A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells |
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Authors: | Taco W Kuijpers Ester MM van Leeuwen Barbara H Barendregt Paul Klarenbeek Daan J aan de Kerk Paul A Baars Machiel H Jansen Niek de Vries René AW van Lier Mirjam van der Burg |
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Affiliation: | 1.Emma Children’s Hospital, Academic Medical Center (AMC), Amsterdam, The Netherlands;2.Department of Experimental Immunology, AMC, The Netherlands;3.Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;4.Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;5.Department of Clinical Immunology and Rheumatology, AMC, The Netherlands |
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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. |
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