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1.
JCI Insight ; 6(7)2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33729999

RESUMO

Autoimmune diseases are characterized by a breakdown of immune tolerance partly due to environmental factors. The short-chain fatty acid acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes antiinflammatory Tregs and protects mice from type 1 diabetes, colitis, and allergies. Here, we show that the effects of acetate extend to another important immune subset involved in tolerance, the IL-10-producing regulatory B cells (B10 cells). Acetate directly promoted B10 cell differentiation from mouse B1a cells both in vivo and in vitro. These effects were linked to metabolic changes through the increased production of acetyl-coenzyme A, which fueled the TCA cycle and promoted posttranslational lysine acetylation. Acetate also promoted B10 cells from human blood cells through similar mechanisms. Finally, we identified that dietary fiber supplementation in healthy individuals was associated with increased blood-derived B10 cells. Direct delivery of acetate or indirect delivery via diets or bacteria that produce acetate might be a promising approach to restore B10 cells in noncommunicable diseases.


Assuntos
Acetatos/metabolismo , Acetatos/farmacologia , Artrite Experimental/terapia , Linfócitos B Reguladores/efeitos dos fármacos , Fibras na Dieta/farmacologia , Acetatos/sangue , Acetilcoenzima A/metabolismo , Acetilação , Animais , Artrite Experimental/imunologia , Linfócitos B Reguladores/fisiologia , Linfócitos B Reguladores/transplante , Diferenciação Celular/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia , Feminino , Humanos , Interleucina-10 , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética
2.
Mucosal Immunol ; 7(5): 1058-67, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24448098

RESUMO

Natural killer T (NKT) cells are innate-like T cells that rapidly recognize pathogens and produce cytokines that shape the ensuing immune response. IL-17-producing NKT cells are enriched in barrier tissues, such as the lung, skin, and peripheral lymph nodes, and the factors that maintain this population in the periphery have not been elucidated. Here we show that NKT17 cells deviate from other NKT cells in their survival requirements. In contrast to conventional NKT cells that are maintained by IL-15, RORγt(+) NKT cells are IL-15 independent and instead rely completely on IL-7. IL-7 initiates a T-cell receptor-independent (TCR-independent) expansion of NKT17 cells, thus supporting their homeostasis. Without IL-7, survival is dramatically impaired, yet residual cells remain lineage committed with no downregulation of RORγt evident. Their preferential response to IL-7 does not reflect enhanced signaling through STAT proteins, but instead is modulated via the PI3K/AKT/mTOR signaling pathway. The ability to compete for IL-7 is dependent on high-density IL-7 receptor expression, which would promote uptake of low levels of IL-7 produced in the non-lymphoid sites of lung and skin. This dependence on IL-7 is also reported for RORγt(+) innate lymphoid cells and CD4(+) Th17 cells, and suggests common survival requirements for functionally similar cells.


Assuntos
Homeostase/imunologia , Interleucina-17/metabolismo , Interleucina-7/metabolismo , Células T Matadoras Naturais/imunologia , Animais , Proliferação de Células , Citometria de Fluxo , Injeções Intraperitoneais , Camundongos , Células T Matadoras Naturais/citologia , Reação em Cadeia da Polimerase , Transdução de Sinais/imunologia
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