title: Patients with T⁺/low NK⁺ IL-2 receptor γ chain deficiency have differentially-impaired cytokine signaling resulting in severe combined immunodeficiency.
abstract: X-linked severe combined immunodeficiency (X-SCID) leads to a T(-) NK(-) B(+) immunophenotype and is caused by mutations in the gene encoding the IL-2 receptor γ-chain (IL2RG). IL2RG(R222C) leads to atypical SCID with a severe early onset phenotype despite largely normal NK- and T-cell numbers. To address this discrepancy, we performed a detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL-2, IL-4, IL-15, and IL-21 in a patient with the IL2RG(R222C) mutation. Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations. T-cell development was variably affected, but led to borderline T-cell receptor excision circle (TREC) levels and a normal repertoire. T cells showed moderately reduced proliferation, failing enhancement by IL-2. While NK-cell development was normal, IL-2 enhancement of NK-cell degranulation and IL-15-induced cytokine production were absent. IL-2 or IL-21 failed to enhance B-cell proliferation and plasmablast differentiation. These functional alterations were reflected by a differential impact of IL2RG(R222C) on cytokine signal transduction, with a gradient IL-4<IL-2/IL-15<IL-21. Thus, IL2RG(R222C) causes a consistently severe clinical phenotype that is not predicted by the variable and moderate impairment of T-cell immunity or TREC analysis.
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.forename: Thomas
authors.initials: T
authors.lastname: Vraetz
authors.forename: Lara
authors.initials: L
authors.lastname: Hartjes
authors.forename: Ales
authors.initials: A
authors.lastname: Janda
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.forename: Myriam R
authors.initials: MR
authors.lastname: Lorenz
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilmour
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint-Basile
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.forename: Steven
authors.initials: S
authors.lastname: Cheuk
authors.forename: Andrew
authors.initials: A
authors.lastname: Gennery
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Ilka
authors.initials: I
authors.lastname: Fuchs
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D009154:Mutation; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016207:Cytokines; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit
keywords: Atypical SCID; Common gamma chain; Cytokine signaling; Leaky SCID; Severe combined immunodeficiency