Towards identification of the unifying principles of vertebrate adaptive immunity

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About 500 million years ago, the two sister groups of vertebrates independently evolved alternative forms of adaptive immunity, representing a striking example of convergent evolution. Whereas the components and functions of the immune system in jawed vertebrates (ranging from sharks to humans) are well characterized, much remains to be learned about adaptive immunity in jawless vertebrates (lampreys and hagfishes). Up to now, progress in understanding immunity in jawless fishes was hampered by their complex life-cycle, long generation time, and the difficulty of raising fish in the laboratory for extended periods, particularly after in vitro fertilization. Based on our recent methodological advances in aquatic husbandry and successful CRISPR/Cas9-mediated genetic modification, we propose to conduct a large-scale analysis of cellular immunity in lampreys laying the foundations for the identification of the unifying principles of vertebrate immunity. Our experiments will address the development and characteristics of different T cell subsets, the molecular basis of antigen receptor assembly, and the function of the two principal T cell lineages during the immune response. We will also examine the structure and function of the stromal microenvironment in the lamprey thymus equivalent, which is considered to be the site of T cell development. A particular focus will be on the functional analysis of a recently discovered MHC-like locus in the context of T cell development, and in the essential self/nonself discrimination mechanism(s) at play during the immune response. We expect that the identification of common design principles of adaptive immunity in vertebrates will provide us with an unprecedented view on immune functions in humans, potentially guiding the development of novel strategies for the treatment of failing immunity in patients with immunodeficiency and/or autoimmunity.