MHC class II compartment subtypes: structure and function

MHC class II compartment subtypes: structure and functionLawrence J Stern1, Ilaria Potolicchio2 and Laura Santambrogio3

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.

Addresses1Department of Pathology University of Massachusetts Medical School

Worcester, MA 01655, USA2Division of Immunology and Allergy, Centre Hospitalier Universitaire

Vaudois, Lausanne, CH, Switzerland3Department of Pathology Albert Einstein College of Medicine, New

York, NY 10461, USA

Corresponding author: Santambrogio, Laura ([email protected])

Current Opinion in Immunology 2006, 18:64–69

This review comes from a themed issue on

Antigen processing and recognition

Edited by Steven Porcelli and Gunter Hammerling

Available online 6th December 2005

0952-7915/$ – see front matter

# 2005 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.coi.2005.11.005

IntroductionLate 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-asso-

ciated membrane protein (Lamp) protein family mem-

bers [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 com-

bination of both— and that these differences are likely to

reflect different maturative stages, have long been appre-

ciated [6,7]. However, the biological significance asso-

ciated 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 traf-

ficking, have been extensively discussed in other reviews

and will not be discussed here [8,9].

Multivesicular MIICMultivesicular 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 developing in the process of vesiculation,

which gives rise to the MVB, and of retrograde fusion,

which allows vesicles to fuse back with the limiting

membrane: the former is closely intertwined with

MHC class II–invariant chain (Ii) arrival from the

trans-golgi network and the latter is involved in MHC

class II–peptide transport to the cell surface [12–16].

In regard to the biogenesis of these compartments, it has

been shown recently that fibroblast stimulation with

epidermal growth factor (EGF) increases the number

of MVBs, as well as the number of internal vesicles per

compartment. This is done by way of a process that is, in

part, related to the transport of phosphorylated EGF

www.sciencedirect.com

MHC class II compartment subtypes Stern, Potolicchio and Santambrogio 65

Figure 1

Schematic representation of MIICs. In professional APCs, both multivesicular (MVB) and multilamellar (MLB) MIICs have been described.

The open/empty conformation of HLA-DR (red) has only been observed in the MLB type. HLA-DM (green) is expressed in both compartments,

albeit particularly abundant in MLB. The carboxy and amino terminals of invariant chains are still evident in MVBs whereas are mostly processed in

MLBs. Electrondense bodies (EDBs) are lysosomal-like MIICs, and have been observed in human monocytes and in GM-CSF differentiated

monocytes. See the text for further details.

receptor (EGF-R) to the MVB and Annexin-1-dependent

inward vesiculation (other members of the Annexin

family have shown to play important roles in the endo-

cytic pathway, involving the generation, localization or

fusion of endocytic compartments) [17�]. This was the

first observation that a growth factor can induce MVB

formation. Similarly, in human monocytes, an increase in

the number of MVBs per cell was observed upon differ-

entiation with granulocyte-macrophage colony-stimulat-

ing factor (GM-CSF) along with a positive correlation

between the number of MVBs per cell and the amount of

total surface HLA-DR [18��]. Thus, during the matura-

tive process, which converts human monocytes to profes-

sional dendritic cells (DCs), up-regulation of the number

of MVBs as well as of the amount of internal vesicles per

MVB occurs. The increased biogenesis ofMVBs and their

vesicular contents upon growth factor stimulation indi-

cates that there is a significant increase in the amount of

cellular membrane conveyed to endosomal compart-

ments. It is likely that in the pre-DC once the endosomal

and lysosomal compartments are on their way to becom-

ing further specialized in MHC class II loading, there is

an increased flux of proteins involved in antigen proces-

sing and an upregulation of the antigen loading machin-

ery. Previous reports have indicated that GM-CSF

stimulation does increase HLA-DR, Ii and HLA-DM


synthesis in several non-professional antigen-presenting

cells (APCs) [18��,19,20]. In this line of research, it has

also recently been reported that the negative charges

provided by acidic residues in the cytoplasmic tail of Ii

located upstream of the Leu-based sorting signals serve to

regulate endosomal morphology and vacuolation [21,22].

These data not only indicate a new biological function of

Ii but also open the field to future investigation of how

proteins involved in MHC class II transport and loading

can shape endosomal compartments to best fit their

functions.

