Cytokine Receptor Diversity in the Lamprey Predicts theMinimal 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-g, 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. The Journal of Immunology, 2022, 209: 1Ÿ8.

Learn more: doi:10.4049/jimmunol.220027

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