Immune cell signaling - Annemiek van Spriel
The ultimate aim of the Immune Cell Signaling group is to understand how immune cells physically organize and compartmentalize signaling molecules into efficient, regulated membrane-proximal signaling complexes. It is well-established that the spatial organization of proteins and lipids in the plasma membrane is critical for initiation of signal transduction and immune cell function. Examples are the formation of the immunological synapse between T cells and dendritic cells, and the organization of multiple pattern-recognition receptors at the immune cell surface upon pathogen or tumor cell recognition. The tetraspanin superfamily of 4-transmembrane proteins,expressed in the plasma membrane of virtually all mammalian cells, have the ability to interact in cis with specific (immune) receptors and signaling molecules (PKC) whereby they form multi-molecular complexes. We discovered that tetraspanins (CD37, CD53) are essential for immune cell proliferation, antigen presentation and antibody production. Still, the molecular mechanisms that underlie tetraspanin function and signaling in immune cells in relation to the development of malignant disease are largely unknown.
We investigate tetraspanin function at the plasma membrane of immune cells (B cells, dendritic cells, macrophages) using a multidisciplinary approach by combining advanced microscopy (FRET-FLIM, super-resolution microscopy) with biochemical, molecular and immunological techniques using primary immune cells isolated from human blood as well as from mouse lymphoid organs. In vivo (anti-tumor) immune responses are investigated in different tetraspanin-deficient mouse models. To get more insight into tetraspanin organization at the cell surface of immune cells, we have recently applied dual color super-resolution microscopy to visualize the nanoscale organization of tetraspanins (CD37, CD53, CD81, CD82). We found tetraspanins to cluster mainly with the same tetraspanin species on B cells and dendritic cells, which challenges the current view of the tetraspanin web of multiple tetraspanin species organized into a single domain. Moreover, we discovered that absence of tetraspanin CD37 leads to constitutive activation of the IL-6 pathway which has important consequences for the development of B cell lymphoma and clinical outcome of patients.
Principle investigator: Annemiek van Spriel
Postdocs: Sjoerd van Deventer
PhD students: Lotte de Winde, Vera Dunlock
Technicians: Erik Jansen
Former lab members: Malou Zuidscherwoude, Sharon Veenbergen, Alie van der Schaaf