Gene

Somatic hypermutation

Somatic cell

Gene expression

Molecular biology

Antibody

Transcriptome

B cell

Affinity maturation

breakpoint cluster region

Genetics

Biochemistry

Oxidative phosphorylation

Biology

Cell biology

Germinal center

Nature Immunology

Antigen-activated B cells diversify variable regions of B cell antigen receptors by somatic hypermutation in germinal centers (GCs). The positive selection of GC B cells that acquire high-affinity mutations enables antibody affinity maturation. In spite of considerable progress, the genomic states underlying this process remain to be elucidated. Single-cell RNA sequencing and topic modeling revealed increased expression of the oxidative phosphorylation (OXPHOS) module in GC B cells undergoing mitoses. Coupled analysis of somatic hypermutation in immunoglobulin heavy chain (Igh) variable gene regions showed that GC B cells acquiring higher-affinity mutations had further elevated expression of OXPHOS genes. Deletion of mitochondrial Cox10 in GC B cells resulted in reduced cell division and impaired positive selection. Correspondingly, augmentation of OXPHOS activity with oltipraz promoted affinity maturation. We propose that elevated OXPHOS activity promotes B cell clonal expansion and also positive selection by tuning cell division times. Xu and colleagues use single-cell transcriptomic analyses to uncover distinct expression dynamics of metabolic programs in germinal center B cells. Coupled analysis of transcriptional states and Igh variable sequences revealed that OXPHOS metabolism is enhanced in GC B cells undergoing positive selection. Their findings suggest BCR signaling tunes GC B cell metabolism to accelerate the cell cycle of positively selected GC B cells.

Coupled analysis of transcriptome and BCR mutations reveals role of OXPHOS in affinity maturation