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

Nat Immunol. 2021 Jul;22(7):904-913. doi: 10.1038/s41590-021-00936-y. Epub 2021 May 24.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / genetics
  • Alkyl and Aryl Transferases / metabolism
  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • DNA Mutational Analysis
  • Female
  • Gene Expression Profiling*
  • Genes, Immunoglobulin Heavy Chain
  • Germinal Center / immunology
  • Germinal Center / metabolism*
  • Immunoglobulin Variable Region
  • Lymphocyte Activation
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mutation*
  • Oxidative Phosphorylation*
  • RNA-Seq
  • Receptors, Antigen, B-Cell / genetics*
  • Receptors, Antigen, B-Cell / metabolism
  • Single-Cell Analysis*
  • Transcriptome*

Substances

  • Immunoglobulin Variable Region
  • Membrane Proteins
  • Receptors, Antigen, B-Cell
  • Alkyl and Aryl Transferases
  • COX10 protein, mouse