Cd74, invariant chain, a modulator of endosomal maturation and potential cancer immunotherapy vaccine
Invariant chain (CD74, Ii) is a multifunctional molecule expressed in antigen presenting cells – mostly in concert with MHC II but also decoupled, for instance in mature dendritic cells (DCs). In addition CD74, which is mostly rapidly internalized from the plasma membrane is a membrane receptor for MIF, macrophage migration inhibitory factor.
CD74, with its two leucine based endosomal sorting signals that binds AP1 and AP2 adaptors was first found to be an essential partner for the proper trafficking of MHC II and therefore efficient antigen loading in the endosomal pathway and antigen presentation. A portion of CD74, CLIP, occupies the antigen binding groove of MHCII before it is replaced by a more specific antigen. The trimeric CD74 delays furthermore endosomal maturation participating in forming the peptide loading compartment. This property depends on a complete molecule and can be eliminated by a single point mutation of the cytosolic tail. The trimeric molecule hasendosomal fusion properties independent on Rab5, PI3 kinase and EEA1 and I will discuss its role in endosomal maturation and how this property can be exploited to study maturation, endosmal fusion, fission and for studying endosomal membrane kinetics after tyrosine kinase receptor activation.
Interestingly, CD74 has been found to interact with several molecules including MHCI and can be used as a vector for simultaneously increasing both MHCI and MHCII mediated immune responses towards specific antigens and is ready to be tested in clinical therapeutic DC based cancer immunotherapy.
Head of NorMIC
CoE Center for Immune Regulation (CIR), University of Oslo, Norway
Directeur Unité UMR144