The transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells

Area of Science:

• Immunology
• Cell Biology

Background:

• Type 1 conventional dendritic cells (cDC1) are crucial for initiating cytotoxic T cell responses via antigen cross-presentation.
• The regulation of cDC1 homeostasis and function remains incompletely understood.

Purpose of the Study:

• To investigate the role of Zeb1 in the regulation of cDC1 homeostasis and function.
• To elucidate the molecular mechanisms by which Zeb1 controls cDC1 cross-presentation.

Main Methods:

• Analysis of Zeb1-deficient mice models.
• Assessment of cDC1 reduction and cell death.
• Evaluation of antigen cross-presentation capacity of cDC1.
• Investigation of microRNA and mRNA expression levels.
• Functional assays of T cell responses.

Main Results:

• Zeb1 deficiency in dendritic cells led to selective reduction and excessive death of splenic cDC1.
• Zeb1-deficient cDC1 exhibited impaired cross-presentation of exogenous antigens, compromising CD8+ T cell responses.
• Zeb1 was found to repress microRNA-96/182, which target Cybb mRNA (encoding NADPH oxidase Nox2).
• This pathway regulates reactive oxygen species-dependent phagosomal membrane rupture for antigen export.
• Restoration of Cybb in Zeb1-deficient cDC1 rescued cross-presentation; microRNA overexpression inhibited it.

Conclusions:

• A novel Zeb1-microRNA-96/182-Cybb pathway controlling cDC1 cross-presentation was identified.
• Zeb1 plays an essential role in maintaining cDC1 homeostasis and function.
• This pathway is critical for effective cytotoxic T cell responses and immune surveillance.