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.

Isabel Z Fernandez ^# ¹, Ryan M Baxter ^# ¹, Josselyn E Garcia-Perez ¹, Elena Vendrame ², Thanmayi Ranganath ², Daniel S Kong ¹, Karl Lundquist ³, Tom Nguyen ⁴, Sidney Ogolla ¹, Jennifer Black ⁵, Csaba Galambos ⁵, James C Gumbart ³, Noor Dawany ⁶, Judith R Kelsen ⁷, Edwin F de Zoeten ⁴, Ralph Quinones ⁸, Hesham Eissa ⁸, Michael R Verneris ⁸, Kathleen E Sullivan ⁹, Rosemary Rochford ¹, Catherine A Blish ² ¹⁰, Ross M Kedl ^# ¹¹, Cullen M Dutmer ^# ¹², Elena W Y Hsieh ^# ¹³ ¹⁴

Affiliations

1 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
2 Department of Medicine, Stanford University School of Medicine, Stanford, CA.
3 School of Physics, Georgia Institute of Technology, Atlanta, GA.
4 Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO.
5 Department of Pathology and Laboratory Medicine, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.
6 Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA.
7 Department of Pediatrics, Division of Gastroenterology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
8 Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.
9 Department of Pediatrics, Division of Allergy and Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
10 Immunology Program, School of Medicine, Stanford University, Stanford, CA.
11 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO ross.kedl@ucdenver.edu.
12 Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO cullen.dutmer@childrenscolorado.org.
13 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO elena.hsieh@ucdenver.edu.
14 Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.
# Contributed equally.

PMID: 31040184 DOI: 10.1084/jem.20182015

Abstract

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 CD56^bright 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.

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