MHC class II molecules on the move for successful antigen presentation

Abstract

Major histocompatibility complex class II (MHC II) molecules are targeted to endocytic compartments, known as MIIC, by the invariant chain (Ii) that is degraded upon arrival in these compartments. MHC II acquire antigenic fragments from endocytosed proteins for presentation at the cell surface. In a unique and complex series of reactions, MHC II succeed in exchanging a remaining fragment of Ii for other protein fragments in subdomains of MIIC before transport to the cell surface. Here, the mechanisms regulating loading and intracellular trafficking of MHC II are discussed.

Figure 1

The cell biology of antigen presentation by MHC II. MHC II αβ heterodimers are assembled in the endoplasmic reticulum (ER) and form a peptide-binding groove that is occupied by Ii. Ii chaperones MHC II often directly (route 1; black solid arrows) and sometimes indirectly after internalization from the cell surface (route 2; gray dashed arrows) into MIIC where Ii is degraded by a series of endosomal proteases with the CLIP fragment remaining (orange). HLA-DM assists exchange of CLIP for relevant exogenous antigenic fragments (red or yellow) in subdomains of MIIC (the internal vesicles) prior to transport for stable integration in the plasma membrane (blue arrows in MIIC) unless internalization is induced by processes like ubiquitination (Ub) of the MHC II β-chain cytoplasmic tail (route 3; pink dashed arrow).

Figure 2

Reciprocal coordination of motor proteins for bidirectional microtubule-based MIIC transport. Left: control of inward transport of MIIC toward the microtubule minus-end. Right: control of plus end-directed transport of MIIC to the cell periphery. Activation of Rab7 precedes formation of the tripartite Rab7-RILP-ORP1L complex. RILP interacts with the dynactin subunit p150^Glued (a). Dynactin then interacts either with dynein (b(−)) or kinesin-2 (KIF3) (b(+)) motor proteins, specifying the direction of vesicle transport. Motor activity requires binding to a second LE membrane receptor, βIII spectrin (c(−)). Full activation of kinesin-2 may require a similar interaction with a general receptor on MIIC (c(+)). In this model, the p150^Glued-associated type of motor specifies the direction of MIIC transport (d).