 signaling in murine early thymic progenitors (ETPs) expressing the heteroreceptor (HR) comprising IL-4 receptor α (IL-4Rα) and IL-13 receptor α 1 (IL-13Rα1) activate STAT6 and inhibit ETP maturation potential toward T cells. In this study, we asked whether IL-4 and IL-13 signaling through the HR mobilizes other STAT molecules to shape ETP fate decision. The findings indicate that HR+ ETPs undergoing cytokine signaling display increased STAT1, but not STAT3, phosphorylation in addition to STAT6 activation. In parallel, the ETPs had a STAT1-dependent heightened expression of IRF-8, a transcription factor essential for development of CD8α+ dendritic cells (DCs). Interestingly, STAT1 phosphorylation and IRF-8 upregulation, which are independent of STAT6 activation, guided ETP maturation toward myeloid cells with a CD8α+ DC phenotype. Furthermore, these CD8α+ DCs display a thymic resident phenotype, as they did not express SIRPα, a molecule presumed to be involved in cell migration. These findings suggest that IL-4 and IL-13 cytokine-induced HR signaling provides a double-edged sword that simultaneously blocks T cell lineage potential but advances myeloid maturation that could impact T cell selection and central tolerance.
Asunto(s)
Diferenciación Celular/inmunología , Células Dendríticas/citología , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Timocitos/citología , Animales , Tolerancia Central/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Factores Reguladores del Interferón/inmunología , Factores Reguladores del Interferón/metabolismo , Interleucina-13/inmunología , Interleucina-4/inmunología , Ratones , Ratones Noqueados , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT6/inmunología , Factor de Transcripción STAT6/metabolismo , Timocitos/inmunología , Timocitos/metabolismoRESUMEN
Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic ß cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The NOD mouse develops T1D spontaneously and serves as an animal model for human T1D. The IL-4Rα/IL-13Rα1 heteroreceptor (HR) serves both IL-4 and IL-13 cytokines, which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e., physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This is likely due to an increase in the frequency of mTGFß+Foxp3int regulatory T cells and the persistence of CD206+ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Receptores de Superficie Celular/metabolismo , Traslado Adoptivo , Animales , Glucemia , Modelos Animales de Enfermedad , Células Secretoras de Insulina/inmunología , Interleucina-13/inmunología , Subunidad alfa1 del Receptor de Interleucina-13/deficiencia , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa1 del Receptor de Interleucina-13/inmunología , Interleucina-4/inmunología , Lectinas Tipo C/inmunología , Macrófagos/inmunología , Receptor de Manosa , Lectinas de Unión a Manosa/inmunología , Ratones , Ratones Endogámicos NOD , Páncreas/citología , Páncreas/inmunología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Células Th17/inmunologíaRESUMEN
Early thymic progenitors (ETPs) are endowed with diverse potencies and can give rise to myeloid and lymphoid lineage progenitors. How the thymic environment guides ETP commitment and maturation toward a specific lineage remains obscure. We have previously shown that ETPs expressing the heteroreceptor (HR) comprising IL-4Rα and IL-13Rα1 give rise to myeloid cells but not T cells. In this article, we show that signaling through the HR inhibits ETP maturation to the T cell lineage but enacts commitment toward the myeloid cells. Indeed, HR+ ETPs, but not HR- ETPs, exhibit activated STAT6 transcription factor, which parallels with downregulation of Notch1, a critical factor for T cell development. Meanwhile, the myeloid-specific transcription factor C/EBPα, usually under the control of Notch1, is upregulated. Furthermore, in vivo inhibition of STAT6 phosphorylation restores Notch1 expression in HR+ ETPs, which regain T lineage potential. In addition, upon stimulation with IL-4 or IL-13, HR- ETPs expressing virally transduced HR also exhibit STAT6 phosphorylation and downregulation of Notch1, leading to inhibition of lymphoid, but not myeloid, lineage potential. These observations indicate that environmental cytokines play a role in conditioning ETP lineage choice, which would impact T cell development.
Asunto(s)
Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Células Precursoras de Linfocitos T/fisiología , Receptores de Superficie Celular/metabolismo , Linfocitos T/fisiología , Timo/inmunología , Animales , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Subunidad alfa1 del Receptor de Interleucina-13/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/fisiología , Receptores de Superficie Celular/genética , Factor de Transcripción STAT6/metabolismo , Transducción de SeñalRESUMEN
IL-4 and IL-13 have been defined as anti-inflammatory cytokines that can counter myelin-reactive T cells and modulate experimental allergic encephalomyelitis. However, it is not known whether endogenous IL-4 and IL-13 contribute to the maintenance of peripheral tolerance and whether their function is coordinated with T regulatory cells (Tregs). In this study, we used mice in which the common cytokine receptor for IL-4 and IL-13, namely the IL-4Rα/IL-13Rα1 (13R) heteroreceptor (HR), is compromised and determined whether the lack of signaling by endogenous IL-4 and IL-13 through the HR influences the function of effector Th1 and Th17 cells in a Treg-dependent fashion. The findings indicate that mice-deficient for the HR (13R-/-) are more susceptible to experimental allergic encephalomyelitis than mice sufficient for the HR (13R+/+) and develop early onset and more severe disease. Moreover, Th17 cells from 13R-/- mice had reduced ability to convert to Th1 cells and displayed reduced sensitivity to suppression by Tregs relative to Th17 effectors from 13R+/+ mice. These observations suggest that IL-4 and IL-13 likely operate through the HR and influence Th17 cells to convert to Th1 cells and to acquire increased sensitivity to suppression, leading to control of immune-mediated CNS inflammation. These previously unrecognized findings shed light on the intricacies underlying the contribution of cytokines to peripheral tolerance and control of autoimmunity.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Subunidad alfa1 del Receptor de Interleucina-13/inmunología , Receptores de Superficie Celular/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Citocinas/biosíntesis , Citocinas/inmunología , Modelos Animales de Enfermedad , Tolerancia Inmunológica , Interleucina-13/biosíntesis , Interleucina-13/metabolismo , Subunidad alfa1 del Receptor de Interleucina-13/deficiencia , Subunidad alfa1 del Receptor de Interleucina-13/genética , Interleucina-4/biosíntesis , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos C57BL , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Transducción de Señal , Células TH1/inmunologíaRESUMEN
IL-13 receptor alpha 1 (IL-13Rα1) associates with IL-4Rα to form a functional IL-4Rα/IL-13Rα1 heteroreceptor (HR) through which both IL-4 and IL-13 signal. Recently, HR expression was associated with the development of M2 type macrophages which function as antigen presenting cells (APCs). Herein, we show that a subset of thymic resident dendritic cells (DCs) expressing high CD11b (CD11bhi) and intermediate CD11c (CD11cint) arise in HR-sufficient but not HR-deficient mice. These DCs, which originate from the bone marrow are able to take up Ag from the peritoneum, traffic through the spleen and the lymph nodes and carry it to the thymus. In addition, since the DCs are able to present Ag to T cells, express high levels of the costimulatory molecule CD24, and comprise a CD8α+ subset, it is likely that the cells contribute to T cell development and perhaps negative selection of self-reactive lymphocytes.
Asunto(s)
Presentación de Antígeno/inmunología , Movimiento Celular/inmunología , Células Dendríticas/inmunología , Subunidad alfa1 del Receptor de Interleucina-13/inmunología , Timo/inmunología , Animales , Antígeno CD11c/inmunología , Antígeno CD11c/metabolismo , Antígeno CD24/inmunología , Antígeno CD24/metabolismo , Células Dendríticas/metabolismo , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
To contain autoimmunity, pathogenic T cells must be eliminated or diverted from reaching the target organ. Recently, we defined a novel form of T cell tolerance whereby treatment with Ag downregulates expression of the chemokine receptor CXCR3 and prevents diabetogenic Th1 cells from reaching the pancreas, leading to suppression of type 1 diabetes (T1D). This report defines the signaling events underlying Ag-induced chemokine receptor-mediated tolerance. Specifically, we show that the mammalian target of rapamycin complex 1 (mTORC1) is a major target for induction of CXCR3 downregulation and crippling of Th1 cells. Indeed, Ag administration induces upregulation of programmed death-ligand 1 on dendritic cells in a T cell-dependent manner. In return, programmed death-ligand 1 interacts with the constitutively expressed programmed death-1 on the target T cells and stimulates docking of Src homology 2 domain-containing tyrosine phosphatase 2 phosphatase to the cytoplasmic tail of programmed death-1. Active Src homology 2 domain-containing tyrosine phosphatase 2 impairs the signaling function of the PI3K/protein kinase B (AKT) pathway, leading to functional defect of mTORC1, downregulation of CXCR3 expression, and suppression of T1D. Thus, mTORC1 component of the metabolic pathway serves as a target for chemokine receptor-mediated T cell tolerance and suppression of T1D.
Asunto(s)
Complejos Multiproteicos/inmunología , Receptores CXCR3/metabolismo , Linfocitos T/inmunología , Serina-Treonina Quinasas TOR/inmunología , Animales , Antígenos/inmunología , Autoinmunidad , Antígeno B7-H1/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Tolerancia Inmunológica , Inmunomodulación , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Endogámicos NOD , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de SeñalRESUMEN
Neonatal immunity exhibits weak Th1 but excessive Th2 responses, and the underlying mechanisms remain elusive. In this article, we show that neonatal basophils readily produce IL-4, a cytokine that proved to be pivotal in shaping the programs of both lymphocyte subsets. Besides promoting Th2 programs, IL-4 is captured by the IL-4 heteroreceptor (IL-4Rα/IL-13Rα1) expressed on dendritic cells and instigates IL-12 downregulation. Under these circumstances, differentiating Th1 cells upregulate IL-13Rα1, leading to an unusual expression of the heteroreceptor, which will serve as a death marker for these Th1 cells during rechallenge with Ag. The resulting Th1/Th2 imbalance impacts childhood immunity culminating in sensitivity to allergic reactions, susceptibility to microbial infection and perhaps poor efficacy of pediatric vaccines.
Asunto(s)
Basófilos/inmunología , Células Dendríticas/inmunología , Regulación del Desarrollo de la Expresión Génica/inmunología , Células TH1/inmunología , Células Th2/inmunología , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Basófilos/citología , Basófilos/efectos de los fármacos , Basófilos/trasplante , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/trasplante , Femenino , Inmunidad Innata , Interleucina-12/genética , Interleucina-12/inmunología , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa1 del Receptor de Interleucina-13/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Datos de Secuencia Molecular , Ovalbúmina/farmacología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Transducción de Señal , Células TH1/citología , Células TH1/efectos de los fármacos , Células TH1/trasplante , Células Th2/citología , Células Th2/efectos de los fármacos , Células Th2/trasplanteRESUMEN
Effective humoral immunity ensues when antigen presentation by B cells culminates in productive cooperation with T lymphocytes. This collaboration, however, remains ill-defined because naive antigen-specific B cells are rare and difficult to track in vivo. Herein, we used a defined transfer model to examine how B lymphocytes, as antigen-presenting cells, shape the development of T-cell memory suitable for generation of relevant antibody responses. Specifically, we examined how B cells presenting different doses of antigen during the initial priming phase shape the development of CD4 T-cell memory and its influence on humoral immunity. The findings indicate that B cells presenting low dose of antigen favour the development of T helper type 1 (Th1) type memory, while those presenting a high antigen dose yielded better Th2 memory cells. The memory Th2 cells supported the production of antibodies by effector B cells and promoted isotype switching to IgG1. Moreover, among the B-cell subsets tested for induction of Th2 memory, the splenic but not peritoneal B220(lo) cells were most effective in sustaining Th2 memory development as well as immunoglobulin isotype switching, and this function involved a tight control by programmed death 1-programmed death ligand 2 interactions.
Asunto(s)
Presentación de Antígeno , Linfocitos B/inmunología , Linfocitos B/metabolismo , Comunicación Celular/inmunología , Cambio de Clase de Inmunoglobulina , Memoria Inmunológica , Células Th2/inmunología , Células Th2/metabolismo , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Interleucina-5/biosíntesis , Antígenos Comunes de Leucocito/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Unión Proteica , Bazo/inmunologíaRESUMEN
In this study, we examined the role IL-13 receptor alpha 1 (IL-13Rα1) plays in macrophage differentiation and function. The findings indicate that IL-13Rα1 is expressed on the M2 but not on the M1 subset of macrophages and specifically heterodimerizes with the IL-4Rα chain to form a type II receptor, which controls the differentiation and function of these cells. Indeed, BM cells from IL-13Rα1(+/+) and IL-13Rα1(-/-) mice yield equivalent numbers of macrophages when cultured under M2 polarizing conditions. However, IL-13Rα1(-/-) BM cells yield a much higher number of macrophages than IL-13Rα1(+/+) BM cells when the differentiation is carried out under M1-polarizing conditions. Further analyses indicated that macrophages that express IL-13Rα1 also display surface markers associated with an M2 phenotype. In addition, the IL-13Rα1(+) macrophages were highly efficient in phagocytizing zymosan bioparticles both in vitro and in vivo, and supported differentiation of naïve T cells to a Th2 phenotype. Finally, when stimulated by IL-13, a cytokine that uses the heteroreceptor, the cells were able to phosphorylate STAT6 efficiently. These previously unrecognized findings indicate that IL-13Rα1 serves as a marker for M2 macrophages and the resulting heteroreceptor influences both their differentiation and function.
Asunto(s)
Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Expresión Génica , Inmunofenotipificación , Interleucina-13/farmacología , Subunidad alfa1 del Receptor de Interleucina-13/genética , Macrófagos/citología , Macrófagos/efectos de los fármacos , Ratones , Ratones Noqueados , Monocitos/inmunología , Monocitos/metabolismo , Fenotipo , Fosforilación/efectos de los fármacos , Carácter Cuantitativo Heredable , Factor de Transcripción STAT6/metabolismoRESUMEN
Health policy precludes neonatal vaccination against influenza. Hence, morbidity and mortality are high under 6 months of age. Lactoferrin may activate diminished numbers of dysfunctional dendritic cells and reverse neonatal vaccine failures. Aluminum hydroxide/ALUM recruits neutrophils that secrete lactoferrin at deposition sites of antigen. We theorized lactoferrin + influenza antigen initiates an equivalent antibody response compared to ALUM. Three-day-old mice received subcutaneously 30 µg of H1N1 hemagglutinin + 200 µg of bovine lactoferrin versus hemagglutinin + ALUM. Controls received hemagglutinin, lactoferrin, or ALUM. After 21 days, sera measured anti-H1N1 (ELISA) and neutralizing antibody (plaque assays). ELISA detected equal antibody production with lactoferrin + hemagglutinin compared to hemagglutinin + ALUM; both sera also neutralized H1N1 virus at a 1:20 dilution (p < 0.01). Controls had no anti-H1N1 antibody. Neonates given lactoferrin had no anaphylaxis when challenged four weeks later. Lactoferrin is a safe and effective adjuvant for inducing antibody against influenza in neonates.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Lactoferrina/farmacología , Infecciones por Orthomyxoviridae/inmunología , Vacunación/métodos , Hidróxido de Aluminio/inmunología , Hidróxido de Aluminio/farmacología , Animales , Animales Recién Nacidos , Bovinos , Perros , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/farmacología , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Lactoferrina/inmunología , Células de Riñón Canino Madin Darby/virología , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/virologíaRESUMEN
The conceptual framework for a gut-brain axis has existed for decades. The Human Microbiome Project is responsible for establishing intestinal dysbiosis as a mediator of inflammatory bowel disease, obesity, and neurodevelopmental disorders in adults. Recent advances in metagenomics implicate gut microbiota and diet as key modulators of the bidirectional signaling pathways between the gut and brain that underlie neurodevelopmental and psychiatric disorders in adults. Evidence linking intestinal dysbiosis to neurodevelopmental disease outcomes in preterm infants is emerging. Recent clinical studies show that intestinal dysbiosis precedes late-onset neonatal sepsis and necrotizing enterocolitis in intensive care nurseries. Moreover, strong epidemiologic evidence links late-onset neonatal sepsis and necrotizing enterocolitis in long-term psychomotor disabilities of very-low-birth-weight infants. The notion of the gut-brain axis thereby supports that intestinal microbiota can indirectly harm the brain of preterm infants. In this review, we highlight the anatomy and physiology of the gut-brain axis and describe transmission of stress signals caused by immune-microbial dysfunction in the gut. These messengers initiate neurologic disease in preterm infants. Understanding neural and humoral signaling through the gut-brain axis will offer insight into therapeutic and dietary approaches that may improve the outcomes of very-low-birth-weight infants.