Additional observations relating to MVB vesicle forma-

tion indicate that there is more than one type of internal

membrane. Vesicles that contain EGF-R internalized

from the cell surface require Annexin 1 for their formation

[17�], whereas vesicles that contain the lipid lysobispho-

sphatidic acid bis (monoacylglycerol) phosphate (LBPA)

require Alix for their biogenesis [23�]. Alix is a cytosolic

protein that interacts with the endosomal sorting com-

plexes required for transport system and controls the

limiting membrane invagination and the inward fission

process from which the internal vesicles originate [23�].Both vesicles are distinct inside the MVB [17�]. It waspreviously accepted that proteins differentially sort

between the limiting and internal MVB membranes, as


66 Antigen processing and recognition

proteins that are meant to recycle back to the plasma

membrane (e.g. the transferrin receptor) were found

particularly enriched on the MVB-limiting membrane,

whereas proteins intended for degradation (e.g. the inter-

nalized EGF-R) were sorted to the internal vesicles for

further lysosomal transport [24–26]. It was also known

that the lipid and protein composition differ between the

limiting membrane and the internal vesicles, with tetra-

spanins, cholesterol and LBPA being particularly

enriched on the inner membranes [27]. These new

reports indicate that the internal structures could also

be much more heterogeneous then previously thought. In

MVBs from professional APCs, a clear demonstration of

the heterogeneity of internal vesicles in relation to MHC

class II, Ii or sorting processes is still lacking. However,

purified exosomes, which derive from the release of

internal vesicles of MVB upon fusion with the plasma

membrane, are particularly enriched in cluster of differ-

entiation (CD)63 — an MHC-class-II-associated tetra-

spanin — but not in LBPA [28]; this indicates that

subpopulations of MVBs or MHC class II+ vesicles within

MVBs might exist.

Recently the three-dimensional structure of MVB in

immature murine DCs was also reported. Electron tomo-

graphy on cryo-immobilized cells had confirmed that the

inner vesicles are not interconnected with the external

limiting membrane [29] and that MHC class II proteins

are distributed on both the limiting membrane and the

internal vesicles. A similar distribution is also observed for

HLA-DM [30]. Upon lipopolysaccharide stimulation a

retrograde fusion event occurs that allows the inner

vesicles to fuse back with the perimetral membrane

and permits peptide-loaded MHC class II proteins to

reach the outer membrane of the compartments for

delivery at the cell surface [30]. On the basis of the

ultrastructural analysis, the authors propose a model by

which the association between MHC class II and H2-M

only occurs on the limiting membrane of the organelle at

the time of the fusion. This form of regulated retrograde

transport appears to be specific to DCs, and can explain

how the highly efficient surface MHC class II transport

occurs without a concomitant release of lysosomal

enzymes [30,31].

Multilamellar MIICA lysosomal-like compartment formed by concentric

lamellae and particularly enriched in MHC class II mole-

cules 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

[33–35], 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 these proteins induced formation of multilamellar

structures that were Lamp-1-, Cathepsin-D- and


CD63-positive and that closely resembled MLB [36].

Similarly, an increase in the number of MLBs was

observed for human monocytes differentiated into DCs

using GM-CSF and interleukin 4 [18��]. Because an

increased synthesis of HLA-DR is observed during

monocyte-to-DC differentiation, it appears possible that

the formation of multilamellar endocytic structures is, at

least in part, triggered by the new synthesis of MHC class

II and Ii proteins. As with MVB, qualitative and quanti-

tative differences have been reported in the composition

of the internal and external membranes ofMLB.Whereas

HLA-DR (empty or loaded) andHLA-DM are present on

both membranes, the tetraspanins CD63 and CD68 are

preferentially expressed in the internal membranes

[37,38�]. Also, cholesterol and LBPA are mostly enriched

in the internal membrane [27]. The physiological rele-

vance of this differential distribution is currently unclear,

even though it has been reported that physical association

between HLA-DM and HLA-DR occurs preferentially

on the internal structures of the MIIC; this leads to the

suggestion that that the absence of HLA-DR–HLA-DM

interactions on the limiting membrane prevents MHC

class II loading [39��]. Thus, the differential membrane

composition could affect MHC class II loading.

