MHC Class II Molecules

Structure:

Class II MHC genes encode two different polypeptide chains, an α chain and a Β chain which associate by noncovalent interactions. The peptide binding cleft in class II molecules is open at both ends, allowing longer peptides to extend beyond the ends, like a long hot dog in a bun. Peptides bound to class II MHC molecules maintain a fairly constant elevation on being cleft.

Antigen Processing:

MHC genes encode glycoproteins expressed primarily on antigen presenting cells (macrophages, dendritic cells, thymic epithelia cells and  B cells). Such glycoproteins present processed antigenic peptides to T_H (CD4 ⁺ cells). Class II MHC molecules bind peptides derived from exogenous antigens that are internalized by phagocytosis or endocytosis . Once an antigen is internalized, it is degraded into peptides within compartments of the endocytic processing pathway. Internalized antigen moves from early to late endosomes and finally to lysosomes, encountering lower pH in each compartment.

Since antigen-presenting cells express both class I and II MHC molecules, a mechanism exists to prevent class II MHC molecules which are synthesized within the RER, from binding to the same set of antigenic peptides as the class I molecules. A special polypeptide, called the invariant chain, ensures this by associating with newly synthesized class II MHC heterodimers in the ER. Part of its polypetide chain lies within the peptide binding groove of the MHC protein, thereby blocking the groove from binding other peptides in the lumen of the ER.

The invariant chain also directs class II MHC proteins from the trans Golgi network to a late endosomal compartment. Here, the invariant chain is cleaved by proteases, leaving only a short fragment bound in the peptide binding groove of the MHC protein, called CLIP (class II associated invariant chain peptide). HLA-DM, a nonclassical MHC class II molecule expressed within endosomal compartments, mediates exchange of antigenic peptides for CLIP.

Monocytes and macrophages that have not interacted with antigen express only low levels of class II molecules. Sometimes class II expression is related to the cell's differentiation stage. For example, class II molecules cannot be detected on preB cells but are expressed on the membrane of mature B cells.