Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response

Takuya Yamaguchi, Chia Jung Chang, Axel Karger, Markus Keller, Florian Pfaff, Eakapol Wangkahart, Tiehui Wang, Christopher J. Secombes, Azusa Kimoto, Mitsuru Furihata, Keiichiro Hashimoto, Uwe Fischer*, Johannes M. Dijkstra

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)
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Related interleukin-2, -15, and -15-like (IL-2, -15, and -15L) are ancient cytokines, with all three genes surviving in extant fish and some mammals. The present study is the first to identify IL-15L functions, namely in rainbow trout. In isolated trout splenocytes, and in vivo, purified recombinant IL-15L+IL-15Rα molecules induced expression of IL-4 and IL-13 homologs, which are markers of type 2 immunity. In contrast, trout IL-15 stimulated type 1 immunity markers, thus IL-15 and IL-15L can have opposing functions. Trout IL-15L was more dependent on “in trans” presentation by the receptor chain IL-15Rα than IL-15, and stimulated CD4CD8(IgM) lymphocytes from thymus and spleen. We propose an important role for IL-15L early in the type 2 immunity cytokine cascade. Trout IL-2 and IL-15 exhibited features reminiscent of their mechanistic and functional dichotomy observed in mammals; for example, IL-15 but not IL-2 required a receptor alpha chain (only IL-15Rα in the case of fish) for its stability, and only IL-15 was efficient in stimulating lymphocytes from mucosal tissues. Data suggest that IL-15L and IL-15 may be particularly effective in stimulating innate lymphocyte type 2 cells (ILC2) and natural killer (NK) cells, respectively, but further identification of the cell types is needed. An interesting finding different from in mammals was the efficient stimulation of CD4+CD8+ thymocytes by IL-2. In short, this study presents fundamental information on the evolution of the IL-2/15/15L cytokine family.

Original languageEnglish
Article number549319
Number of pages30
JournalFrontiers in Immunology
Publication statusPublished - 29 Oct 2020


  • evolution
  • fish
  • IL-15
  • IL-15-like
  • IL-15Rα
  • IL-2
  • type 2 immunity


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