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

Lookup NU author(s): Dr Florian Gothe, Dr David McDonald, Dr Meghan Acres, Dr Karin Engelhardt, Professor Sophie HambletonORCiD



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Rockefeller University Press, 2019.

For re-use rights please refer to the publisher's terms and conditions.


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.

Publication metadata

Author(s): Zhang Z, Gothe F, Pennamen P, James JR, McDonald D, Mata CP, Modis Y, Alazami AM, Acres M, Haller W, Bowen C, Doffinger R, Sinclair J, Brothers S, Zhang Y, Matthews H, Naudion S, Pelluard F, Alajlan H, Yamazaki Y, Notarangelo LD, Thaventhiran JED, Engelhardt KR, Al-Mousa H, Hambleton S, Rooryck C, Smith KGC, Lenardo MJ

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2019

Volume: 216

Issue: 6

Pages: 1311-1327

Print publication date: 30/04/2019

Online publication date: 30/04/2019

Acceptance date: 04/04/2019

Date deposited: 07/05/2019

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press


DOI: 10.1084/jem.20182304


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