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Degenerate to Nonredundant Cytokine Signaling Networks in Support of Intrathymic T Cell Development: An Evolutionary Transition

By 10th February 2020No Comments

The following study was conducted by Scientists from Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. Study is published in Proceedings of the National Academy of Sciences Journal as detailed below.

Proceedings of the National Academy of Sciences; 116(52): 26759-26767

Evolutionary Transition from Degenerate to Nonredundant Cytokine Signaling Networks Supporting Intrathymic T Cell Development


In mammals, intrathymic T cell development strictly depends on the activity of the IL-7 cytokine signaling pathway, leading to catastrophic immunodeficiency when even 1 of the components in the pathway fails. Here we report the unexpected observation that the development of T cells in the thymus of the teleost Danio rerio (zebrafish) is instead supported by the collective actions of several cytokine signaling pathways, with IL-7 signaling playing only a minor role. This finding suggests that during the course of evolution, a degenerate network was converted into a state of precarious brittleness, possibly because some of the evolutionarily ancient constitutive cytokine pathways had to be repurposed to meet increased demands for sophisticated regulation during the mammalian immune response.


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.


Proceedings of the National Academy of Sciences



Lawir, D.-F., I. Hess, et al. (2019). “Evolutionary transition from degenerate to nonredundant cytokine signaling networks supporting intrathymic T cell development.” Proceedings of the National Academy of Sciences 116(52): 26759-26767.