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.

CD8+ T lymphocyte, IL2RG gene, X chromosome, acrodermatitis, article, case report, cell proliferation, child, computed tomography scanner, controlled study, enzyme linked immunosorbent assay, flow cytometry, gene, gene mutation, genotype, histogram, human, human tissue, humoral immunity, immune deficiency, immunofluorescence test, male, molluscum contagiosum, nucleotide sequence, peripheral blood mononuclear cell, pneumonia, preschool child, protein expression, sequence analysis,
Erasmus MC: University Medical Center Rotterdam

Kuijpers, T.W, van Leeuwen, E.M.M, Barendregt, B.H, Klarenbeek, P, Aan de Kerk, D.J, Baars, P.A, … van der Burg, M. (2013). A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells. Haematologica, 98(7), 1030–1038. doi:10.3324/haematol.2012.077511