GSE136250
Evolutionary transition from degenerate to non-redundant cytokine signaling networks supporting intrathymic T cell development
In mammals, T cell development in the thymus is critically dependent on the presence of the IL7 cytokine. Here, we describe the identification of the zebrafish ortholog of mammalian IL7, based on chromosomal localization, expression patterns, and deduced protein sequence. 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 mild a reduction of thymocytes, contrasting with the much stronger reduction of T cell development il7r-deficient fish. Genetic interaction studies between il7 and crlf2(tslpr) suggest the contribution of an additional, as yet unidentified cytokine(s) 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 multi-component network of gc cytokines. This network configuration thus explains why deficiencies of single components have little detrimental effect. By contrast, the dependence on a single cytokine in the mammalian thymus has catastrophic consequences in case of congenital deficiencies in genes affecting the IL7 signaling pathway. We speculate that the transition from a degenerate to a non-redundant cytokine network supporting intrathymic T cell development emerged as the consequence of repurposing evolutionary ancient constitutive cytokine pathways for regulatory functions in the mammalian peripheral immune system. Overall design: The experiments aimed at identifying the role of the il7 cytokine in lymphocyte development of zebrafish. The transcriptomes of whole kidney marrow in wild-type and il7 mutant fish were compared for differences in expression levels