Functional characterization of a nonmammalian IL-21: Rainbow trout Oncorhynchus mykiss IL-21 upregulates the expression of the Th cell signature cytokines IFN-γ, IL-10, and IL-22

T. Wang, P. Diaz-Rosales, M.M. Costa, S.A.M. Martin, S. Campbell, M. Snow, B. Collet, C.J. Secombes

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In mammals, IL-21 is a common γ chain cytokine produced by activated CD4+ T cells and NKT cells that acts on multiple lineages of cells. Although IL-21 has also been discovered in birds, amphibians, and fish, to date, no functional studies have been reported for any nonmammalian IL-21 molecule. We have sequenced an IL-21 gene (tIL-21) in rainbow trout, which has a six-exon/five-intron structure, is expressed in immune tissues, and is induced by bacterial and viral infection and the T cell stimulant PHA. In contrast to mammals, calcium ionophore and PMA act synergistically to induce tIL-21. Recombinant tIL-21 (rtIL-21) induced a rapid and long-lasting (4–72 h) induction of expression of IFN-γ, IL-10, and IL-22, signature cytokines for Th1-, Th2-, and Th17-type responses, respectively, in head kidney leukocytes. However, rtIL-21 had little effects on the expression of other cytokines studied. rtIL-21 maintained the expression of CD8α, CD8β, and IgM at a late stage of stimulation when their expression was significantly decreased in controls and increased the expression of the Th cell markers CD4, T-bet, and GATA3. Intraperitoneal injection of rtIL-21 confirmed the in vitro bioactivity and increased the expression of IFN-γ, IL-10, IL-21, IL-22, CD8, and IgM. Inhibition experiments revealed that the activation of JAK/STAT3, Akt1/2, and PI3K pathways were responsible for rtIL-21 action. This study helps to clarify the role of IL-21 in lower vertebrates for the first time, to our knowledge, and suggests IL-21 is a likely key regulator of T and B cell function in fish.
Original languageEnglish
Pages (from-to)708-721
Number of pages14
JournalThe Journal of Immunology
Issue number2
Early online date15 Dec 2010
Publication statusPublished - 15 Jan 2011



  • Amino Acid Sequence
  • Animals
  • Cloning, Molecular
  • Interferon-gamma
  • Interleukin-10
  • Interleukins
  • Molecular Sequence Data
  • Novirhabdovirus
  • Oncorhynchus mykiss
  • Rhabdoviridae Infections
  • T-Lymphocytes, Helper-Inducer
  • Up-Regulation
  • Yersinia Infections
  • Yersinia ruckeri

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