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Evolutionary transition from degenerate to nonredundant cytokine signaling networks supporting intrathymic T cell development

MPS-Authors

Lawir,  Divine-Fondzenyuy
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Hess,  Isabell
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sikora,  Katarzyna
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Iwanami,  Norimasa
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Siamishi,  Iliana
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Schorpp,  Michael
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Boehm,  Thomas
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Lawir, D.-F., Hess, I., Sikora, K., Iwanami, N., Siamishi, I., Schorpp, M., et al. (2019). Evolutionary transition from degenerate to nonredundant cytokine signaling networks supporting intrathymic T cell development. Proceedings of the National Academy of Sciences of the United States of America, 116, 26759-26767. doi:org/10.1073/pnas.1915223116.


Cite as: http://hdl.handle.net/21.11116/0000-0005-61DA-8
Abstract
In mammals, T cell development critically depends on the IL-7 cytokine signaling pathway. Here we describe the identification of the zebrafish ortholog of mammalian IL-7 based on chromosomal localization, deduced protein sequence, and expression patterns. To examine the biological role of il7 in teleosts, we generated an il7 allele lacking most of its coding exons using CRISPR/Cas9-based mutagenesis. il7-deficient animals are viable and exhibit no obvious signs of immune disorder. With respect to intrathymic T cell development, il7 deficiency is associated with only a mild reduction of thymocyte numbers, contrasting with a more pronounced impairment of T cell development in il7r-deficient fish. Genetic interaction studies between il7 and il7r mutants, and il7 and crlf2(tslpr) mutants suggest the contribution of additional, as-yet unidentified cytokines to intrathymic T cell development. Such activities were also ascertained for other cytokines, such as il2 and il15, collectively indicating that in contrast to the situation in mammals, T cell development in the thymus of teleosts is driven by a degenerate multicomponent network of γc cytokines; this explains why deficiencies of single components have little detrimental effect. In contrast, the dependence on a single cytokine in the mammalian thymus has catastrophic consequences in cases of congenital deficiencies in genes affecting the IL-7 signaling pathway. We speculate that the transition from a degenerate to a nonredundant cytokine network supporting intrathymic T cell development emerged as a consequence of repurposing evolutionarily ancient constitutive cytokine pathways for regulatory functions in the mammalian peripheral immune system.