The adaptive immune system of jawless vertebrates

• Applicant: Dr. Thomas Boehm
• Subject Area: Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545620134

About 500 million years ago, the first vertebrates emerged, featuring a radically restructured immune system. Novel adaptive immune facilities became integrated with sophisticated but largely stereotyped evolutionarily ancient innate immune functions. Surprisingly, adaptive immunity appears to evolved independently at least twice in the early phases of vertebrate evolution. Jawed vertebrates comprising more than 60,000 species ranging from cartilaginous fishes to humans rely on the Rag1/2-mediated assembly of immunoglobulin domain-encoding modules to form antiboda and T cell receptor genes; by contrast, the ~ 200 species of jawless vertebrates (lampreys and hagfishes) rely on the cytidine deaminase (CDA)-mediated assembly of leucine rich domain-encoding genomic cassettes to form functional variable lymphocyte receptor genes (VLRs). The mechanisms underlying the development of the immune system of jawed vertebrates are well known; by contrast, the study of the immune system of lampreys/hagfishes is in its infancy. The current project aims at elucidating the cellular and molecular determinants of the lamprey lymphoid system, capitalizing on our recent advances in lamprey husbandry and genetic interrogation using the CRISPR/Cas9 system. Specifically, we aim at establishing the key features of (i) lymphocyte lineage development to distinguish the various B- and T-like lineages; (ii) the formation of lymphoid organs, such as the thymus-equivalent (thymoid) and general haematopoietic organs, and the distribution of lymphocytes in different organs, with a focus on mucosal sites and the gut; (iii) the diversity of primary VLR repertoires and their subsequent modification via selection and in the context of immune reactions. Moreover, we will, (iv) work towards the establishment of in vitro systems to examine cytidine deaminase-based assembly of VLR genes, to determine the substrate- and species-specific characteristics of these reactions. The detailed description of the lamprey lymphoid system arising from these studies will form the basis for clade-specific comparisons to illuminate the design principles of adaptive immunity in vertebrates and to reconstruct the characteristics of the immune system of the common vertebrate ancestor.

• DFG Programme: Reinhart Koselleck Projects