Clonotype-specificity reveals differential roles of somatic hypermutation in epitope targeting

Описание: 2026 Immcantation Users Group Meeting https://immcantation.github.io/users-...
Title: Clonotype-specificity reveals differential roles of somatic hypermutation in epitope targeting
Speaker: Vishal Rao, Icahn School of Medicine at Mount Sinai (US)
Abstract:
The human antibody repertoire uses a wide range of V genes against diverse pathogenic threats. While some V genes show pathogen-specific biases, others are repeatedly used across different infections. This raises the question of whether somatic hypermutations (SHMs) in these shared V genes evolve toward recognition of specific epitopes. We investigated this using the public antibody M15, which targets the S2 domain of sarbecoviruses and is elicited upon SARS-CoV-2 infection/vaccination. From two cohorts of mRNA vaccinees and public databases (CoV-AbDAb, Observed Antibody Space), we identified 147 M15-like sequences based on VJ gene identity (assigned using the ‘changeo’ package in Immcantation) and over 70% CDR3 similarity. Using these, we identified convergent SHMs in the light chain, enriched within the M15 clonotype compared with antibodies using the same V gene against unrelated antigens. Reverting these clonotype-enriched SHMs to their germline residues reduced M15 binding affinity 12-fold, equivalent to the reconstructed germline antibody, underscoring their role in affinity maturation. Cryo-EM structure of M15 bound to S2 showed that these SHMs enable interactions with a hydrophobic cleft in a novel central interface epitope, occluded in prefusion spike. Serum antibodies targeting this site increase with repeated SARS-CoV-2 vaccinations. In contrast, among SARS-CoV-2 mRNA vaccinated individuals, we show that SHMs shared across spike-specific germinal center B cell clonotypes, are commonly acquired and exhibit similar functional roles in antibodies interacting with other viral antigens. Overall, our results reveal two layers of SHM function: common, pan-antigenic SHMs, and rare clonotype-enriched SHMs that enable affinity maturation toward atypical epitopes.