Natural killer cell hyporesponsiveness and impaired development in a CD247-deficient patient Mar Valés-Gómez, PhD, Gloria Esteso, PhD, Cigdem Aydogmus,

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Presentation transcript:

Natural killer cell hyporesponsiveness and impaired development in a CD247-deficient patient Mar Valés-Gómez, PhD, Gloria Esteso, PhD, Cigdem Aydogmus, MD, Alfonso Blázquez-Moreno, BSc, Ana V. Marín, BSc, Alejandro C. Briones, BSc, Beatriz Garcillán, PhD, Eva-María García-Cuesta, BSc, Sheila López Cobo, BSc, Sule Haskologlu, MD, Manuela Moraru, MD, Funda Cipe, MD, Kerry Dobbs, BS, Figen Dogu, MD, Silvia Parolini, PhD, Luigi D. Notarangelo, MD, Carlos Vilches, MD, PhD, Maria J. Recio, PhD, José R. Regueiro, PhD, Aydan Ikinciogullari, MD, Hugh T. Reyburn, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 3, Pages 942-945.e4 (March 2016) DOI: 10.1016/j.jaci.2015.07.051 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 CD247 genotype correlates with expression of CD247 and CD16 and NCR3 expression on NK cells. NK receptor expression levels in CD3−CD56dim NK cells from the CD247−/− patient were compared with those of CD247+/− and CD247+/+ relatives or age-matched control subjects for intracellular CD247 (A), CD16 on FcεRγ+ or FcεRγ− cells (B), NCR1 (C), NCR3 (D), and 2B4 (E). Data are shown as geometric mean fluorescence intensity (Geo MFI). /, First/second sample taken 3 months apart *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2016 137, 942-945.e4DOI: (10.1016/j.jaci.2015.07.051) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Hyporesponsiveness (A-C) and impaired maturation (D-F) of CD247-deficient NK cells. Comparative degranulation in response to the indicated stimuli for the 3 CD247 genotypes (Fig 2, A), CD3δ- and CD3γ-deficient patients versus healthy control subjects (Fig 2, B), and healthy adults versus children (Fig 2, C). CD3-deficient (squares) and CD247-deficient primary immunodeficiencies were compared among them and with CD247+/− and CD247+/+ relatives or age-matched control subjects for peripheral blood CD56bright NK cells (Fig 2, D), KIR2D+CD56dim NK cells (Fig 2, E), and CD94/NKG2A+CD56dim NK cells (Fig 2, F). /, First/second sample. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2016 137, 942-945.e4DOI: (10.1016/j.jaci.2015.07.051) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Genetic and phenotypic characterization of CD247 deficiency. A, The index patient inherited a CD247 mutation affecting the start codon that is shown within the CD247 protein (p.M1T or p.0) and gene (c.2T>C, g.147T>C) structure, as well as in the comparative chromatograms (arrows). EC, Extracellular region; SP, signal peptide; TM, transmembrane region. B, Genetic pedigree. Circles indicate female subjects, and squares indicate male subjects (slashes indicate deaths). Dotted and full symbols indicate heterozygosity and homozygosity for the mutation, respectively. Empty symbols and symbols marked with ? indicate noncarrier and unknown mutation status, respectively. Only tested subjects are numbered. C, PBMCs from the CD247−/− patient, a relative heterozygous for the CD247 initiation codon mutation (+/−) and a family member homozygous for nonmutant CD247 sequence (+/+) were stained with directly labeled mAbs specific for CD3ε and CD56. The cells were then fixed, permeabilized, blocked with mouse serum, and stained with a directly labelled mAb specific for the cytoplasmic tail of CD247. The flow cytometric data were analyzed by using the Kaluza program (Beckman Coulter, Fullerton, Calif). Red, CD3ε+CD56− T cells; green, CD3ε+CD56+ T cells; light blue, CD3ε−CD56dim NK cells; dark blue, CD3ε−CD56bright NK cells; gray, non-NK/non-T cells. Journal of Allergy and Clinical Immunology 2016 137, 942-945.e4DOI: (10.1016/j.jaci.2015.07.051) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 A, Representative dot plots showing staining for CD56 and CD16 on CD3− lymphocytes of the CD247−/− patient and a healthy control subject. B, Overlay histograms showing levels of NCR1, NCR3, and 2B4 expression on CD3−CD56dim NK cells in the CD247−/− patient and a healthy control subject. Shaded gray plots, Isotype control staining; solid black line, NCR1, NCR3, or 2B4 staining. Journal of Allergy and Clinical Immunology 2016 137, 942-945.e4DOI: (10.1016/j.jaci.2015.07.051) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Deficient expansion of NK cells of the CD247−/− patient during in vitro culture can be remedied by addition of IL-2. PBMCs were purified by means of centrifugation on Ficoll-Hypaque and then placed in culture in RPMI 1640 medium with 10% AB− human serum and irradiated (40 Gy) feeder cells (RPMI 8866, Daudi, and 221/AEH cells) in the presence or absence of 50 IU/mL rIL-2. After 7 days of culture, half the medium was removed and replaced with fresh medium (with or without IL-2). On day 10, the cells were harvested and counted, and aliquots of the cultures were stained with directly labeled mAbs specific for CD3 and CD56. Journal of Allergy and Clinical Immunology 2016 137, 942-945.e4DOI: (10.1016/j.jaci.2015.07.051) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions