Periodic Reporting for period 4 - ImmUne (Towards identification of the unifying principles of vertebrate adaptive immunity)
Okres sprawozdawczy: 2023-12-01 do 2024-11-30
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). The ImmUne project has addressed the development of lymphocyte lineages, identifying several T cell lineages, and the structure of primary lymphoid organs, focusing on the thymus equivalent, and has identified the first components of a quality control system that ensures the generation and selection of a self-tolerant repertoire of somatically diversifying antigen receptors. Our results indicate that whereas the cellular aspects of the adaptive immune system of lampreys are very similar to those known from jawed vertebrates, the molecular underpinnings of antigen receptor structure, assembly, and selection in lampreys differ substantially. Our results thus illuminate an alternative solution to the problem of adaptive immunity in this distinct branch of vertebrates, and highlight a unique case of convergent evolution.
Work in the ImmUne project has delivered a number of important results.
(1) We have determined the molecular characteristics of thymopoioetic transcription factors of the Foxn1/4 gene family. The results show that the evolutionarily malleable part resides in the N-terminal protein domain. Remarkably, replacement of the lamprey Foxn1 gene for a mutated mouse Foxn1 gene results in complete functional rescue of T cell development. (2) We have found that lamprey possess no less than six VLR isotypes, five of which define distinct T cell lineages. This result was entirely unexpected; it indicates that functional diversity in lampreys does not depend on differentiation of cells with the same antigen receptor, but rather appears to be distributed among cells expressing distinct receptors. (3) We have found that antigen receptor selection on the T cell lineage depends on a kind of molecular ruler, determining an optimal number of LRR repeats of the receptors. Accordingly, we have identified a polymorphic gene family that appears to be required for the generation of the T cell lineage. Ongoing studies aim at determining the molecular mechanism by which the selector elements and VLR receptors interact. (4) Unlike the situation in jawed vertebrates, where on recombinase is responsible for antigen receptor assembly, lampreys have recruited the descendants of an ancient cytidine deaminase to assemble the VLR receptors; remarkably their action is lineage-specific, with the B cell lineage-cytidien deaminase being most similar to the AID enzyme known from jawed vertebartes. This result strongly suggests that cytidine deaminases of all vertebrates have a common origin and that they represent the primordial mechanism for somatic assembly of incomplete antigen receptor genes.
The results emerging from the ImmUne project are in the final stages of analysis and will be made public in a timely fashion.
(1) We have determined the molecular characteristics of thymopoioetic transcription factors of the Foxn1/4 gene family. The results show that the evolutionarily malleable part resides in the N-terminal protein domain. Remarkably, replacement of the lamprey Foxn1 gene for a mutated mouse Foxn1 gene results in complete functional rescue of T cell development. (2) We have found that lamprey possess no less than six VLR isotypes, five of which define distinct T cell lineages. This result was entirely unexpected; it indicates that functional diversity in lampreys does not depend on differentiation of cells with the same antigen receptor, but rather appears to be distributed among cells expressing distinct receptors. (3) We have found that antigen receptor selection on the T cell lineage depends on a kind of molecular ruler, determining an optimal number of LRR repeats of the receptors. Accordingly, we have identified a polymorphic gene family that appears to be required for the generation of the T cell lineage. Ongoing studies aim at determining the molecular mechanism by which the selector elements and VLR receptors interact. (4) Unlike the situation in jawed vertebrates, where on recombinase is responsible for antigen receptor assembly, lampreys have recruited the descendants of an ancient cytidine deaminase to assemble the VLR receptors; remarkably their action is lineage-specific, with the B cell lineage-cytidien deaminase being most similar to the AID enzyme known from jawed vertebartes. This result strongly suggests that cytidine deaminases of all vertebrates have a common origin and that they represent the primordial mechanism for somatic assembly of incomplete antigen receptor genes.
The results emerging from the ImmUne project are in the final stages of analysis and will be made public in a timely fashion.
Our work has identified common design principles of adaptive immunity in vertebrates, and has highlighted critical differences. Moreover, our results illuminate a remarkable combination of innovation and domestication that resulted in the emergence of adaptive immunity in early vertebrates. Because convergent evolution has left such an important mark on vertebrate immunity, we expect that continued research will more firmly establish the evolutionary trajectory of vertebrate immune systems and will provide a view on its future plasticity, which potentially is relevant with respect to the assessment of future zoonotic infections.