Epi-microRNA mediated metabolic reprogramming ensures affinity maturation

Area of Science:

• Immunology
• Cell Biology
• Epigenetics

Background:

• Positively selected germinal center B (GC-B) cells must divide in the hypoxic light zone (LZ) to mature antibody affinity.
• The metabolic adaptations enabling GC-B cell proliferation in the LZ remain unclear.

Approach:

• Investigated the role of microRNA (miR)-155 in metabolic reprogramming of GC-B cells during positive selection.
• Utilized transcriptome examination and mass spectrometry to analyze miR-155's regulatory mechanisms.
• Examined the interaction between miR-155, Kdm2a, and histone methylation (H3K36me2) under hypoxic conditions.

Key Points:

• miR-155 promotes metabolic adaptation in high-affinity GC-B cells within the germinal center light zone.
• miR-155 represses Kdm2a, a hypoxia-induced histone demethylase, thereby regulating H3K36me2 levels.
• This regulation enhances oxidative phosphorylation (OXPHOS) by optimizing nuclear mitochondrial gene expression under hypoxia.
• The miR-155-Kdm2a pathway prevents excessive reactive oxygen species production and apoptosis, ensuring cell survival.

Conclusions:

• miR-155-mediated epigenetic regulation is essential for enhancing mitochondrial fitness in high-affinity GC-B clones.
• This metabolic adaptation supports GC-B cell expansion and subsequent antibody affinity maturation.
• The findings reveal a novel mechanism controlling B cell metabolism and survival during an immune response.