Asunto(s)
Encéfalo/fisiología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/fisiología , Enfermedades del Recién Nacido/microbiología , Microbiota/fisiología , Modelos Biológicos , Transducción de Señal/fisiología , Disbiosis/microbiología , Enterocolitis Necrotizante/microbiología , Humanos , Recién Nacido , Recién Nacido de muy Bajo Peso , Sepsis/microbiologíaRESUMEN
NOD.H-2h4 mice given NaI in their drinking water develop iodine-accelerated spontaneous autoimmune thyroiditis (ISAT) with chronic inflammation of the thyroid by T and B cells and production of anti-mouse thyroglobulin (MTg) autoantibody. CD28(-/-) NOD.H-2h4 mice, which have reduced numbers of CD4(+)Foxp3(+) regulatory T cells (Tregs), were developed to examine the role of Tregs in ISAT development. CD28(-/-) NOD.H2-h4 mice develop more severe ISAT than do wild-type (WT) mice, with collagen deposition (fibrosis) and low serum T4. CD28(-/-) mice have increased expression of proinflammatory cytokines IFN-γ and IL-6, consistent with increased mononuclear cell infiltration and tissue destruction in thyroids. Importantly, transferring purified CD4(+)Foxp3(+) Tregs from WT mice reduces ISAT severity in CD28(-/-) mice without increasing the total number of Tregs, suggesting that endogenous Tregs in CD28(-/-) mice are functionally ineffective. Endogenous CD28(-/-) Tregs have reduced surface expression of CD27, TNFR2 p75, and glucocorticoid-induced TNFR-related protein compared with transferred CD28(+/+) Tregs. Although anti-MTg autoantibody levels generally correlate with ISAT severity scores in WT mice, CD28(-/-) mice have lower anti-MTg autoantibody responses than do WT mice. The percentages of follicular B cells are decreased and those of marginal zone B cells are increased in spleens of CD28(-/-) mice, and they have fewer thyroid-infiltrating B cells than do WT mice. This suggests that CD28 deficiency has direct and indirect effects on the B cell compartment. B cell-deficient (B(-/-)) NOD.H-2h4 mice are resistant to ISAT, but CD28(-/-)B(-/-) mice develop ISAT comparable to WT mice and have reduced numbers of Tregs compared with WT B(-/-) mice.
