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

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 <i>il7</i> in teleosts, we generated an <i>il7</i> allele lacking most of its coding exons using CRISPR/Cas9-based mutagenesis. <i>il7</i>-deficient animals are viable and exhibit no obvious signs of immune disorder. With respect to intrathymic T cell development, <i>il7</i> deficiency is associated with only a mild reduction of thymocyte numbers, contrasting with a more pronounced impairment of T cell development in <i>il7r</i>-deficient fish. Genetic interaction studies between <i>il7</i> and <i>il7r</i> mutants, and <i>il7</i> and <i>crlf2</i>(<i>tslpr</i>) 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 γ_c 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.