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Signaling by Fyn-ADAP via the Carma1–Bcl-10–MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells

Nature Immunology volume 14, pages 1127–1136 (2013)Cite this article

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A Corrigendum to this article was published on 21 January 2014

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Abstract

Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma and various autoimmune disorders. Here we identified a signaling pathway that was exclusively responsible for the production of inflammatory cytokines but not for cytotoxicity. Recognition of tumor cells expressing the NK cell–activatory ligands H60 or CD137L by mouse natural killer (NK) cells led to efficient cytotoxicity and the production of inflammatory cytokines. Both of those effector functions required the kinases Lck, Fyn and PI(3)K (subunits p85α and p110δ) and the signaling protein PLC-γ2. However, a complex of Fyn and the adaptor ADAP exclusively regulated the production of inflammatory cytokines but not cytotoxicity in NK cells. That unique function of ADAP required a Carma1–Bcl-10–MAP3K7 signaling axis. Our results have identified molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.

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Figure 1: CD137 functions as an independent activation receptor in NK cells.
Figure 2: Lck is crucial in CD137-mediated signaling.
Figure 3: Fyn has a critical role in mediating the effector function of NK cells.
Figure 4: The PI(3)K subunits p85α and p110δ are essential for the cytotoxicity and cytokine production of NK cells.
Figure 5: ADAP is essential for the cytokine production but not for the cytotoxicity of NK cells.
Figure 6: Carma1 is essential for the cytotoxicity and cytokine production of NK cells.
Figure 7: MAP3K7 links Carma1 to the CD137-mediated effector function of NK cells.
Figure 8: ADAP is essential for the cytokine production but not for the cytotoxicity of human NK cells.

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  • 23 September 2013

    In the version of this article initially published online, the affiliation of author Bart Vanhaesebroeck was incorrect. The correct affiliation is as follows: Center for Cell Signaling, Barts Cancer Institute, Queen Mary University of London, London, UK. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank L. Sammarco and her Lulu's Lemonade Stand for support through Blood Center's Research Foundation, inspiration and motivation; K.E. Nichols (Children's Hospital, Philadelphia) for Adap−/− mice; D.R. Littman (New York University) for Carma1−/− mice; J. Zhang and Y. Xiao (Loyola University Chicago Stritch School of Medicine) for Map3k7fl/fl and Map3k7fl/flMx1-Cre spleens; Y. Chen and B. Ren (Blood Research Institute, Milwaukee) for wild-type and Fyn−/− spleens; V. Arumugam and T. Foster for technical help; and T. Heil, L. Savatski, P.J. Newman and Q. Shi for critical reading. Supported by the US National Institutes of Health (R01 A1064828 and R01 AI102893 to S.M.), the American Cancer Society (S.M. and M.S.T.), Midwest Athletes Against Childhood Cancer Fund (M.S.T. and S.M.) and Hyundai Hope on Wheels (M.S.T.).

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Authors and Affiliations

  1. Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Milwaukee, Wisconsin, USA

    Kamalakannan Rajasekaran, Pawan Kumar, Kristina M Schuldt, Monica S Thakar & Subramaniam Malarkannan

  2. Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA

    Erik J Peterson

  3. Centre for Cell Signaling, Barts Cancer Institute, Queen Mary University of London, London, UK

    Bart Vanhaesebroeck

  4. Genentech, South San Francisco, California, USA

    Vishva Dixit

  5. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Monica S Thakar

  6. Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Subramaniam Malarkannan

  7. Department of Microbiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Subramaniam Malarkannan

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Contributions

K.R. designed and executed analysis of the cytotoxic potential and production of inflammatory cytokines of Fyn−/−, p110δ(D910A), Adap−/−, Carma1−/− and Carma1(ΔCARD) NK cells (freshly isolated or cultured with IL-2), did various NK cell–activation assays, prepared cell lysates, did immunoblot analysis and immunoprecipitation assays, purified human primary NK cells and used them for siRNA treatment and functional analyses, and helped in revising the manuscript; P.K. designed siRNA and knocked down various mouse signaling proteins; K.M.S. maintained various animal colonies and prepared NK cells (freshly isolated or cultured with IL-2) for studies; V.D. provided Carma1(ΔCARD) mice; E.J.P. provided Adap−/− spleens and discussed the data; B.V. provided p110δ(D910A) mice; E.J.P. and B.V. helped in the final editing of the manuscript; M.S.T. helped in the preparation of the manuscript; and S.M. conceived of the study, designed experiments, analyzed the data and wrote the manuscript.

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Correspondence to Subramaniam Malarkannan.

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Rajasekaran, K., Kumar, P., Schuldt, K. et al. Signaling by Fyn-ADAP via the Carma1–Bcl-10–MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells. Nat Immunol 14, 1127–1136 (2013). https://doi.org/10.1038/ni.2708

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