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Molecular Mechanisms of Natural Killer cell Cytotoxicity

Objective

The study of immunodeficiency syndromes such as familial hemophagocytic lymphohistiocytosis (FHL) and Griscelli Syndrome type 2 (GS2) has revealed a crucial role for Munc13-4, Stx11, Munc18-2 and Rab27a – members of protein families that regulate vesicle trafficking and membrane fusion – in cytotoxic granule exocytosis. Loss-of-function mutations in these proteins result in loss of target cell killing by NK cells and CD8+ T cells, resulting in a life-threatening sepsis-like condition. The precise molecular role of these proteins in granule release remains, however, incompletely understood.
The objective of this project is to elucidate presynaptic signaling cascades leading to NK cell exocytosis, and thus obtain a detailed map of the sub-cellular events leading to granule release. The project is divided into three specific aims. Post-translational modifications of the known regulators of exocytosis will be studied. In a second line of investigation, other, as yet unknown, proteins that might be involved in this process, like priming factors, and scaffold and adaptor proteins will be explored. This work will be facilitated by insights from the fields of neuroscience and hormone release; the mechanisms of which also share an exocytic pathway, and for which molecules important for this process have already been discovered. Additionally, to obtain a complete picture of the signaling pathways involved, spatiotemporal patterns of second messenger dynamics during granule release will be assessed. Importantly, primary, human NK cells will be employed throughout this study.
In conclusion, this project aims to increase the understanding of the complex molecular mechanisms involved in NK cell cytotoxicity, thus broadening the spectrum of immunodeficiency syndromes and improving the clinical diagnosis and treatment of FHL patients.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/neurobiology
  • /natural sciences/biological sciences/neurobiology/neuroscience

Call for proposal

FP7-PEOPLE-2011-IIF
See other projects for this call

Funding Scheme

MC-IIF - International Incoming Fellowships (IIF)

Coordinator

KAROLINSKA INSTITUTET
Address
Nobels Vag 5
17177 Stockholm
Sweden
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 181 418,40
Administrative Contact
Klas Karlsson (Mr.)