Ana V. Marin, MSc, Anaïs Jiménez-Reinoso, MSc, Alejandro C

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Ana V. Marin, MSc, Anaïs Jiménez-Reinoso, MSc, Alejandro C

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Presentation transcript:

Primary T-cell immunodeficiency with functional revertant somatic mosaicism in CD247 Ana V. Marin, MSc, Anaïs Jiménez-Reinoso, MSc, Alejandro C. Briones, MSc, Miguel Muñoz-Ruiz, MSc, Cigdem Aydogmus, MD, Luke J. Pasick, BSc, Jorge Couso, MSc, Marina S. Mazariegos, MSc, Angel F. Alvarez-Prado, MSc, Alfonso Blázquez-Moreno, MSc, Funda E. Cipe, MD, Sule Haskologlu, MD, Figen Dogu, MD, Matías Morín, PhD, Miguel A. Moreno-Pelayo, PhD, Félix García-Sánchez, PhD, Juana Gil-Herrera, MD, PhD, Edgar Fernández-Malavé, PhD, Hugh T. Reyburn, PhD, Almudena R. Ramiro, PhD, Aydan Ikinciogullari, MD, Maria J. Recio, PhD, Jose R. Regueiro, PhD, Beatriz Garcillán, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 1, Pages 347-349.e8 (January 2017) DOI: 10.1016/j.jaci.2016.06.020 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Patient characterization. A, Peripheral blood phenotype. B, Surface CD3ε expression in the indicated subsets. Numbers indicate % MFI relative to controls. C, Intracellular (i) expression of the indicated CD. Numbers indicate % iCD247− or iCD247+ in iCD3δ+ (T) cells. D, CD247 WB of sorted T cells. Numbers indicate % normalized band intensity relative to control. E, Mutations and predicted proteins. EC, Extracellular; IC, intracellular; MFI, mean fluorescence intensity; SP, signal peptide; TM, transmembrane; WB, Western blot. ***P ≤ .001. Journal of Allergy and Clinical Immunology 2017 139, 347-349.e8DOI: (10.1016/j.jaci.2016.06.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Impaired TCR-induced signaling in primary (A and B) and cultured T cells (C and D). % CD69+ cells (Fig 2, A) or CFSE dilution (Fig 2, B) after stimulation with anti-CD3ε for 24 hours or 5 days, respectively. C, Representative pZAP-70 and pERK levels after stimulation with anti-CD3ε (left) and MFI + SEM relative to unstimulated cells of 4 independent experiments (right). D, T-cell growth in allogeneic cultures. CFSE, Carboxyfluorescein diacetate succinimidyl ester; pERK, phospho-extracellular signal–regulated kinase. *P ≤ .05. Journal of Allergy and Clinical Immunology 2017 139, 347-349.e8DOI: (10.1016/j.jaci.2016.06.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Patient characterization. A, Reduced % of recent thymic emigrants defined as CD4+ CD45RA+ CD31+ lymphocytes (age-matched control range,E5 77%-96%). B, Reduced naive T-cell compartment. T-cell maturation stages in CD4+ and CD8bright cells were defined as naive (CD45RO−CD27+), central memory (CD45RO+CD27+), effector memory (CD45RO+CD27−), or effector (CD45RO−CD27−). Control in Fig E1, A and B, was a 20-year-old healthy donor. C, Reduced TCRβ clonality in PBMCs. D, Chest computed axial tomography showing normal-sized thymus. Journal of Allergy and Clinical Immunology 2017 139, 347-349.e8DOI: (10.1016/j.jaci.2016.06.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 CD247 deficiency due to a homozygous mutation. A, CD247 gene and protein, including the germline mutation (NCBI/ClinVar: rs672601318, NM_000734.3:c.2T>C and NG_007384.1:g.5146T>C in exon 1) and the next in-frame ATG. B, Top, CD247 mutation and haplotypes based on the indicated microsatellite markers (black = disease-associated chromosome). Bottom, pedigree with haplotypes for studied individuals. Circles, squares, and diamonds indicate females, males, or unknown sex, respectively. Journal of Allergy and Clinical Immunology 2017 139, 347-349.e8DOI: (10.1016/j.jaci.2016.06.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 In vitro T-cell growth and phenotype. Surface CD3ε expression in cultured T cells with gates and % for CD3εneg, CD3εlow, and CD3εhigh subpopulations at different time points. SSC, Side scatter. Journal of Allergy and Clinical Immunology 2017 139, 347-349.e8DOI: (10.1016/j.jaci.2016.06.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Summary of CD247 germline and somatic mutations. Molecular basis of the 3 reported CD247-deficient patients, 1 patient/box: Exon 2,E6 Exon 4,E7 and Exon 1 (present report). EC, Extracellular; IC, intracellular; LP, leader peptide; TM, transmembrane; WT, wild-type. Journal of Allergy and Clinical Immunology 2017 139, 347-349.e8DOI: (10.1016/j.jaci.2016.06.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions