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Cytidine deaminase 2 is required for VLRB antibody gene assembly in lampreys

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Science Immunology  13 Mar 2020:
Vol. 5, Issue 45, eaba0925
DOI: 10.1126/sciimmunol.aba0925

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Antibody assembly in lampreys

For B lymphocytes in jawless vertebrates to produce antibodies, a combination of VLRB gene cassettes must be stitched together to create a functional antibody gene. Circumstantial evidence based on gene expression data had previously implicated the CDA2 cytidine deaminase in this process but genetic proof was lacking. By devising techniques for CRIPSR-Cas9–mediated mutagenesis of in vitro fertilized lamprey eggs and subsequent rearing of lamprey larvae in the laboratory, Morimoto et al. showed that loss-of-function mutations in CDA2 result in loss of antibody gene assembly without disrupting the formation of functional genes encoding lamprey T cell receptors. The methods pioneered in this study establish lampreys as a genetically tractable model system and will facilitate further advances in understanding immunity in this ancient group of vertebrates.

Abstract

The antibodies of jawless vertebrates consist of leucine-rich repeat arrays encoded by somatically assembled VLRB genes. It is unknown how the incomplete germline VLRB loci are converted into functional antibody genes during B lymphocyte development in lampreys. In Lampetra planeri larvae lacking the cytidine deaminase CDA2 gene, VLRB assembly fails, whereas the T lineage–associated VLRA and VLRC antigen receptor gene assemblies occur normally. Thus, CDA2 acts in a B cell lineage–specific fashion to support the somatic diversification of VLRB antibody genes. CDA2 is closely related to activation-induced cytidine deaminase (AID), which is essential for the elaboration of immunoglobulin gene repertoires in jawed vertebrates. Our results thus identify a convergent mechanism of antigen receptor gene assembly and diversification that independently evolved in the two sister branches of vertebrates.

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