Positive selection of IgG+ over IgM+ B cells in the germinal center reaction

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 5; pp. 988 - 1001.e5
• Main Authors: Sundling, Christopher, Lau, Angelica W.Y., Bourne, Katherine, Young, Clara, Laurianto, Candy, Hermes, Jana R., Menzies, Rosemary J., Butt, Danyal, Kräutler, Nike J., Zahra, David, Suan, Dan, Brink, Robert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.05.2021; Elsevier Limited
• Subjects: Affinity; Antibodies; Antigens; B cells; Cell cycle; Cell division; Class switching; Clonal selection; constant region; Depletion; germinal center; Germinal centers; heavy chain; IgD; IgG; IgM; Immunoglobulin G; Immunoglobulin M; Inactivation; Lymphocytes B; Medicin och hälsovetenskap; Positive selection; Receptors; Recombination; Serology; Somatic hypermutation; class switching; constant region; heavy chain; IgD; IgG; positive selection; antibodies; germinal center; B cells; IgM
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2021.03.013

Positive selection of high-affinity B cells within germinal centers (GCs) drives affinity maturation of antibody responses. Here, we examined the mechanism underlying the parallel transition from immunoglobulin M (IgM) to IgG. Early GCs contained mostly unswitched IgM+ B cells; IgG+ B cells subsequently increased in frequency, dominating GC responses 14–21 days after antigen challenge. Somatic hypermutation and generation of high-affinity clones occurred with equal efficiency among IgM+ and IgG+ GC B cells, and inactivation of Ig class-switch recombination did not prevent depletion of IgM+ GC B cells. Instead, high-affinity IgG+ GC B cells outcompeted high-affinity IgM+ GC B cells via a selective advantage associated with IgG antigen receptor structure but independent of the extended cytoplasmic tail. Thus, two parallel forms of GC B-cell-positive selection, based on antigen receptor variable and constant regions, respectively, operate in tandem to ensure high-affinity IgG antibodies predominate in mature serum antibody responses. [Display omitted] •IgM+ and IgG+ GC B cells both undergo SHM and generate high-affinity variants•High-affinity IgG+ GC B cells are retained over high-affinity IgM+ GC B cells•Positive selection does not require the extended cytoplasmic domain of IgG•Rare, aberrant IgD+ GC B cells are also positively selected over IgM+ GC B cells Early germinal centers (GCs) contain unswitched IgM+ and switched IgG+ B cells but ultimately support mature IgG antibody responses. Sundling et al. show that IgG+ B cells are enriched and IgM+ B cells depleted from GCs by a process of positive selection based on the antigen receptor constant region.