A recently performed three-dimensional reconstruction

of MLBs reveals that they are organized in a concentric

series of independent membrane rings. Although there is

no contact between the limiting membrane and the

internal sheets, some invaginations of the outer mem-

brane penetrate the inner layers [40�]. On the basis of

morphological observations, the authors propose a model

in which the inner sheets in MLB form after progressive

rounds of internalisation of the outer membrane. It is not

clear how MHC class II–peptide complexes from such

structures reach the cell surface. As an alternative to the

cell surface fusion of organelles [41], transport of mole-

cules fromMIIC has been also described to occur through

compartment tubulation. The emergence of tubular

structures from the MLB has been described in human

DCs after treatment with lipopolysaccharide, which sug-

gests that this as a possible route [37]. However, as no

membrane continuity between the internal and the exter-

nal membranes was identified by electron tomography,

the authors of that study argued that the MHC class II

molecules are trapped within the inner layers and that

transport of molecules to the cell surface, if it occurs at all,

might involve only the external membrane. Thus, even

though MLBs can be defined as MHC-II-loading com-

partments, the modality of MHC class II transport to the

cell surface from the MLB is still unclear.

Until recently, a clear biochemical signature that distin-

guishes MVBs fromMLBs was not known; this is because

all proteins known to be expressed in one compartment

were also expressed in the other, albeit in different

quantities or, in case of Ii, in differently processed forms



Figure 2

The open/empty form of HLA-DR is more highly expressed in lysosomal MLB MIICs than in late endosomal MVB MIICs. Ultrathin cryosection

of MIICs in human monocytes differentiated with GM-CSF and interleukin 4. Immunolabelling is performed with MEM-265 (15 nm gold), an antibody

specific for open/empty HLA-DR [48], and with rabbit sera to HLA-DR (10 nm gold). Multivesicular bodies (MVBs) and multilamellar bodies (MLBs)

are labeled. More details are presented in [18��]. This is the first evidence that conformational variants of HLA-DR are polarized between

ultrastructurally different MIIC. The understanding of how differential HLA-DR conformations relate to qualitative and quantitative differences in

antigen processing and MHC II loading is still to be determined.

[18��,32,42]. We have recently reported that MLBs

uniquely express an open/empty conformation of HLA-

DR (Figure 2), which can be identified using specific

antibodies; this clearly establishes— for the first time— a

qualitative difference between MVBs and MLBs and

opens the field to future investigations of differences

in the modality of antigen processing and loading

between the two compartments [18��].

Electrondense bodiesElectron 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 com-

partments are delimitated by a single perimetral mem-

brane 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 myeloperoxidase-positive secre-

tory lysosomes observed in monocytes and in cytotoxic T

cells. These secretory lysosomes can release their con-

tents upon fusion of their limiting membrane with the

plasma membrane. In doing so, membrane proteins can

be transported at the cell surface and soluble lysosomal

enzymes are released extracellularly. This form of secre-

tion is less sophisticated than the regulated retrograde

transport described for MVBs, which appear to specifi-

cally single out MHC class II–peptide complexes for


surface transport while retaining lysosomal enzymes

[31]. These compartments were only recently described

and their role in processing and presentation compared to

the more professional MVBs and MLBs still remain to be

further defined [18��,43].

ConclusionsThe differential ultrastructure of MVBs and MLBs,

reflective of their differential lipid and protein composi-

tion, 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 lyso-

somal compartments at low pH can be conformationally

different from MHC class II bound to the same peptide

but generated at a more neutral pH, for example at the

cell surface or in early endosomes [45��]. The differences

are dependent upon HLA-DM, which edits out the

neutral pH conformation. Additional differences in pep-

tide generation and loading modality could exist between

MVB, MLB and EDB. An often reported difference

between MVBs and MLBs is the fact that in the latter

the amino and carboxy terminals of Ii are proteolyzed, and

the peptide-editing molecule HLA-DM is expressed at

higher levels [7,18��,42,46,47]. In addition, we have

recently reported that the empty/open conformation of


68 Antigen processing and recognition

HLA-DR is uniquely expressed in MLB [18��]. These

differences could, in part, be explained by the lower pH

present in the MLB, which can facilitate Ii proteolysis by

cathepsins as well as formation of empty HLA-DR. A

challenge for the future is to quantify differences in

antigen processing and modality of antigen MHC class

II loading between structurally different MIICs.

AcknowledgementsWe would like to thank Sebastian Amigorena for critical reading of thereview

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest�� of outstanding interest

1. de Duve C: The lysosome turns fifty. Nat Cell Biol 2005,7:847-849.

