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.

Partial T cell defects and expanded CD56bright NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene / Cifaldi, C.; Cotugno, N.; Di Cesare, S.; Giliani, S.; Di Matteo, G.; Amodio, D.; Piano Mortari, E.; Chiriaco, M.; Buonsenso, D.; Zangari, P.; Pagliara, D.; Gaspari, S.; Carsetti, R.; Palma, P.; Finocchi, A.; Locatelli, F.; Rossi, P.; Doria, M.; Cancrini, C.. - In: JOURNAL OF LEUKOCYTE BIOLOGY. - ISSN 0741-5400. - 108:2(2020), pp. 739-748. [10.1002/JLB.5MA0220-239R]

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

Piano Mortari E.;Locatelli F.;
2020

Abstract

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.
2020
common gamma chain; cytokine signaling; primary immune deficiency
01 Pubblicazione su rivista::01a Articolo in rivista
Partial T cell defects and expanded CD56bright NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene / Cifaldi, C.; Cotugno, N.; Di Cesare, S.; Giliani, S.; Di Matteo, G.; Amodio, D.; Piano Mortari, E.; Chiriaco, M.; Buonsenso, D.; Zangari, P.; Pagliara, D.; Gaspari, S.; Carsetti, R.; Palma, P.; Finocchi, A.; Locatelli, F.; Rossi, P.; Doria, M.; Cancrini, C.. - In: JOURNAL OF LEUKOCYTE BIOLOGY. - ISSN 0741-5400. - 108:2(2020), pp. 739-748. [10.1002/JLB.5MA0220-239R]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1479518
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