Abstract
Vaccination induces “public” antibody clonotypes common to all individuals of a species, that may mediate universal protection against pathogens. Only few studies tried to trace back the origin of these public B-cell clones. Here we used Illumina sequencing and computational modeling to unveil the mechanisms shaping the structure of the fish memory antibody response against an attenuated Viral Hemorrhagic Septicemia rhabdovirus. After vaccination, a persistent memory response with a public VH5JH5 IgM component was composed of dominant antibodies shared among all individuals. The rearrangement model showed that these public junctions occurred with high probability indicating that they were already favored before vaccination due to the recombination process, as shown in mammals. In addition, these clonotypes were in the naïve repertoire associated with larger similarity classes, composed of junctions differing only at one or two positions by amino acids with comparable properties. The model showed that this property was due to selective processes exerted between the recombination and the naive repertoire. Finally, our results showed that public clonotypes greatly expanded after vaccination displayed several VDJ junctions differing only by one or two amino acids with similar properties, highlighting a convergent response. The fish public memory antibody response to a virus is therefore shaped at three levels: by recombination biases, by selection acting on the formation of the pre-vaccination repertoire, and by convergent selection of functionally similar clonotypes during the response. We also show that naive repertoires of IgM and IgT have different structures and sharing between individuals, due to selection biases. In sum, our comparative approach identifies three conserved features of the antibody repertoire associated with public memory responses. These features were already present in the last common ancestors of fish and mammals, while other characteristics may represent species-specific solutions.
Highlights
The adaptive immune system provides vertebrates with a unique ability to generate antigen-specific memory cells associated with an increased protection against previously encountered pathogens
We analyzed the spleen B cell repertoire at 5 months post-vaccination to characterize the long-term persisting reactive B cells, which we called “memory” following A Radbruch’s definition in Farber et al [25]. This was first performed with a global cost-effective CDR3 spectratyping of all expressed combinations of heavy chain variable (VH) and constant (C) genes, to identify the Ig gene segments implicated in the response and relevant for further analysis by high-throughput sequencing (Supplementary Methods)
Regarding B cells and Ab responses, lack of lymph nodes and germinal centers, slow kinetics of Abs responses, poor affinity maturation are important differences compared to humans and mice
Summary
The adaptive immune system provides vertebrates with a unique ability to generate antigen-specific memory cells associated with an increased protection against previously encountered pathogens Such responses depend on the available immunological repertoire. The global characterization of the antibody (Ab) repertoires of unchallenged mammals and fish has highlighted the presence of highly frequent clonotypes shared between several individuals [5,6,7,8,9]. This observation indicates that repertoires are not determined by likely random rearrangements of Ig gene segments [2, 10]. Certain receptors might be shared between unchallenged controls due to their high generation probability
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