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- Title
Patients with T<sup>+/low</sup> NK<sup>+</sup> IL-2 receptor γ chain deficiency have differentially-impaired cytokine signaling resulting in severe combined immunodeficiency.
- Authors
Fuchs, Sebastian; Rensing‐Ehl, Anne; Erlacher, Miriam; Vraetz, Thomas; Hartjes, Lara; Janda, Ales; Rizzi, Marta; Lorenz, Myriam R.; Gilmour, Kimberly; Saint‐Basile, Geneviève; Roifman, Chaim M.; Cheuk, Steven; Gennery, Andrew; Thrasher, Adrian J.; Fuchs, Ilka; Schwarz, Klaus; Speckmann, Carsten; Ehl, Stephan
- 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). IL2RGR222C 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 IL2RGR222C 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 Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations.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 IL2RGR222C on cytokine signal transduction, with a gradient IL-4<IL-2/IL-15<IL-21. Thus, IL2RGR222C causes a consistently severe clinical phenotype that is not predicted by the variable and moderate impairment of T-cell immunity or TREC analysis.
- Publication
European Journal of Immunology, 2014, Vol 44, Issue 10, p3129
- ISSN
0014-2980
- Publication type
Article
- DOI
10.1002/eji.201444689