2. Chang MH, Karageorgos LE, Meikle PJ: CD107a (LAMP-1)and CD107b (LAMP-2). J Biol Regul Homeost Agents 2002,16:147-151.

3. Riese RJ, Chapman HA: Cathepsins and compartmentalizationin antigen presentation. Curr Opin Immunol 2000, 12:107-113.

4. Neefjes JJ, Stollorz V, Peters PJ, Geuze HJ, Ploegh HL: Thebiosynthetic pathway ofMHC class II but not class I moleculesintersects the endocytic route. Cell 1990, 61:171-183.

5. Geuze HJ: The role of endosomes and lysosomes inMHC classII functioning. Immunol Today 1998, 19:282-287.

6. Kleijmeer MJ, Raposo G, Geuze HJ: Characterization of MHCclass II compartments by immunoelectron microscopy.Methods 1996, 10:191-207.

7. Kleijmeer MJ, Morkowski S, Griffith JM, Rudensky AY, Geuze HJ:Major histocompatibility complex class II compartments inhuman and mouse B lymphoblasts represent conventionalendocytic compartments. J Cell Biol 1997, 139:639-649.

8. Katzmann DJ, Odorizzi G, Emr SD: Receptor downregulationand multivesicular-body sorting. Nat Rev Mol Cell Biol 2002,3:893-905.

9. Robinson MS, Bonifacino JS: Adaptor-related proteins.Curr Opin Cell Biol 2001, 13:444-453.

10. Neefjes J: CIIV, MIIC and other compartments for MHC class IIloading. Eur J Immunol 1999, 29:1421-1425.

11. Gruenberg J, Stenmark H: The biogenesis of multivesicularendosomes. Nat Rev Mol Cell Biol 2004, 5:317-323.

12. ChowA, ToomreD,GarrettW,Mellman I:Dendriticcellmaturationtriggers retrograde MHC class II transport from lysosomes tothe plasma membrane. Nature 2002, 418:988-994.

13. Murk JL, Stoorvogel W, Kleijmeer MJ, Geuze HJ: The plasticity ofmultivesicular bodies and the regulation of antigenpresentation. Semin Cell Dev Biol 2002, 13:303-311.

14. Boes M, Bertho N, Cerny J, Op den Brouw M, Kirchhausen T,Ploegh H: T cells induce extended class II MHC compartmentsin dendritic cells in a Toll-like receptor-dependent manner.J Immunol 2003, 171:4081-4088.

15. McCormick PJ, Martina JA, Bonifacino JS: Involvement ofclathrin and AP-2 in the trafficking of MHC class IImolecules to antigen-processing compartments.Proc Natl Acad Sci USA 2005, 102:7910-7915.

16. Dugast M, Toussaint H, Dousset C, Benaroch P: AP2 clathrinadaptor complex, but not AP1, controls the access of themajor histocompatibility complex (MHC) class II toendosomes. J Biol Chem 2005, 280:19656-19664.


17.�

White IJ, Bailey LM, Aghakhani MR, Moss SE, Futter CE: EGFstimulates annexin 1-dependent inward vesiculation in amultivesicular endosome subpopulation. Embo J 2005, in press.

This is a first report that a growth factor induces MVB formation andincreases the number of internal vesicles.

18.��

Potolicchio I, Chitta S, Xu X, Fonseca D, Crisi G, Horejsi V,Strominger JL, Stern LJ, Raposo G, Santambrogio L:Conformational variation of surface class II MHC proteinsduring myeloid dendritic cell differentiation accompaniesstructural changes in lysosomal MIIC. J Immunol 2005,175:4935-4947.

The first report that the open empty conformation of HLA-DR is onlyobserved in lysosomal MIICs (EDBs and MLBs), and not in late endoso-mal MIICs (MVBs).

19. Re F, Belyanskaya SL, Riese RJ, Cipriani B, Fischer FR,Granucci F, Ricciardi-Castagnoli P, Brosnan C, Stern LJ,Strominger JL et al.: Granulocyte-macrophage colony-stimulating factor induces an expression program inneonatal microglia that primes them for antigen presentation.J Immunol 2002, 169:2264-2273.

20. Hornell TM, Beresford GW, Bushey A, Boss JM, Mellins ED:Regulation of the class II MHC pathway in primary humanmonocytes by granulocyte-macrophage colony-stimulatingfactor. J Immunol 2003, 171:2374-2383.

21. Bakke O, Nordeng TW: Intracellular traffic to compartments forMHC class II peptide loading: signals for endosomal andpolarized sorting. Immunol Rev 1999, 172:171-187.

22. Nordeng TW, Gregers TF, Kongsvik TL, Meresse S, Gorvel JP,Jourdan F, Motta A, Bakke O: The cytoplasmic tail of invariantchain regulates endosome fusion and morphology.Mol Biol Cell 2002, 13:1846-1856.

23.�

Matsuo H, Chevallier J, Mayran N, Le Blanc I, Ferguson C,Faure J, Blanc NS, Matile S, Dubochet J, Sadoul R et al.:Role of LBPA and Alix in multivesicular liposomeformation and endosome organization. Science 2004,303:531-534.

This is the first report that it is necessary for LBPA to associate with Alixfor vesicles to form in MVBs.

24. Hopkins CR, Miller K, Beardmore JM: Receptor-mediatedendocytosis of transferrin and epidermal growth factorreceptors: a comparison of constitutive and ligand-induceduptake. J Cell Sci Suppl 1985, 3:173-186.

25. Futter CE, Pearse A, Hewlett LJ, Hopkins CR: Multivesicularendosomes containing internalized EGF-EGF receptorcomplexes mature and then fuse directly with lysosomes.J Cell Biol 1996, 132:1011-1023.

26. Bonifacino JS, Traub LM: Signals for sorting of transmembraneproteins to endosomes and lysosomes. Annu Rev Biochem2003, 72:395-447.

27. Gruenberg J: Lipids in endocytic membrane transport andsorting. Curr Opin Cell Biol 2003, 15:382-388.

28. Wubbolts R, Leckie RS, Veenhuizen PT, Schwarzmann G,Mobius W, Hoernschemeyer J, Slot JW, Geuze HJ, Stoorvogel W:Proteomic and biochemical analyses of human B cell-derivedexosomes. Potential implications for their function andmultivesicular body formation. J Biol Chem 2003,278:10963-10972.

29. Murk JL, Humbel BM, Ziese U, Griffith JM, Posthuma G, Slot JW,Koster AJ, Verkleij AJ, Geuze HJ, Kleijmeer MJ: Endosomalcompartmentalization in three dimensions: implicationsfor membrane fusion. Proc Natl Acad Sci USA 2003,100:13332-13337.

30. Kleijmeer M, Ramm G, Schuurhuis D, Griffith J, Rescigno M,Ricciardi-Castagnoli P, Rudensky AY, Ossendorp F, Melief CJ,Stoorvogel W, Geuze HJ: Reorganization of multivesicularbodies regulates MHC class II antigen presentation bydendritic cells. J Cell Biol 2001, 155:53-63.

31. Chow AY, Mellman I: Old lysosomes, new tricks: MHC IIdynamics in DCs. Trends Immunol 2005, 26:72-78.

32. Pieters J, Horstmann H, Bakke O, Griffiths G, Lipp J: Intracellulartransport and localization ofmajor histocompatibility complex



class II molecules and associated invariant chain. J Cell Biol1991, 115:1213-1223.

33. Arkema JM, Schadee-Eestermans IL, Broekhuis-Fluitsma DM,Hoefsmit EC: Localization of class II molecules in storagevesicles, endosomes and lysosomes in human dendritic cells.Immunobiology 1991, 183:396-407.

34. Harding CV, Geuze HJ: Immunogenic peptides bind toclass II MHC molecules in an early lysosomal compartment.J Immunol 1993, 151:3988-3998.

35. Kleijmeer MJ, Morkowski S, Griffith JM, Rudensky AY,Geuze HJ: Major histocompatibility complex class IIcompartments in human andmouseB lymphoblasts representconventional endocytic compartments. J Cell Biol 1997,139:639-649.

36. Calafat J, Nijenhuis M, Janssen H, Tulp A, Dusseljee S,Wubbolts R, Neefjes J: Major histocompatibility complexclass II molecules induce the formation of endocytic MIIC-likestructures. J Cell Biol 1994, 126:967-977.

37. Barois N, de Saint-Vis B, Lebecque S, Geuze HJ, Kleijmeer MJ:MHC class II compartments in human dendritic cells undergoprofound structural changes upon activation. Traffic 2002,3:894-905.

38. Engering A, Kuhn L, Fluitsma D, Hoefsmit E, Pieters J: Differentialpost-translational modification of CD63 molecules duringmaturation of human dendritic cells. Eur J Biochem 2003,270:2412-2420.

39.��

Zwart W, Griekspoor A, Kuijl C, Marsman M, van Rheenen J,Janssen H, Calafat J, van Ham M, Janssen L, van Lith M et al.:Spatial separation of HLA-DM/HLA-DR interactions withinMIIC and phagosome-induced immune escape. Immunity 2005,22:221-233.

Analysis of the in vivo association between HLA-DR and HLA-DM inMIICs. Productive MHC class II loading was shown to occur in the innermembranes but not on the limiting membrane.

40.�

Murk JL, Lebbink MN, Humbel BM, Geerts WJ, Griffith JM,Langenberg DM, Verreck FA, Verkleij AJ, Koster AJ, Geuze HJ etal.: 3-D Structure of multilaminar lysosomes in antigen

Five things you might no

1.Elsevier is a founder member of the WHO’sHINARI andAGORA initiatito scientific literature. More than 1000 journals, including the Trend

significantly red

2.The online archive of Elsevier’s premier Cell Press journal co

Free access to the recent archive, including Cell, Neuron,ScienceDirect and the Cell Press journal sites

3.Have you contributed to an Elsevier journal, book or series? Did you kno

stand-alone CDs when ordered directly from us?

+1 800 782 4927 (US) or +1 800 460 31or +44 1865 474 010

4.Elsevier has a long tradition of liberal copyright policies a

preprints on public servers and the posting of final papers on internaallow authors to freely post the final text version of their papers on both

5.The Elsevier Foundation is a knowledge-centered foundation makingculturally rich global organization, the Foundation has funded, for ex

Philadelphia, provided storybooks to children in Cape Town, sponsorBrigham and Women’s Hospital and given funding to the 3rd Inter


presenting cells reveals trapping of MHC II on the internalmembranes. Traffic 2004, 5:936-945.

Three-dimensional reconstruction of MLBs and its implication for MHCclass II trafficking.

41. Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G: Thebiogenesis and functions of exosomes. Traffic 2002, 3:321-330.

42. Peters PJ, Raposo G, Neefjes JJ, Oorschot V, Leijendekker RL,Geuze HJ, Ploegh HL:Major histocompatibility complex class IIcompartments in human B lymphoblastoid cells are distinctfrom early endosomes. J Exp Med 1995, 182:325-334.

43. Greiner A, Lautwein A, Overkleeft HS, Weber E, Driessen C:Activity and subcellular distribution of cathepsins in primaryhuman monocytes. J Leukoc Biol 2003, 73:235-242.

44. Rath S, Lin RH, Rudensky A, Janeway CA Jr: T and B cellreceptors discriminate major histocompatibility complexclass II conformations influenced by the invariant chain.Eur J Immunol 1992, 22:2121-2127.

45.��

Pu Z, Lovitch SB, Bikoff EK, Unanue ER: T cells distinguishMHC-peptide complexes formed in separate vesicles andedited by H2-DM. Immunity 2004, 20:467-476.

Report that conformational variants of peptide-loaded MHC class IImolecules are generated by HLA-DM editing, and their implication forthe immune response.

46. Ferrari G, Knight AM, Watts C, Pieters J: Distinct intracellularcompartments involved in invariant chain degradation andantigenic peptide loading of major histocompatibility complex(MHC) class II molecules. J Cell Biol 1997, 139:1433-1446.

47. Pierre P, Denzin LK, Hammond C, Drake JR, Amigorena S,Cresswell P, Mellman I: HLA-DM is localized to conventionaland unconventional MHC class II-containing endocyticcompartments. Immunity 1996, 4:229-239.

48. Carven GJ, Chitta S, Hilgert I, Rushe MM, Baggio RF, Palmer M,Arenas JE, Strominger JL, Horejsi V, Santambrogio L et al.:Monoclonal antibodies specific for the empty conformationof HLA-DR1 reveal aspects of the conformational changeassociated with peptide binding. J Biol Chem 2004,279:16561-16570.

t know about Elsevier

ves, which enable the world’s poorest countries to gain free accesss and Current Opinion collections, will be available for free or atuced prices.

llection will become freely available from January 2005.Inmunity and Current Biology, will be available on both12 months after articles are first published.

w that all our authors are entitled to a 30% discount on books andFor more information, call our sales offices:

10 (Canada, South & Central America)(rest of the world)

nd for many years has permitted both the posting ofl servers. Now, Elsevier has extended its author posting policy totheir personal websites and institutional repositories or websites.

grants and contributions throughout the world. A reflection of ourample, the setting up of a video library to educate for children ined the creation of the Stanley L. Robbins Visiting Professorship atnational Conference on Children’s Health and the Environment.


MHC class II compartment subtypes: structure and function

Documents