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1.
J Immunol ; 205(8): 2039-2045, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32917785

RESUMO

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.


Assuntos
Células Dendríticas/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Timo/imunologia , Animais , Microambiente Celular/genética , Microambiente Celular/imunologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Interleucina-13/genética , Interleucina-4/genética , Camundongos , Camundongos Knockout , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Linfócitos T/patologia , Timo/patologia
2.
Cell Immunol ; 364: 104360, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33866285

RESUMO

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.


Assuntos
Células da Medula Óssea/fisiologia , Diabetes Mellitus Tipo 1/terapia , Células Progenitoras Endoteliais/fisiologia , Fatores Imunológicos/uso terapêutico , Células Secretoras de Insulina/fisiologia , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Diferenciação Celular , Autorrenovação Celular , Células Cultivadas , Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Glutamato Descarboxilase/genética , Humanos , Imunoglobulinas/genética , Fatores Imunológicos/genética , Camundongos , Camundongos Endogâmicos NOD , Proteínas Recombinantes de Fusão/genética , Regeneração , Fluxo Sanguíneo Regional
3.
J Immunol ; 202(11): 3173-3186, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30996000

RESUMO

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.


Assuntos
Fator Regulador 1 de Interferon/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Células Th1/imunologia , Vacinas Virais/imunologia , Viroses/imunologia , Animais , Animais Recém-Nascidos , Apoptose , Proteína 11 Semelhante a Bcl-2/metabolismo , Resistência à Doença , Humanos , Imunidade , Recém-Nascido , Fator Regulador 1 de Interferon/genética , Subunidade alfa1 de Receptor de Interleucina-13/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais
4.
J Immunol ; 201(10): 2947-2958, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30291166

RESUMO

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.


Assuntos
Diferenciação Celular/imunologia , Células Dendríticas/citologia , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Timócitos/citologia , Animais , Tolerância Central/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Interleucina-13/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Knockout , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT6/imunologia , Fator de Transcrição STAT6/metabolismo , Timócitos/imunologia , Timócitos/metabolismo
5.
J Immunol ; 199(3): 894-902, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28646042

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Receptores de Superfície Celular/metabolismo , Transferência Adotiva , Animais , Glicemia , Modelos Animais de Doenças , Células Secretoras de Insulina/imunologia , Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/deficiência , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/imunologia , Interleucina-4/imunologia , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Receptor de Manose , Lectinas de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos NOD , Pâncreas/citologia , Pâncreas/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia
6.
J Immunol ; 199(7): 2236-2248, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28801358

RESUMO

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.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/imunologia , Receptores de Superfície Celular/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Tolerância Imunológica , Interleucina-13/biossíntese , Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/deficiência , Subunidade alfa1 de Receptor de Interleucina-13/genética , Interleucina-4/biossíntese , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Transdução de Sinais , Células Th1/imunologia
7.
J Immunol ; 199(8): 2767-2776, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28893952

RESUMO

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.


Assuntos
Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Células Precursoras de Linfócitos T/fisiologia , Receptores de Superfície Celular/metabolismo , Linfócitos T/fisiologia , Timo/imunologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Subunidade alfa1 de Receptor de Interleucina-13/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/fisiologia , Receptores de Superfície Celular/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais
8.
J Immunol ; 197(9): 3554-3565, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27671108

RESUMO

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.


Assuntos
Complexos Multiproteicos/imunologia , Receptores CXCR3/metabolismo , Linfócitos T/imunologia , Serina-Treonina Quinases TOR/imunologia , Animais , Antígenos/imunologia , Autoimunidade , Antígeno B7-H1/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Tolerância Imunológica , Imunomodulação , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos NOD , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais
9.
Genesis ; 53(3-4): 257-69, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25677367

RESUMO

The vertebrate kidney plays an essential role in removing metabolic waste and balancing water and salt. This is carried out by nephrons, which comprise a blood filter attached to an epithelial tubule with proximal and distal segments. In zebrafish, two nephrons are first formed as part of the embryonic kidney (pronephros) and hundreds are formed later to make up the adult kidney (mesonephros). Previous studies have focused on the development of the pronephros while considerably less is known about how the mesonephros is formed. Here, we characterize mesonephros development in zebrafish and examine the nephrons that form during larval metamorphosis. These nephrons, arising from proliferating progenitor cells that express the renal transcription factor genes wt1b, pax2a, and lhx1a, form on top of the pronephric tubules and develop a segmentation pattern similar to pronephric nephrons. We find that the pronephros acts as a scaffold for the mesonephros, where new nephrons fuse with the distal segments of the pronephric tubules to form the final branching network that characterizes the adult zebrafish kidney.


Assuntos
Embrião não Mamífero/fisiologia , Rim/embriologia , Mesonefro/embriologia , Néfrons/embriologia , Pronefro/embriologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Embrião não Mamífero/citologia , Regulação da Expressão Gênica no Desenvolvimento , Técnicas Imunoenzimáticas , Hibridização In Situ , Rim/metabolismo , Mesonefro/metabolismo , Metamorfose Biológica , Néfrons/metabolismo , Organogênese/fisiologia , Pronefro/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
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