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Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency  Melissa C. Mizesko, MD,

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Presentation on theme: "Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency  Melissa C. Mizesko, MD,"— Presentation transcript:

1 Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency  Melissa C. Mizesko, MD, Pinaki P. Banerjee, PhD, Linda Monaco-Shawver, BA, Emily M. Mace, PhD, William E. Bernal, MD, Julie Sawalle-Belohradsky, Bernd H. Belohradsky, MD, Valerie Heinz, Alexandra F. Freeman, MD, Kathleen E. Sullivan, MD, PhD, Steven M. Holland, MD, Troy R. Torgerson, MD, PhD, Waleed Al-Herz, MD, Janet Chou, MD, Imelda C. Hanson, MD, Michael H. Albert, MD, Raif S. Geha, MD, Ellen D. Renner, MD, Jordan S. Orange, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 131, Issue 3, Pages (March 2013) DOI: /j.jaci Copyright © Terms and Conditions

2 Fig 1 DOCK8 deficiency impairs NK cell cytotoxicity, which is not restored by IL-2. Control donor PBMCs (n = 15) and PBMCs from DOCK8-deficient and STAT3 mutant patients were used in chromium-release assays ex vivo without (A) or with (B) 4 hours of stimulation with 1000 U of IL-2. Cytotoxic function was expressed as lytic units (LU)10/NK cell. Error bars represent means ± SEMs for patients analyzed 3 times. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © Terms and Conditions

3 Fig 2 DOCK8-deficient patients have NK cells. Results of flow cytometric analysis of the percentage of CD56+CD3− cells in PBMCs are shown. Dotted lines display ranges for the control donors (n = 15). Error bars represent means ± SDs for patients analyzed 3 times. The inset displays the mean NK cell percentages for DOCK8-deficient patients compared with control donors and STAT3-deficient patients. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © Terms and Conditions

4 Fig 3 F-actin content is normal in DOCK8-deficient patients. Flow cytometry was performed for F-actin content within CD56+CD3− PBMCs from patients and control subjects (n = 15). Values were normalized to each specific control used. Error bars represent means ± SDs for patients analyzed 3 times. The inset displays the mean NK cell F-actin content for DOCK8-deficient patients compared with control subjects and STAT3-deficient patients. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © Terms and Conditions

5 Fig 4 Abnormal F-actin accumulation at the DOCK8-deficient NK cell IS. A, Representative confocal immunofluorescent micrographs of ex vivo natural killer (eNK):K562 cell conjugates showing differential interference contrast (DIC) F-actin (red), CD18 (green), perforin (blue), pericentrin (pink), and an overlay. B-D, Measurement of F-actin accumulation (Fig 4, B) at, CD18 accumulation (Fig 4, C) at, and MTOC polarization (Fig 4, D) to the IS. Points represent single cell values. Error bars represent means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © Terms and Conditions

6 Fig 5 Stable knockdown of DOCK8 inhibits NK cell cytotoxicity. A, NK cell lines (YTS) transduced with empty vector (EV), shRNA targeting DOCK8 (DOCK8 kd), or a scramble sequence were used in chromium-release cytotoxicity assays. B, DOCK8 expression measured by using real-time PCR normalized to human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Experiments were performed in triplicate, and representative graphs are depicted. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © Terms and Conditions

7 Fig 6 DOCK8 knockdown abrogates synaptic F-actin accumulation and granule polarization. Representative confocal immunofluorescence micrographs of conjugates between YTS cells containing DOCK8-targeting or control scrambled shRNA and KT86 target cells are shown. Differential interference contrast (DIC) with localization of F-actin (red), CD18 (green), perforin (pink), and an overlay are shown. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © Terms and Conditions

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