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.

Cifaldi, C., Cotugno, N., Di Cesare, S., Giliani, S., Di Matteo, G., Amodio, D., et al. (2020). Partial T cell defects and expanded CD56bright NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene. JOURNAL OF LEUKOCYTE BIOLOGY, 108(2), 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

Cifaldi, Cristina;Cotugno, Nicola;Di Cesare, Silvia;Di Matteo, Gigliola;Amodio, Donato;Palma, Paolo;Finocchi, Andrea;Rossi, Paolo;Cancrini, Caterina
2020-01-01

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
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
English
common gamma chain
cytokine signaling
primary immune deficiency
Cifaldi, C., Cotugno, N., Di Cesare, S., Giliani, S., Di Matteo, G., Amodio, D., et al. (2020). Partial T cell defects and expanded CD56bright NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene. JOURNAL OF LEUKOCYTE BIOLOGY, 108(2), 739-748 [10.1002/JLB.5MA0220-239R].
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/259398
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