Nature. 2020 Oct 28. doi: 10.1038/s41586-020-2865-9. | PubMed

Carla R Nowosad^1,2, Luka Mesin¹, Tiago B R Castro^1,2, Christopher Wichmann^2,3, Gregory P Donaldson², Tatsuya Araki¹, Ariën Schiepers¹, Ainsley A K Lockhart², Angelina M Bilate², Daniel Mucida⁴, Gabriel D Victora⁵

1. Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA.
2. Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA.
3. Mucosal Immunology Group, Department of Pediatrics, University Medical Center Rostock, Rostock, Germany.
4. Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA. mucida@rockefeller.edu.
5. Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA. victora@rockefeller.edu.

Abstract

Germinal centres, the structures in which B cells evolve to produce antibodies with high affinity for various antigens, usually form transiently in lymphoid organs in response to infection or immunization. In lymphoid organs associated with the gut, however, germinal centres are chronically present. These gut-associated germinal centres can support targeted antibody responses to gut infections and immunization1. But whether B cell selection and antibody affinity maturation take place in the face of the chronic and diverse antigenic stimulation characteristic of these structures under steady state is less clear2-8. Here, by combining multicolour 'Brainbow' cell-fate mapping and sequencing of immunoglobulin genes from single cells, we find that 5-10% of gut-associated germinal centres from specific-pathogen-free (SPF) mice contain highly dominant 'winner' B cell clones at steady state, despite rapid turnover of germinal-centre B cells. Monoclonal antibodies derived from these clones show increased binding, compared with their unmutated precursors, to commensal bacteria, consistent with antigen-driven selection. The frequency of highly selected gut-associated germinal centres is markedly higher in germ-free than in SPF mice, and winner B cells in germ-free germinal centres are enriched in 'public' clonotypes found in multiple individuals, indicating strong selection of B cell antigen receptors even in the absence of microbiota. Colonization of germ-free mice with a defined microbial consortium (Oligo-MM12) does not eliminate germ-free-associated clonotypes, yet does induce a concomitant commensal-specific B cell response with the hallmarks of antigen-driven selection. Thus, positive selection of B cells can take place in steady-state gut-associated germinal centres, at a rate that is tunable over a wide range by the presence and composition of the microbiota.

Presented By Carla Nowosad | ORCID iD