Regulation of Foxo1 expression is critical for central B cell tolerance and allelic exclusion.
Cell Rep
; 43(6): 114283, 2024 Jun 25.
Article
em En
| MEDLINE
| ID: mdl-38796853
ABSTRACT
Resolving the molecular mechanisms of central B cell tolerance might unveil strategies that prevent autoimmunity. Here, using a mouse model of central B cell tolerance in which Forkhead box protein O1 (Foxo1) is either deleted or over-expressed in B cells, we show that deleting Foxo1 blocks receptor editing, curtails clonal deletion, and decreases CXCR4 expression, allowing high-avidity autoreactive B cells to emigrate to the periphery whereby they mature but remain anergic and short lived. Conversely, expression of degradation-resistant Foxo1 promotes receptor editing in the absence of self-antigen but leads to allelic inclusion. Foxo1 over-expression also restores tolerance in autoreactive B cells harboring active PI3K, revealing opposing roles of Foxo1 and PI3K in B cell selection. Overall, we show that the transcription factor Foxo1 is a major gatekeeper of central B cell tolerance and that PI3K drives positive selection of immature B cells and establishes allelic exclusion by suppressing Foxo1.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
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Fosfatidilinositol 3-Quinases
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Alelos
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Proteína Forkhead Box O1
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Tolerância Imunológica
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article