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ZIB Paper presentation

07.02.2011

Wiebke Ginter

Nuocytes represent a new innate effector leukocytethat mediates type-2 immunityDaniel 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

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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

Type II immunity and Question

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Type II immunity and Question

IL-13 is critical in immune response to helminths and asthmaWhich cell types to produce this cytokine?

Supp. 1a

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

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CD4+ splenocytes

Supp.1

Th1 conditions Th2 conditions

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Localisation of eGFP+ cells

Fig. 1c

Supp. 2b

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no T cell

no APC

no gd T cell

no NK/NKT cell

no NK/NKT cell

no DC mono…

no macroph,

granolo

no eosno mast

no pDC

no B cell

Surface markers

Supp. 2a,c

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

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Induction of Nuocytes by IL-25 and IL-33

Fig. 1

IL-25 receptor SU of IL-33 receptor

Direct action of these IL

Redundant action

Nuocytes: Lin- eGFP+T1/ST2+IL17BR+

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Presence in imunosurveillance sites

Supp. 4

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Helminth infection

Small intestine

Supp. 2d Fig. 2a

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IL25 and IL33: partially redundant roles

Il17br-/- Il1rl1-/- IL17br-/-

Il1rl1-/-

No IL25R No SU IL33R

No IL25R, IL33R

Fig.2

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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+

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Cytokine profile

Fig. 3Supp. 9

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

Il17br-/-

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Restoring protective IR in IL17BR-/- mice

Fig. 4

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IL13 of nuocytes is necessary and sufficient for worm expulsion

Fig. 4IL13 from nuocytes is the only important source

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Dialogue between T cells and nuocytes

Fig. 4

T cells Nuocytes

Enhance cytokines, augment resp

Maintain: expansion survival

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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?

T cells Nuocytes

Enhance cytokines, augment resp

Maintain: expansion survival

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Supplementary

Saenz, 2010, Trends in Immunology

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no T cell

no APC

no gd T cell

no NK/NKT cell

no NK/NKT cell

no DC mono…

no macroph, granolo

no eosno mast

no pDC

no B cell

Surface markers

Supp. 2a,c

21DR Neill et al. Nature 000, 1-4 (2010) doi:10.1038/nature08900

Adoptive transfer of wild-type nuocytes, but not IL13-deficient nuocytes, restores rapid worm expulsion in N. brasiliensis-infected Il17br

_/_ mice.