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

Accepted version
Peer-reviewed

Type

Article

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Authors

Gothe, Florian 
Pennamen, Perrine 
James, John R 
McDonald, David 

Abstract

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 a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause 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 of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

Description

Keywords

Alleles, Autoimmunity, Genotype, HEK293 Cells, Humans, Immune Tolerance, Immunity, Immunologic Deficiency Syndromes, Interleukin-2 Receptor beta Subunit, Killer Cells, Natural, Lentivirus, Mutation, Mutation, Missense, Phenotype, Phosphorylation, STAT3 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, T-Lymphocytes

Journal Title

J Exp Med

Conference Name

Journal ISSN

0022-1007
1540-9538

Volume Title

216

Publisher

Rockefeller University Press

Rights

All rights reserved
Sponsorship
Wellcome Trust (083650/Z/07/Z)
Wellcome Trust (101908/Z/13/Z)
Wellcome Trust (099966/Z/12/Z)