Abstract
Invariant chain (Ii/CD74) has been identified as a surface receptor for migration inhibitory factor (MIF). Most cells that express Ii also synthesize major histocompatibility complex class II (MHC II) molecules, which depend on Ii as a chaperone and a targeting factor. The assembly of nonameric complexes consisting of one Ii trimer and three MHC II molecules (each of which is a heterodimer) has been regarded as a prerequisite for efficient delivery to the cell surface. Due to rapid endocytosis, however, only low levels of Ii-MHC II complexes are displayed on the cell surface of professional antigen presenting cells and very little free Ii trimers. The association of Ii and MHC II has been reported to block the interaction with MIF, thus questioning the role of surface Ii as a receptor for MIF on MHC II-expressing cells. Recent work offers a potential solution to this conundrum: Many Ii-complexes at the cell surface appear to be under-saturated with MHC II, leaving unoccupied Ii subunits as potential binding sites for MIF. Some of this work also sheds light on novel aspects of signal transduction by Ii-bound MIF in B-lymphocytes: membrane raft association of Ii-MHC II complexes enables MIF to target Ii-MHC II to antigen-clustered B-cell-receptors (BCR) and to foster BCR-driven signaling and intracellular trafficking.
Highlights
Invariant chain (Ii/CD74) leads at least two lives that so far remain strangely unconnected: its first life was unraveled by identifying Ii as a non-polymorphic, invariant, polypeptide associated with polymorphic major histocompatibility complex class II (MHC II) molecules in the late 1970s [1]
Professional antigen presenting cells express only very few free Ii/CD74 trimers at the cell surface that can serve as receptors for the cytokine migration inhibitory factor (MIF)
Professional antigen presenting cells express only very few free Ii/CD74 trimers at the cell under-saturated Ii complexes is present at this location in the form of pentamers (Ii3(ab)) and surface that can serve as receptors for the cytokine MIF
Summary
Invariant chain (Ii/CD74) leads at least two lives that so far remain strangely unconnected: its first life was unraveled by identifying Ii as a non-polymorphic, invariant, polypeptide associated with polymorphic major histocompatibility complex class II (MHC II) molecules in the late 1970s [1]. Several co-receptors that assist Ii in signal transduction have been identified in the meantime and signal transduction pathways have been assigned to MIF-Ii-coreceptor complexes [20,21,22,23,24,25,26,27,28,29]. These findings firmly establish Ii in the cytokine/signal transduction field. Invariant chain has been the topic of an excellent recent review by Schröder [30] and the readers are referred to this paper for a concise coverage of Ii biology
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