The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• The precise molecular mechanisms governing germinal center (GC) dark zone (DZ) and light zone (LZ) formation remain largely undefined.
• Understanding these pathways is critical for deciphering adaptive immune responses and associated pathologies.

Purpose of the Study:

• To elucidate the role of the FOXO1 transcription factor in regulating GC dark zone and light zone differentiation.
• To investigate the downstream targets and cooperative interactions of FOXO1 within the GC microenvironment.

Main Methods:

• Utilized a mouse model lacking FOXO1 expression in GC B cells.
• Analyzed gene expression profiles, B cell maturation markers, somatic hypermutation, affinity maturation, and class switch recombination.
• Investigated the transcriptional regulation of CXCR4 and BCL6 interactions.

Main Results:

• FOXO1 expression is exclusively found in the GC DZ and is indispensable for its formation.
• FOXO1-deficient mice developed LZ-only GCs, exhibiting a loss of DZ gene programs.
• FOXO1-negative GC B cells showed normal somatic hypermutation but impaired affinity maturation and class switch recombination.
• FOXO1 sustains the DZ program via CXCR4 trans-activation and BCL6-mediated trans-repression of immune activation, DNA repair, and plasma cell differentiation genes.

Conclusions:

• FOXO1 is a critical regulator of GC dark zone formation and function, controlling key B cell differentiation processes.
• FOXO1's interaction with BCL6 highlights a complex regulatory network within the GC.
• These findings suggest that constitutive FOXO1 activity may be necessary for the pathogenesis of BCL6-driven lymphomas.