title: A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells.
abstract: Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B(+)T(-)NK(-) X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8(+) T cells and increased over time. Only the revertant CD8(+) T cells showed normal expression of CD132 and the various CD8(+) T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ(+) T cells and differentiated CD4(+)CD27(-) effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8(+) T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells.
authors: Emma Children's Hospital, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors: Taco W
authors: TW
authors: Kuijpers
authors: Ester M M
authors: EM
authors: van Leeuwen
authors: Barbara H
authors: BH
authors: Barendregt
authors: Paul
authors: P
authors: Klarenbeek
authors: Daan J
authors: DJ
authors: aan de Kerk
authors: Paul A
authors: PA
authors: Baars
authors: Machiel H
authors: MH
authors: Jansen
authors: Niek
authors: N
authors: de Vries
authors: René A W
authors: RA
authors: van Lier
authors: Mirjam
authors: M
authors: van der Burg
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D049109:Cell Proliferation; D002648:Child; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics* / Q000502:physiology; D018655:Lymphocyte Count; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology
chemical_list: C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit
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