A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation

J Exp Med. 2019 Jun 3;216(6):1255-1267. doi: 10.1084/jem.20182015. Epub 2019 Apr 30.


The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rβ, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rβ, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rβ surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rβ-/- animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rβ expression and signaling in T and NK cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Autoimmunity / genetics
  • Cell Compartmentation
  • Cell Proliferation / genetics
  • Cytomegalovirus Infections / genetics
  • Cytomegalovirus Infections / immunology
  • Homozygote
  • Humans
  • Immunophenotyping
  • Interleukin-15 / metabolism
  • Interleukin-2 / metabolism
  • Interleukin-2 Receptor beta Subunit / chemistry
  • Interleukin-2 Receptor beta Subunit / genetics*
  • Killer Cells, Natural / immunology*
  • Models, Molecular
  • Mutation / genetics*
  • Phenotype
  • Siblings
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • Treatment Outcome


  • IL2RB protein, human
  • Interleukin-15
  • Interleukin-2
  • Interleukin-2 Receptor beta Subunit