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1.
Cell Metab ; 32(3): 457-467.e5, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738204

RESUMO

Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type.


Assuntos
Acetatos/metabolismo , Anti-Inflamatórios/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Acetatos/sangue , Acetatos/imunologia , Animais , Anti-Inflamatórios/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
2.
Nat Immunol ; 20(10): 1311-1321, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31527833

RESUMO

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.


Assuntos
Linfócitos B/imunologia , Complexo II de Transporte de Elétrons/genética , Inflamação/metabolismo , Linfocitose/imunologia , Mitocôndrias/metabolismo , Mutação/genética , Anti-Inflamatórios/farmacologia , Respiração Celular , Células Cultivadas , Fumaratos/metabolismo , Glicólise , Humanos , Inflamação/genética , Interleucina-6/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Consumo de Oxigênio , Estudos Prospectivos , Transdução de Sinais , Sequenciamento do Exoma
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