MHC class II trafficking function and antigen presentation

Invariant chain structure and its functions

The two MHC class II molecule forms a peptide binding groove between the ?1 and ?1 domains , the ? chain contributing most of the specificity When first synthesized , this binding is prevented by a protein called the invariant chain , which is progressively cleaved off and replaced newly produced peptides in the endosomes (Chain and Playfair , 2001 br

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Recently , it has been demonstrated that expression of the invariant chain (Ii ) facilitates the presentation of various antigens by major histocompatibility complex (class II ) molecules . Ii is a

type II membrane protein with the C terminal domain expressed at the luminal side of the endoplasmic reticulum membrane . The following support for two roles of Ii was found . I ) Ii carries a signal sequence on its cytoplastic domain that is responsible for sorting Ii and associated MHC class II molecules from the secretory to endocytic route . ii ) Ii impedes loading of peptides to the MHC class II grooves (Freisewinkel et al 1993 ? and ? chains bind to unfolded ER polypeptides and are largely contained in aggregates , including the immunoglobulin binding protein Ii binds to the peptide binding cleft and to some other regions of heterodimers and stabilizes the conformation of MHCII molecules (Germain and Rinker , 1993

CLIP region and its function

The exchange of CLIP for an appropriate antigenic peptide occurs in a late esdosomal compartment known as MHC class II compartment . The ? DM dimer remains intracellular and is abundant in MHC vesicles . DM molecules appear to bind and stabilize classical class II dimmers and catalyze the removal of CLIP from the antigen binding groove to allow the binding of other antigenic peptides available in the compartment (Koopman , Moorland ,

.599 . MHC class II molecules associate with the invariant chain (Ii ) in the endoplasmic reticulum (ER ) of antigen-presenting cells (APCs , with the CLIP (class-II-associated Ii peptide ) region of Ii occupying the peptide-binding groove of the class II a-b heterodimer . This association serves both to prevent peptide binding to the class II molecules within the ER and to direct class II molecules into the endosomal /lysosomal pathway , where antigen processing and assembly of peptide-loaded MHC class II molecules occur (Watts 1997

The endosomal /lysosomal system is rich in proteases , particularly cysteine proteases , and these enzymes are crucial both for the generation of peptides from antigenic proteins , and for the removal of Ii from class II molecules . CLIP is the final fragment of Ii and is generated by the protease cathepsin S (Riese , 1996 . CLIP is not spontaneously released from class II molecules in most cases , and exchange of this fragment for antigenic peptides is mediated by the accessory protein DM [HLA-DM in humans , H2-DM in the mouse] (Morris et al , 1994

DM was initially identified because cells that lacked this protein expressed high levels of CLIP-MHC-class-II complexes at their cell surface , and as a consequence had an altered reactivity with certain class II reactive monoclonal antibodies (Mellins et al , 1990 . DM is mainly localized in the vesicles of the endosomal...