Cytokine Receptor Diversity in the Lamprey Predicts the Minimal Essential Cytokine Networks of Vertebrates

The vertebrate adaptive immune systems (Agnatha and Gnathostomata) use sets of T and B lymphocyte lineages that somatically generate highly diverse repertoires of Ag-specific receptors and Abs. In Gnathostomata, cytokine networks regulate the activation of lymphoid and myeloid cells, whereas little is known about these components in Agnathans. Most gnathostome cytokines are four-helix bundle cytokines with poorly conserved primary sequences. In contrast, sequence conservation across bilaterians has been observed for cognate cytokine receptor chains, allowing their structural classification into two classes, and for downstream JAK/STAT signaling mediators. With conserved numbers among Gnathostomata, human cytokine receptor chains (comprising 34 class I and 12 class II) are able to interact with 28 class I helical cytokines (including most ILs) and 16 class II cytokines (including all IFNs), respectively. Hypothesizing that the arsenal of cytokine receptors and transducers may reflect homologous cytokine networks, we analyzed the lamprey genome and transcriptome to identify genes and transcripts for 23 class I and five class II cytokine receptors alongside one JAK signal mediator and four STAT transcription factors. On the basis of deduction of their respective orthologs, we predict that these receptors may interact with 16 class I and 3 class II helical cytokines (including IL-4, IL-6, IL-7, IL-12, IL-10, IFN-γ, and thymic stromal lymphoprotein homologs). On the basis of their respective activities in mammals, this analysis suggests the existence of lamprey cytokine networks that may regulate myeloid and lymphoid cell differentiation, including potential Th1/Th2 polarization. The predicted networks thus appear remarkably homologous to those of Gnathostomata, albeit reduced to essential functions.