Central tolerance shapes the neutralizing B cell repertoire against a persisting virus in its natural host

• 成果类型: Article
• 署名作者: Florova, Marianna; Mota, Tiago Abreu -; Paesen, Guido C.; Beetschen, Anna Sophia; Cornille, Karen; Marx, Anna-Friederike; Narr, Kerstin; Sahin, Mehmet; Dimitrova, Mirela; Swarnalekha, Nivedya; Wagner, Jane Beil -; Savic, Natasa; Pelczar, Pawel; Buch, Thorsten; King, Carolyn G.; Bowden, Thomas A.; Pinschewer, Daniel D.
• 署名单位: University of Basel; University of Oxford; Wellcome Centre for Human Genetics; University of Basel; University of Zurich; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Basel; Helmholtz Association; Max Delbruck Center for Molecular Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10051
• DOI: 10.1073/pnas.2318657121
• 发表日期: 2024-03-12
• 关键词: lymphocytic choriomeningitis virus; immunoglobulin-secreting cells; antibody mutation trajectories; humoral immune-response; allelic inclusion; clonal deletion; heavy-chain; bone-marrow; mouse model; hiv-1

摘要

Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus-host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV- neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up- regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire.