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Yet the evolutionary origins of such systems remain incompletely understood. In this review, we examine adaptive immunity from a comparative perspective across Metazoa, focusing on the design principles that link molecular diversification, immune cell differentiation, and proliferative dynamics. We first outline the two adaptive immune architectures found in vertebrates. Jawed vertebrates employ immunoglobulin-based and T-cell receptor-based recognition generated through recombination-activating gene (RAG)-mediated V(D)J recombination, whereas jawless vertebrates assemble variable lymphocyte receptors using cytidine-deaminase-dependent diversification of leucine-rich repeat modules. Despite their distinct molecular entities, these systems converge on shared design principles, including somatic diversification, developmental restriction of genome editing, immune cell differentiation, and specialized microenvironments for immune education. To introduce evolutionarily more ancient systems, several diversification mechanisms of antigen receptors in invertebrates will be subsequently surveyed. These systems generate substantial molecular diversity without canonical clonal selection, suggesting that immune recognition and diversification can be achieved through multiple evolutionary strategies. Particular attention is given to emerging insights into invertebrate immune cell diversification, where single-cell transcriptomics is revealing complex hematopoietic lineages and regulatory programs. These observations suggest that adaptive immunity did not emerge abruptly but rather represents one solution within a broader evolutionary landscape of immune diversification strategies. Understanding how diversification, proliferation, and cellular organization interact across animal lineages will help clarify the fundamental design constraints that shaped the evolution of vertebrate adaptive immune systems.<\/jats:p>","DOI":"10.1093\/intimm\/dxag018","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T11:35:13Z","timestamp":1776166513000},"page":"482-493","source":"Crossref","is-referenced-by-count":0,"title":["Multiple evolutionary routes to immune diversification across animals"],"prefix":"10.1093","volume":"38","author":[{"given":"Mizuki","family":"Taguchi","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Ume\u00e5 University , Ume\u00e5 901 87 ,","place":["Sweden"]},{"name":"The Laboratory for Molecular Infection Medicine, Sweden (MIMS), Ume\u00e5 University , Ume\u00e5 901 87 ,","place":["Sweden"]},{"name":"Ume\u00e5 Centre for Microbial Research (UCMR), Ume\u00e5 University , Ume\u00e5 901 87 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"de La Forest Divonne","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Ume\u00e5 University , Ume\u00e5 901 87 ,","place":["Sweden"]},{"name":"The Laboratory for Molecular Infection Medicine, Sweden (MIMS), Ume\u00e5 University , Ume\u00e5 901 87 ,","place":["Sweden"]},{"name":"Ume\u00e5 Centre for Microbial Research (UCMR), Ume\u00e5 University , Ume\u00e5 901 87 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5497-4666","authenticated-orcid":false,"given":"Ryo","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Ume\u00e5 University , Ume\u00e5 901 87 ,","place":["Sweden"]},{"name":"The Laboratory for Molecular Infection Medicine, Sweden (MIMS), Ume\u00e5 University , Ume\u00e5 901 87 ,","place":["Sweden"]},{"name":"Ume\u00e5 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