RESUMO
During immune reactions, functionally distinct B-cell subsets are generated by stochastic processes, including class-switch recombination (CSR) and plasma cell differentiation (PCD). In this study, we show a strong association between individual B-cell fates and mitochondrial functions. CSR occurs specifically in activated B cells with increased mitochondrial mass and membrane potential, which augment mitochondrial reactive oxygen species (mROS), whereas PCD occurs in cells with decreased mitochondrial mass and potential. These events are consequences of initial slight changes in mROS in mitochondria(high) B-cell populations. In CSR-committed cells, mROS attenuates haeme synthesis by inhibiting ferrous ion addition to protoporphyrin IX, thereby maintaining Bach2 function. Reduced mROS then promotes PCD by increasing haeme synthesis. In PCD-committed cells, Blimp1 reduces mitochondrial mass, thereby reducing mROS levels. Identifying mROS as a haeme synthesis regulator increases the understanding of mechanisms regulating haeme homeostasis and cell fate determination after B-cell activation.
Assuntos
Subpopulações de Linfócitos B/metabolismo , Mitocôndrias/metabolismo , Plasmócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/imunologia , Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular , Rastreamento de Células , Expressão Gênica , Heme/biossíntese , Switching de Imunoglobulina/genética , Ativação Linfocitária , Masculino , Potencial da Membrana Mitocondrial/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/citologia , Plasmócitos/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Cultura Primária de Células , Protoporfirinas/metabolismo , Espécies Reativas de Oxigênio/imunologia , Processos Estocásticos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Mutually exclusive cell fate determination of CD4 helper or CD8 killer T cells occurs in the thymus. These T-cell subsets are not believed to redirect other lineages. Here we showed that retinoic acid and transforming growth factor-ß1 promoted the differentiation of CD8αα T cells from CD4 T cells in a Runx3-dependent manner. These cells were inferred to belong to immunoregulatory populations because subpopulations of CD8αα+TCRαß T cells are known to suppress activated T cells, and mice with Runx3(-/-) T cells showed defects during recovery from experimental allergic encephalomyelitis. Our results demonstrate that CD4 T cells play fundamental roles in controlling immune reactions through promotion and attenuation. We accordingly anticipate that clarifying the mechanisms underlying this process will provide insights leading to autoimmune and immunodeficiency disease therapies.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Tecido Linfoide/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Separação Celular , Células Cultivadas , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/fisiologia , Citocinas/fisiologia , Proteínas de Ligação a DNA/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Citometria de Fluxo , Tecido Linfoide/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/metabolismo , TranscriptomaRESUMO
Maxillofacial dysmorphogenesis is found in 5% of the population. To begin to understand the mechanisms required for maxillofacial morphogenesis, we employed the inhibitors of the differentiation 2 (Id2) knock-out mouse model, in which Id proteins, members of the regulator of basic helix-loop-helix (bHLH) transcription factors, modulate cell proliferation, apoptosis, and differentiation. We now report that spatially-restricted growth defects are localized at the skull base of Id2 KO mice. Curiously, at birth, neither the mutant Id2 KO nor wild-type (WT) mice differed, based upon cephalometric and histological analyses of cranial base synchondroses. In postnatal week 2, a narrower hypertrophic zone and an inhibited proliferative zone in presphenoid synchondrosis (PSS) and spheno-occipital synchondrosis (SOS) with maxillary hypoplasia were identified in the Id2 mutant mice. Complementary studies revealed that exogenous bone morphogenetic proteins (BMPs) enhanced cartilage growth, matrix deposition, and chondrocyte proliferation in the WT but not in the mutant model. Id2-deficient chondrocytes expressed more Smad7 transcripts. Based on our results, we assert that Id2 plays an essential role, acting downstream of BMP signaling, to regulate cartilage formation at the postnatal stage by enhancing BMP signals through inhibiting Smad7 expression. As a consequence, abnormal endochondral ossification was observed in cranial base synchondroses during the postnatal growth period, resulting in the clinical phenotype of maxillofacial dysmorphogenesis.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Condrogênese/fisiologia , Proteína 2 Inibidora de Diferenciação/metabolismo , Maxila/embriologia , Maxila/crescimento & desenvolvimento , Morfogênese/fisiologia , Transdução de Sinais/fisiologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Diferenciação Celular , Proliferação de Células , Condrócitos/citologia , Condrócitos/fisiologia , Humanos , Proteína 2 Inibidora de Diferenciação/genética , Maxila/anormalidades , Maxila/anatomia & histologia , Camundongos , Camundongos Knockout , Base do Crânio/anormalidades , Base do Crânio/anatomia & histologia , Base do Crânio/embriologia , Base do Crânio/crescimento & desenvolvimento , Proteína Smad7/genética , Proteína Smad7/metabolismoRESUMO
Runt-related (Runx) transcriptional regulators play essential roles in various cell fate determination processes, and dysfunction of these regulators causes many human diseases. Considerable insight into the functions of Runx proteins was provided mainly by studies of hematopoietic and skeletal disorders. Recently, extensive investigations have revealed new functions of these transcription factors in immune cell differentiation and functioning. In the present review, we discuss the mechanisms of selective IgA production in the intestine and report the involvement of Runx proteins in this process.
Assuntos
Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Imunoglobulina A/metabolismo , Mucosa Intestinal/metabolismo , Animais , Subunidades alfa de Fatores de Ligação ao Core/genética , Humanos , Imunoglobulina A/genética , Modelos BiológicosRESUMO
IgA is a specific isotype required for mucosal immunity and is the most abundant Ab produced in vivo. Recently, several inductive signals for IgA class switch recombination have been identified; however, the molecular details of the action of these signals and the specific factors acting in B cells remain elusive. In this study, we show that combination of retinoic acid (RA) and TGF-beta1 with other factors induced a much higher frequency of IgA-switched cells than reported previously. In addition, IgA production is severely impaired in Runx2-Runx3 double-deficient mice. In Runx2-Runx3-deficient B cells, both RA- and TGF-beta1-dependent inductions of alpha germline transcription are completely blocked. These data suggest that Runx proteins play an essential role in IgA class switching acting downstream of RA and TGF-beta1 signaling.