Splenic fibroblasts control marginal zone B cell movement and function via two distinct Notch2-dependent regulatory...

Area of Science:

• Immunology
• Cell Biology
• Developmental Biology

Background:

• Innate-like splenic marginal zone (MZ) B (MZB) cells are critical for rapid responses to blood-borne pathogens.
• The mechanisms integrating extrinsic and intrinsic factors for accelerated MZB cell responsiveness remain largely unknown.

Purpose of the Study:

• To investigate the role of Delta-like1 (Dll1) Notch ligands in regulating MZB cell biology.
• To elucidate the downstream signaling pathways involved in MZB cell programming.

Main Methods:

• Utilized genetic manipulation in mice to study Dll1 function.
• Analyzed gene expression related to cell growth and migration.
• Investigated the role of sphingosine-1 phosphate receptor 1 (S1PR1) in B cell localization.

Main Results:

• Dll1, but not Dll4, ligands from splenic fibroblasts are essential for MZB cell pool size, migration, and function.
• D111-Notch2 signaling controls both Myc-dependent cell growth and Myc-independent regulation of cell movement, including S1PR1.
• S1pr1 deficiency impairs MZB cell entry into the MZ and leads to splenic retention upon Notch signaling withdrawal.

Conclusions:

• Specialized splenic niches, via Dll1-Notch2 signaling, program MZB cells for a poised state and patrolling behavior.
• Conserved Myc-dependent and Myc-independent Notch2-regulated mechanisms are key to MZB cell function.
• These findings have implications for understanding human B cell subsets and lymphomas.