Ton C. Doan, BA, Brian M. Jeong, MSc, Mackenzie E. Coden, BA, Lucas F

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Matrix protein tenascin-C expands and reversibly blocks maturation of murine eosinophil progenitors Ton C. Doan, BA, Brian M. Jeong, MSc, Mackenzie E. Coden, BA, Lucas F. Loffredo, BSc, Swati Bhattacharyya, PhD, Sergio E. Chiarella, MD, John Varga, MD, Hiam Abdala-Valencia, PhD, Sergejs Berdnikovs, PhD Journal of Allergy and Clinical Immunology Volume 142, Issue 2, Pages 695-698.e4 (August 2018) DOI: 10.1016/j.jaci.2018.02.054 Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Protocol for bone marrow and ex vivo lung eosinophil differentiation culture, separated into 3 critical phases: precursor expansion, eosinophil commitment, and eosinophil maturation. Cells were cultured with SCF and FLT3L for 4 days before induction to eosinophil commitment via IL-5. B, Expression of Siglec-F (eosinophil marker) and Sca-1 (stem cell marker) on CD45+ cells at terminal bone marrow culture end point on day 15. Control culture consistently resulted in more than 90% Siglec-F+Sca-1− eosin-positive eosinophils. Morphology of these cells is shown in cytospin preparations stained with differential staining solution. C, Kinetics of bone marrow–derived eosinophil differentiation and Sca-1 expression on CD45+Siglec-F+/− by flow cytometry. Asterisks denote differences between each time point and day 3 culture start time point for each of the treatment curves; asterisk color matches treatment curve color. D, Quantification of CD45+Sca-1+ cells by flow cytometry in bone marrow–derived eosinophil cultures. Blue, control culture; green, TNC-supplemented culture; asterisks denote differences between 2 cultures. E, Kinetics of expression of IL-5Rα on cells throughout bone marrow culture quantified by flow cytometry. TNC significantly downregulated IL-5 receptor during days 5 and 7 of culture (IL-5–induced eosinophil lineage commitment phase); 3 wells/treatment/culture time point, N = 3 independent donor cultures. SCF, Stem cell factor; SSC, side scatter. *P < .05. ****P < .0001. Journal of Allergy and Clinical Immunology 2018 142, 695-698.e4DOI: (10.1016/j.jaci.2018.02.054) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, Withdrawal of TNC from day 6 bone marrow culture rescued IL-5–induced eosinophil commitment. MFI levels of Sca-1 on CD45+Siglec-F+ eosinophils on day 15 of the culture are shown. Cytospin preparations confirmed restoration of mature eosinophil phenotype after TNC withdrawal. B, Quantification of CD45+Siglec-F+ eosinophils on day 15 of bone marrow culture. Withdrawal of TNC on day 6 doubled the yield of mature eosinophils. C, In a model of allergic inflammation, TNC−/− mice had a significant reduction in both common myeloid progenitors (CD45+c-kit+CD34+ population, top scatterplots) and Lin− CD45+Siglec-F+Sca-1+ eosinophil progenitors (Lineage expression shown out of CD45+Siglec-F+Sca-1+ parent population, bottom histograms). N = 8 for WT, N = 4 for TNC−/− mice. The experiment was repeated twice. D, IL-5 culture of ex vivo lung homogenates. Lineage histograms shown are out of CD45+Siglec-F+Sca-1+ parent gates. Eosinophils from TNC−/− lungs showed accelerated maturation and reduced numbers of Lin−Siglec-F+Sca-1+ cells, whereas TNC peptide addition reversed this effect. Bar graphs on the left show normalized mature eosinophil counts (out of total structural and hematopoietic cells) in cytospin preparations of the whole lung ex vivo cultures (40×, 10 different fields scored/treatment). Bar graphs on the right quantify the percentage of Sca-1+Lin− cells out of the total population of Siglec-F+ cells in IL-5 culture of ex vivo lung homogenates; 3 wells/treatment/culture time point, N = 2-3 independent donor cultures. MFI, Median fluorescence intensity. *P < .05. **P < .01. Journal of Allergy and Clinical Immunology 2018 142, 695-698.e4DOI: (10.1016/j.jaci.2018.02.054) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Total cell counts in bone marrow–derived eosinophil cultures. Blue, control culture; green, TNC-supplemented culture; 3 wells/treatment/culture time point, N = 3 independent donor cultures. Asterisks denote differences between 2 cultures for each corresponding time point. *P < .05. Journal of Allergy and Clinical Immunology 2018 142, 695-698.e4DOI: (10.1016/j.jaci.2018.02.054) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Expression of IL-5Rα on CD45+Siglec-F+ eosinophil progenitors at day 6 in bone marrow culture. FMO, Fluorescence Minus One. Journal of Allergy and Clinical Immunology 2018 142, 695-698.e4DOI: (10.1016/j.jaci.2018.02.054) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Quantification of flow cytometry data shown in Fig 2, C. *P < .05. ****P < .0001. Journal of Allergy and Clinical Immunology 2018 142, 695-698.e4DOI: (10.1016/j.jaci.2018.02.054) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions