Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance

• DOI: 10.1084/jem.20182304
• Publication Date: 2019-04-30T18:47:39Z
• Authors: Zinan Zhang; Florian Gothe; Perrine Pennamen; John R. James; David McDonald; Carlos P. Mata; Yorgo Modis; Anas M. Alazami; Meghan Acres; Wolfram Haller; Claire Bowen; Rainer Döffinger; Jan Sinclair; Shannon Brothers; Yu Zhang; Helen F. Matthews; Sophie Naudion; Fanny Pelluard; Huda Alajlan; Yasuhiro Yamazaki; Luigi D. Notarangelo; James E. Thaventh...; Karin R. Engelhardt; Hamoud Al-Mousa; Sophie Hambleton; Caroline Rooryck; Kenneth G.C. Smith; Michael J. Lenardo
• Keywords: Peripheral tolerance

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (IL2RB) gene defects as cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB eight individuals from four consanguineous families that disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression IL-2Rβ were unable to respond IL-2 stimulation. By contrast, natural killer cells retained partial function. loss function was recapitulated recombinant system caused reduced binding. Stem cell transplant ameliorated clinical symptoms one patient; forced wild-type also increased responsiveness patient vitro. Insights these can inform development IL-2-based therapeutics immunological diseases cancer.