Partial T cell defects and expanded CD56bright NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene

Cristina Cifaldi, Nicola Cotugno, Silvia Di Cesare, Silvia Giliani, Gigliola Di Matteo, Donato Amodio, Eva Piano Mortari, Maria Chiriaco, Danilo Buonsenso, Paola Zangari, Daria Pagliara, Stefania Gaspari, Rita Carsetti, Paolo Palma, Andrea Finocchi, Franco Locatelli, Paolo Rossi, Margherita Doria, Caterina Cancrini

Research output: Contribution to journalArticlepeer-review


X-linked severe combined immunodeficiency (X-SCID) caused by full mutation of the IL2RG gene leads to T B+ NK phenotype and is usually associated with severe opportunistic infections, diarrhea, and failure to thrive. When IL2RG hypomorphic mutation occurs, diagnosis could be delayed and challenging since only moderate reduction of T and NK cells may be present. Here, we explored phenotypic insights and the impact of the p.R222C hypomorphic mutation (IL2RGR222C) in distinct cell subsets in an 8-month-old patient with atypical X-SCID. We found reduced CD4+ T cell counts, a decreased frequency of naïve CD4+ and CD8+ T cells, and an expansion of B cells. Ex vivo STAT5 phosphorylation was impaired in CD4+CD45RO+ T cells, yet compensated by supraphysiological doses of IL-2. Sanger sequencing on purified cell subsets showed a partial reversion of the mutation in total CD3+ cells, specifically in recent thymic emigrants (RTE), effector memory (EM), and CD45RA+ terminally differentiated EM (EMRA) CD4+ T cells. Of note, patient's NK cells had a normal frequency compared to age-matched healthy subjects, but displayed an expansion of CD56bright cells with higher perforin content and cytotoxic potential, associated with accumulation of NK-cell stimulatory cytokines (IL-2, IL-7, IL-15). Overall, this report highlights an alteration in the NK-cell compartment that, together with the high disease-phenotype variability, should be considered in the suspicion of X-SCID with hypomorphic IL2RG mutation.

Original languageEnglish
Pages (from-to)739-748
Number of pages10
JournalJournal of Leukocyte Biology
Issue number2
Publication statusPublished - Aug 1 2020


  • common gamma chain
  • cytokine signaling
  • primary immune deficiency

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology


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