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ZIB Paper presentation 07.02.2011 Wiebke Ginter

Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity Daniel R. Neill1*, See Heng Wong1*, Agustin Bellosi1*, Robin J. Flynn1, Maria Daly1, Theresa K. A. Langford1,

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ZIB Paper presentation 07.02.2011 Wiebke Ginter

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  1. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity Daniel R. Neill1*, See Heng Wong1*, Agustin Bellosi1*, Robin J. Flynn1, Maria Daly1, Theresa K. A. Langford1, Christine Bucks2, Colleen M. Kane2, Padraic G. Fallon3, Richard Pannell1, Helen E. Jolin1 & Andrew N. J. McKenzie1 ZIB Paper presentation 07.02.2011 Wiebke Ginter

  2. Type II immunity and Question • Plays role in helminth infection and asthma • Eosinophilia, mucus secretion, IgE production • IL-4, IL5, IL-13 • Produced by basophils, eosinophils and mast cells • Role in Nippostrongylus brasiliensis expulsion unknown Nippostrongylus brasiliensis • intestinal nematode of rodents • closely related to the human hookworms (Ancylostoma and Necator) • infect 740 million people in tropical countries • N. brasiliensis widely used model for nematode parasites Maizels, 2003, Nat. Rev. Immunol

  3. Type II immunity and Question • Plays role in helminth infection and asthma • Eosinophilia, mucus secretion, IgE production • IL-4, IL5, IL-13 • Produced by basophils, eosinophils and mast cells • Role in Nippostrongylus brasiliensis expulsion unknown IL-13 is critical in immune response to helminths and asthma Which cell types to produce this cytokine? Supp. 1a

  4. CD4+ splenocytes Th1 conditions Th2 conditions Supp.1

  5. Localisation of eGFP+ cells Fig. 1c Supp. 2b

  6. Surface markers no NK/NKT cell no NK/NKT cell no DC mono… no APC no gd T cell no T cell no eos no macroph, granolo no mast no pDC no B cell Supp. 2a,c

  7. New cells are no mast, B, T, NK or LTi cells

  8. Induction of Nuocytes by IL-25 and IL-33 Nuocytes: Lin- eGFP+T1/ST2+IL17BR+ Fig. 1 IL-25 receptor SU of IL-33 receptor  Redundant action  Direct action of these IL

  9. Presence in imunosurveillance sites Supp. 4

  10. Helminth infection Small intestine Fig. 2a Supp. 2d

  11. IL25 and IL33: partially redundant roles Fig.2

  12. Nuocyte Cultures Fig. 3 • IL33 and IL7 needed for expansion • Most cell surface markers maintained • Did not differentiate Supp. 8 Nuocytes: Lin- ICOS+T1/ST2+IL17BR+IL-7Rα+

  13. Cytokine profile Fig. 3 Supp. 9

  14. Adoptive transfer of cultured nuocytes into Il17br-/-mice restores an IL25-responsive phenotype Il17br-/-

  15. Restoring protective IR in IL17BR-/- mice Fig. 4

  16. IL13 of nuocytes is necessary and sufficient for worm expulsion IL13 from nuocytes is the only important source Fig. 4

  17. Enhance cytokines, augment resp T cells Nuocytes Maintain: expansion survival Dialogue between T cells and nuocytes Fig. 4

  18. Enhance cytokines, augment resp T cells Nuocytes Maintain: expansion survival Summary • new class of cells: Nuocytes • important for the type-2 immunity: protection from parasitic helminths • release of type II cytokines, activating eosinophiles and goblet cells and secreting mucus and IgE • Key source of IL-13 release during early steps of helminth infection • Expand rapidly in response to IL-25 and IL-33 (type-2 initiators) • Lack: nuocytes expansion ↓, defect in worm expulsion • present in immunosurveillance sites • Secrete high levels of IL13 and IL5 • Enhance T cell responses • highly specialized type type-2 regulatory cells • New possible target for immune modulation? Asthma treatment?

  19. Supplementary Saenz, 2010, Trends in Immunology

  20. Surface markers no NK/NKT cell no NK/NKT cell no T cell no APC no DC mono… no gd T cell no macroph, granolo no eos no pDC no B cell no mast Supp. 2a,c

  21. Adoptive transfer of wild-type nuocytes, but not IL13-deficient nuocytes, restores rapid worm expulsion in N. brasiliensis-infected Il17br_/_ mice. DR Neill et al. Nature000, 1-4 (2010) doi:10.1038/nature08900

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