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Katie Frith, MD, Anne-Laure Joly, PhD, Cindy S. Ma, PhD, Stuart G

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Presentation on theme: "Katie Frith, MD, Anne-Laure Joly, PhD, Cindy S. Ma, PhD, Stuart G"— Presentation transcript:

1 The FOXP3Δ2 isoform supports Treg cell development and protects against severe IPEX syndrome 
Katie Frith, MD, Anne-Laure Joly, PhD, Cindy S. Ma, PhD, Stuart G. Tangye, PhD, Zuzana Lohse, PhD, Christina Seitz, PhD, Charles F. Verge, PhD, John Andersson, PhD, Paul Gray, MD  Journal of Allergy and Clinical Immunology  Volume 144, Issue 1, Pages e8 (July 2019) DOI: /j.jaci Copyright © 2019 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Altered FOXP3 isoform expression caused by the c.305delT mutation. A-C, FACS staining with anti-FOXP3 antibody targeting the exon 2–encoded domain (clone 150D/E4, y-axis) versus anti-FOXP3 antibody targeting an epitope common to all FOXP3 isoforms (clone 236A/E7, x-axis). Black plots are gated on CD4+CD25+CD127lo FOXP3total cells and show the signal from the FOXP3 exon 2 antibody (y-axis) is absent in FOXP3+ cells from the proband P1 (Fig 1, A) and his grandfather P2 (Fig 1, B) in contrast to a representative healthy control subject age and sex matched to the proband (Fig 1, C). D and E, Mean fluorescence intensity (MFI) of FOXP3 containing exon 2 signal relative to naive T cells (gray plots; CD4+CD45RA+FOXP3−) in resting Treg cells (rTreg; CD4+CD25+CD127loTotalFOXP3+; Fig 2, D) or aTreg cells (CD4+CD25hiCD127loCD45RA−TotalFOXP3+; Fig 2, E) and compared with age- and sex-matched healthy control subjects. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2019 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Peripheral blood of P2 presents an unusually high proportion of activated FOXP3+CD4+ T cells. A-C, Flow cytometric analysis of CD127 and FOXP3 expression in CD4+ T cells in the proband P1 (Fig 2, A), grandfather P2 (Fig 2, B), and a representative healthy control subject age matched to the proband (Fig 2, C). D, Quantification of aTreg cells (aTreg; CD4+CD25hiCD127loCD45RA−TotalFOXP3+) of all Treg cells in P1 and P2 in comparison with age- and sex-matched healthy control subjects. E and F, Proportion of FOXP3 exon 2–positive and negative Treg cells (CD4+CD25+CD127loFOXP3) in the carrier mother (Fig 2, E) in comparison with an age- and sex-matched representative control subject (Fig 2, F). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2019 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig E1 FOXP3 gene and FOXP3 protein and 4 isoforms. FOXP3 gene showing 11 coding exons (E1-E11) and FOXP3 protein showing 4 functional domains: a carboxyl terminal forkhead domain; and 3 protein/protein interaction domains, a central zinc finger (ZF), a leucine zipper (LZ), and a proline-rich transcriptional repressor domain (PRR). Four FOXP3 isoforms are also shown: FOXP3fl, the full-length FOXP3 isoform; FOXP3Δ2, the FOXP3 isoform missing the region encoded by exon 2; FOXP3Δ7, an isoform missing the region encoded by exon 7; and FOXP3Δ2Δ7, an isoform missing the region encoded by exons 2 and 7. Finally, the position of a novel p.Phe102fs mutation is shown. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2019 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig E2 Family pedigree. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2019 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E3 Sanger sequencing of the FOXP3 gene. A, P1 (proband) Sanger sequencing of FOXP3. B, P2 (proband's grandfather) Sanger sequencing of FOXP3. C, C1 (proband's carrier mother) Sanger sequencing of FOXP3. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2019 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E4 FOXP3 transcripts in a Sashimi plot from the Integrative Genomics Viewer (IGV) to visualize alternative splicing of FOXP3 transcripts derived from RNA-sequencing data pooled from the 2 patients with IPEX syndrome (P1 and P2, red) and age-matched control subjects (blue). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2019 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E5 T-cell phenotype of proband (P1). A and B, Flow cytometric analysis of CD45RA and CCR7 expression on CD4+ and CD8+ T cells from the proband (P1) compared with a healthy age-matched control subject. C, Flow cytometric analysis of Ki67 expression on CD4+FOXP3− cells from P1 and P2 compared with age- and sex-matched healthy control subjects. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2019 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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