MHC class II compartment subtypes: structure and function

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Reports from the past couple of years point to an emerging association of the biogenesis, composition and ultrastructural morphology of MHC class II compartments (MIICs) with their functions in antigen processing and loading. Growth factors and cytokines involved in dendritic cell maturation have been shown to regulate MIIC biogenesis, and the MHC-class-II-associated invariant chain chaperone has been reported to regulate endosomal morphology and vacuolation. Differences among ultrastructurally distinct MIICs have begun to be appreciated with regard to variation in antigen loading capacity and to polarization of MHC class II conformational variants among different compartments. Finally, the MIIC ultrastructure organizes the mechanism of MHC class II surface trafficking. Together, these findings begin to shed light on the connection between MIIC protein content, MIIC morphology and MHC class II-related antigen processing.

Introduction

Late endosomes and lysosomal organelles are sub-cellular compartments, which in all cell types are the site of degradation of both endogenous and exogenous materials [1]. These organelles are characterized by acidic pH, the presence of proteases and expression of lysosome-associated membrane protein (Lamp) protein family members [2, 3]. Lysosomal compartments are used also in several immune and non-immune cell types to perform specific functions distinct from protein degradation. Indeed, in professional antigen presenting cells, late endosomes and lysosomes are enriched in MHC class II proteins and in other molecules involved in peptide processing, loading and editing (human leukocyte antigen [HLA]-DM, HLA-DO, gamma-interferon-inducible lysosomal thiol reductase, and cathepsins), and become specialized organelles termed MIICs (for MHC class II containing compartments). It is in these that most antigen processing and MHC class II loading occurs [4, 5]. The observations that MIIC can appear with different morphologies — multivesicular, multilamellar, or a combination of both — and that these differences are likely to reflect different maturative stages, have long been appreciated [6, 7]. However, the biological significance associated with the different morphologies and the exact contribution of each compartment to antigen processing and MHC class II loading processes are still ill-defined (Figure 1). During the past couple of years, several reports have begun to shed light on the relationship between MIIC biogenesis, ultrastructural morphology, protein composition and specific roles in antigen processing and presentation.

This new body of information will be the focus of this review. Contribution of the molecular mechanism of endosomal protein sorting (endosomal sorting complexes required for transport [ESCORT], ubiquination and adaptor protein complexes [AP]-1, -2, -3 and -4 adaptors), which also play a role in endosomal formation and trafficking, have been extensively discussed in other reviews and will not be discussed here [8, 9].

Section snippets

Multivesicular MIIC

Multivesicular bodies (MVBs) are a type of MIICs that have a diameter of between 400 and 500 nm. They are composed of a limiting membrane that encloses several internal vesicles that have diameters of between 40 and 90 nm [10, 11]. They are commonly described as late endosomal compartments and are enriched in MHC class II proteins. MVBs receive bio-synthetic cargo from the trans-Golgi network, as well as molecules that have been internalized by way of endocytosis [5]. An increasing interest is

Multilamellar MIIC

A lysosomal-like compartment formed by concentric lamellae and particularly enriched in MHC class II molecules was the first MIIC to be identified [32] (Figure 1). These multilamellar bodies (MLBs) are more specifically expressed in APCs, such as DCs, B cells and macrophages [33, 34, 35], compared with MVBs, which are ubiquitously distributed. The biogenesis of MLBs appears to be dependent on the presence of MHC class II and Ii. In fact, transfection of kidney epithelial cells that had both of

Electrondense bodies

Electron dense bodies (EDBs) have recently been described as a novel lysosomal-like MIIC (Lamp-1+, HLA-DR+ and HLA-DM+) that is present in peripheral CD14+ human monocytes [18••] (Figure 1). These compartments are delimitated by a single perimetral membrane and are occupied by electrondense material. Among APCs and related cell types, these compartments have, to date, been found together with MVBs in human monocytes and in pre-DC populations [18••]. EDBs have a similar structure to the

Conclusions

The differential ultrastructure of MVBs and MLBs, reflective of their differential lipid and protein composition, has long been known. However, the degree to which this differential endosomal morphology affects antigen presentation has only begun to be appreciated. It has recently been reported that differential loading pathways produce distinct MHC class II–peptide conformers that differentially prime T cells [44, 45••]. MHC class II–peptide complexes formed in late endosomal and lysosomal

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank Sebastian Amigorena for critical reading of the review

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