Asunto(s)
Linfocitos B/inmunología , Antígenos CD28/deficiencia , Linfocitos T Reguladores/inmunología , Tiroiditis Autoinmune/inmunología , Animales , Autoanticuerpos/inmunología , Antígenos CD4/metabolismo , Fibrosis/inmunología , Factores de Transcripción Forkhead/metabolismo , Inflamación , Interferón gamma/biosíntesis , Interleucina-6/biosíntesis , Recuento de Linfocitos , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Yoduro de Sodio/administración & dosificación , Tiroglobulina/inmunología , Glándula Tiroides/inmunología , Tiroiditis Autoinmune/inducido químicamente , Tiroxina/sangre , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
The events controlling the transition of T cells from effector to memory remain largely undefined. Many models have been put forth to account for the origin of memory precursors, but for CD4 T cells initial studies reported that memory T cells derive from IFN-γ-nonproducing effectors, whereas others suggested that memory emanates from highly activated IFN-γ-producing effectors. In this study, using cell proliferation, expression of activation markers, and production of IFN-γ as a measure of activation, we defined two types of effector CD4 T cells and investigated memory generation. The moderately activated early effectors readily transit to memory, whereas the highly activated late effectors, regardless of their IFN-γ production, develop minimal memory. Boosting with Ag-free adjuvant, however, rescues late effectors from cell death and sustains both survival and IFN-γ cytokine responses in lymphopenic hosts. The adjuvant-mediated memory transition of late effectors involves the function of TLRs, most notably TLR9. These findings uncover the mechanism by which late effector CD4 T cells are driven to transit to memory and suggest that timely boosts with adjuvant may enhance vaccine efficacy.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Memoria Inmunológica/inmunología , Linfopenia/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Interferón gamma , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Receptor Toll-Like 9/inmunología , Receptor Toll-Like 9/metabolismoRESUMEN
Dendritic cells (DCs) have been shown to play a major role in oral tolerance, and this function has been associated with their ability to produce anti-inflammatory cytokines and to induce suppressive regulatory T cells. In this study, we demonstrate that upon oral administration of Ag, lamina propia (LP) DCs engage specific T cells and acquire a novel mechanism by which they transfer tolerance against diverse T cell specificities. Indeed, when Ig-myelin oligodendrocyte glycoprotein (MOG) carrying the MOG(35-55) epitope was orally administered into either T cell-sufficient or -deficient mice, only the T cell-sufficient hosts yielded CD8α(+) and CD8α(-) LP DCs that were able to transfer tolerance to a variety of MHC class II-restricted effector T cells. Surprisingly, these LP DCs upregulated programmed cell death ligand 1 during the initial interaction with MOG-specific T cells and used this inhibitory molecule to suppress activation of T cells regardless of Ag specificity. Furthermore, oral Ig-MOG was able to overcome experimental autoimmune encephalomyelitis induced with CNS homogenate, indicating that the DCs are able to modulate disease involving diverse T cell specificities. This previously unrecognized attribute potentiates DCs against autoimmunity.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Inmunidad Mucosa/inmunología , Membrana Mucosa/inmunología , Administración Oral , Traslado Adoptivo , Animales , Autoantígenos/inmunología , Autoinmunidad/inmunología , Separación Celular , Encefalomielitis Autoinmune Experimental/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunidad Innata/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunologíaRESUMEN
Upon exposure to Ag on the day of birth, neonatal mice mount balanced primary Th1 and Th2 responses, with the former displaying upregulated IL-13Rα1 expression. This chain associates with IL-4Rα to form a heteroreceptor (IL-4Rα/IL-13Rα1) that marks the Th1 cells for death by IL-4 produced by Th2 cells during rechallenge with Ag, hence the Th2 bias of murine neonatal immunity. The upregulation of IL-13Rα1 on neonatal Th1 cells was due to the paucity of IL-12 in the neonatal environment. In this study, we show that by day 8 after birth, naive splenic T cells are no longer susceptible to IL-13Rα1 upregulation even when exposed to Ag within the neonatal environment. Furthermore, during the 8-d lapse, the naive splenic T cells spontaneously and progressively upregulate the IL-12Rß2 chain, perhaps due to colonization by commensals, which induce production of IL-12 by cells of the innate immune system such as dendritic cells. In fact, mature T cells from the thymus, a sterile environment not accessible to microbes, did not upregulate IL-12Rß2 and were unable to counter IL-13Rα1 upregulation. Finally, the 8-d naive T cells were able to differentiate into Th1 cells even independently of IL-12 but required the cytokine to counter upregulation of IL-13Rα1. Thus, in neonatal mice, IL-12, which accumulates in the environment progressively, uses IL-12Rß2 to counter IL-13Rα1 expression in addition to promoting Th1 differentiation.