RT Journal Article
SR Electronic
T1 Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 476697
DO 10.1101/476697
A1 Zinan Zhang
A1 Florian Gothe
A1 Perrine Pennamen
A1 John James
A1 David MacDonald
A1 Carlos P. Mata
A1 Yorgo Modis
A1 Meghan Acres
A1 Wolfram Haller
A1 Claire Bowen
A1 Rainer Doffinger
A1 Jan Sinclair
A1 Shannon Brothers
A1 Anas Alazami
A1 Yu Zhang
A1 Helen Matthews
A1 Sophie Naudion
A1 Fanny Pelluard
A1 Yasuhiro Yamazaki
A1 Luigi Notarangelo
A1 Hamoud Almousa
A1 James Thaventhiran
A1 Karin R. Engelhardt
A1 Sophie Hambleton
A1 Caroline Rooryck
A1 Ken Smith
A1 Michael J. Lenardo
YR 2018
UL http://biorxiv.org/content/early/2018/11/26/476697.abstract
AB Interleukin-2, which conveys essential signals for effective immunity and immunological tolerance, operates through a heterotrimeric receptor comprised of α, β and γ chains. Genetic deficiency of the α or γ chain causes debilitating disease. Here we identify human interleukin-2 receptor (IL-2R) β chain (CD122) gene defects as a cause of life-threatening dysregulation of immunity and peripheral tolerance. We report homozygous mutations in the human IL-2Rβ gene from four consanguineous families, comprising either recessive missense mutations in five children or an early stop-gain mutation in two deceased fetuses and a premature neonate. All patients surviving to childhood presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, and dermatological abnormalities, as well as cytomegalovirus disease in most cases. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to normally respond to high-dose IL-2 stimulation. By contrast, patient natural killer (NK) cells retained partial IL-2Rβ expression and cytotoxic function. IL-2Rβ loss of function was recapitulated in a recombinant system, in which endoplasmic reticulum sequestration was revealed as the mechanism by which certain missense mutations cause disease. Hematopoietic stem cell transplant resulted in resolution of clinical symptoms in one patient. The hypomorphic nature of this disease highlights the significance of variable IL-2Rβ expression in different lymphocyte subsets as a means of modulating immune function. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.