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

18 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

Bibliographical note

We thank Mrs. Susann Schares and Katrin Giesow for excellent technical assistance and Dr. Gunther Keil for his valuable advice regarding expression of recombinant proteins in insect cells. We also thank Prof. Oriol Sunyer from the University of Pennsylvania, USA, for providing us mAbs against rainbow trout CD4. A large part of this manuscript has been released as a pre-print (116).

TY and UF were supported by the EU FP7 Grant 311993 (TARGETFISH) and the German Research Council Grant No. FI 604/7-1. JD was supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan, Grants-in-Aid for Scientific Research No. 25450319. TW received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland), that was funded by the Scottish Funding Council (grant reference HR09011). EW was supported by the Ministry of Science and Technology of Thailand and Mahasarakham University.


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


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