Conserved IL-2Rγc Signaling Mediates Lymphopoiesis in Zebrafish

J Immunol. 2016 Jan 1;196(1):135-43. doi: 10.4049/jimmunol.1403060. Epub 2015 Nov 20.


The IL-2 receptor γ common (IL-2Rγc) chain is the shared subunit of the receptors for the IL-2 family of cytokines, which mediate signaling through JAK3 and various downstream pathways to regulate lymphopoiesis. Inactivating mutations in human IL-2Rγc result in SCID, a primary immunodeficiency characterized by greatly reduced numbers of lymphocytes. This study used bioinformatics, expression analysis, gene ablation, and specific pharmacologic inhibitors to investigate the function of two putative zebrafish IL-2Rγc paralogs, il-2rγc.a and il-2rγc.b, and downstream signaling components during early lymphopoiesis. Expression of il-2rγc.a commenced at 16 h post fertilization (hpf) and rose steadily from 4-6 d postfertilization (dpf) in the developing thymus, with il-2rγc.a expression also confirmed in adult T and B lymphocytes. Transcripts of il-2rγc.b were first observed from 8 hpf, but waned from 16 hpf before reaching maximal expression at 6 dpf, but this was not evident in the thymus. Knockdown of il-2rγc.a, but not il-2rγc.b, substantially reduced embryonic lymphopoiesis without affecting other aspects of hematopoiesis. Specific targeting of zebrafish Jak3 exerted a similar effect on lymphopoiesis, whereas ablation of zebrafish Stat5.1 and pharmacologic inhibition of PI3K and MEK also produced significant but smaller effects. Ablation of il-2rγc.a was further demonstrated to lead to an absence of mature T cells, but not B cells in juvenile fish. These results indicate that conserved IL-2Rγc signaling via JAK3 plays a key role during early zebrafish lymphopoiesis, which can be potentially targeted to generate a zebrafish model of human SCID.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Cell Line
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Janus Kinase 3 / genetics*
  • Lymphopoiesis / genetics
  • Lymphopoiesis / immunology*
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • Morpholinos / genetics
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Interleukin-2 / genetics
  • Receptors, Interleukin-2 / immunology*
  • STAT5 Transcription Factor / genetics
  • Severe Combined Immunodeficiency / genetics
  • Severe Combined Immunodeficiency / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / immunology*


  • Morpholinos
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Interleukin-2
  • STAT5 Transcription Factor
  • Zebrafish Proteins
  • ihb394 protein, zebrafish
  • Janus Kinase 3
  • MAP Kinase Kinase 1