Regulation of MHC class II and CD86 expression by March-I in immunity and disease

Abstract

The expression of MHC-II and CD86 on the surface of antigen-presenting cells (APCs) must be tightly regulated to foster antigen-specific CD4 T-cell activation and to prevent autoimmunity. Surface expression of these proteins is regulated by their dynamic ubiquitination by the E3 ubiquitin ligase March-I. March-I promotes turnover of peptide-MHC-II complexes on resting APCs and termination of March-I expression promotes MHC-II and CD86 surface stability. In this review, we will highlight recent studies examining March-I function in both normal and pathological conditions.

Figure 1

LEFT PANEL: MHC-II αβ dimers associate with Invariant chain (Ii) in the endoplasmic reticulum, traffic through the Golgi apparatus, and are delivered to the plasma membrane. MHC-II-Ii complexes are internalized by clathrin-mediated endocytosis and traffic to multivesicular antigen processing compartments. Some of these complexes sort onto the intralumenal vesicles of multivesicular antigen processing compartments, where Ii is degraded until only a small fragment of Ii remains bound to MHC-II. Following removal of residual Ii-derived peptides from the peptide binding groove of MHC-II and high affinity peptide binding, pMHC-II complexes traffic to the plasma membrane. MIDDLE PANEL: After arrival at the cell surface, pMHC-II internalizes to early endosomes by clathrin-independent endocytosis. In resting DCs and B cells, pMHC-II is ubiquitinated by the E3 ubiquitin ligase March-I either at the plasma membrane or in early endosomes and is targeted for lysosomal degradation. RIGHT PANEL: Activation of APCs (for example, by engagement of TLR ligands) results in rapid down-regulation of March-I expression. Internalized pMHC-II is therefore not ubiquitinated and returns to the plasma membrane by Rab11a-dependent recycling, thereby prolonging pMHC-II half-life and stabilizing pMHC-II complexes on the plasma membrane.