Transport and function of co-stimulatory ligand CD70

• Antragsteller: Dr. Ulf Geumann
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2010 bis 2013
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 183792157

T cells are key elements in the adaptive immune response. As a first step in T cell activation, the T cell receptor recognizes an antigenic peptide bound to MHC which is usually presented by dendritic cells (DCs). This antigen recognition only leads to clonal amplification of antigen specific T cells if they receive further input by co-stimulatory receptors. An important interaction in this context is the one between CD70 on DCs and its receptor CD27 (a member of the TNF receptor family) on T cells. CD70 protein is normally sequestered in late endosomal vesicles that also contain MHC class II (so-called MIICs) and is only brought to the plasma membrane when the DC forms an immune synapse with a specific T cell. In this way, antigen presentation and co-stimulation are coordinated in time and space. My goal is to gain insight into the molecular mechanisms that regulate the transport of CD70 and related co-stimulatory ligands. Recent work in the host laboratory has identified the MHC class II chaperone Invariant chain (Ii) as the molecule that guides CD70 to MIICs. Their collaborators (the Neefjes laboratory) have identified potential novel regulators of MIIC transport. I will build on these findings to establish by which route and mechanism CD70 reaches MIICs and the cell surface by applying biochemical, genetic and microscopic approaches. For this purpose, I will use model cell lines as well as primary DCs. Protocols for efficient exogenous gene expression in DCs have been established and will permit us to follow trafficking of molecules of interest in real time, also during physiological interaction with T cells. Furthermore, it will be investigated whether the mechanisms of intracellular transport that we elucidate also apply to other co-stimulatory ligands that perform key functions in DCs. It is expected that this work will give important insights in the regulatory principles that dictate the initiation and course of the T cell response.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: Niederlande
• Gastgeberin: Professorin Dr. Jannie Borst