B Cell-Intrinsic IRF4 Haploinsufficiency Impairs Affinity Maturation

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• The germinal center (GC) reaction is vital for adaptive immunity, generating high-affinity antibodies.
• Transcription factor IRF4 is known to be essential for plasma cell and GC B cell fates.
• The continuous role of IRF4 in later GC selection phases remains unclear.

Purpose of the Study:

• To investigate the role of IRF4 in the later stages of the GC reaction and antibody affinity maturation.
• To determine if IRF4 influences the selection of high-affinity GC B cells (GCBs).

Main Methods:

• Utilized an antigen-specific murine B cell model with halved *Irf4* gene copy number (*Irf4* haploinsufficiency).
• Assessed antigen presentation, isotype switching, GC formation, somatic hypermutation, proliferation, and T cell help.
• Analyzed Blimp-1 regulation in high-affinity GCBs.

Main Results:

• *Irf4* haploinsufficiency did not affect antigen presentation, GC formation, somatic hypermutation, or proliferation.
• High-affinity GCB selection was impaired in *Irf4* haploinsufficient cells.
• Suboptimal Blimp-1 regulation and reduced T cell help were observed in *Irf4* haploinsufficient GCBs.

Conclusions:

• IRF4 is essential for efficient selection of high-affinity GCBs beyond its early role.
• IRF4 promotes productive T follicular helper cell interactions and optimal Blimp-1 expression during GC selection.
• IRF4 plays a continuous role in the late phase of the antibody response for affinity maturation.