Competition for refueling rather than cyclic reentry initiation evident in germinal centers

Area of Science:

• Immunology
• Cell Biology

Background:

• Antibody affinity maturation is crucial for adaptive immunity, occurring in germinal centers (GCs).
• GC B cells undergo cycles of mutation and selection, involving dark zones (DZs) and light zones (LZs).
• Cyclic reentry, where B cells reenter the cell cycle to return to DZs, is essential for continued GC responses.

Purpose of the Study:

• To investigate the regulation of cyclic reentry and T cell-mediated B cell refueling in GCs.
• To determine the role of B cell receptor affinity and T cell help in these processes.
• To elucidate the relationship between cyclic reentry initiation and B cell refueling.

Main Methods:

• Utilized Fucci2 reporter mice to track cell cycle progression.
• Performed T cell ablation and MHCII deletion experiments.
• Assessed B cell receptor affinity and antigen-acquiring abilities.

Main Results:

• Confirmed association between B cell receptor affinity and S phase initiation for cyclic reentry.
• Found that T cell ablation/MHCII deletion did not prevent resting LZ cells from reentering the cell cycle.
• Demonstrated that T cell refueling of LZ cells is affinity-dependent but independent of competition for reentry.
• Showed that refueling is limited by competition and intrinsic antigen-acquisition abilities.

Conclusions:

• Cyclic reentry initiation and B cell refueling are independently regulated processes within GCs.
• Independent regulation allows for sustained B cells of varying competencies and dynamic T cell support.
• This mechanism may support complex antibody maturation and clonal diversity against evolving pathogens.