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.
