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A revised model for invariant

chain-mediated assembly of MHC

class II peptide receptors

Norbert Koch

1

, Alexander D. McLellan

2

and Ju¨rgen Neumann

1

1

Division of Immunobiology, Institute of Genetics, University of Bonn, Bonn, Germany 2Department of Microbiology and Immunology, University of Otago, Otago, New Zealand

The enormous number of allelic MHC class II

glycoproteins provides the immune system with a large set of heterodimeric receptors for the binding of pathogen-derived peptides. How do inherited allo- or isotypic subunits of MHC class II combine to produce such a variety of functional peptide receptors? We pro-pose a new mechanism in which pairing of matched MHC class II a- and b-subunits is coordinated by the invariant chain chaperone. The assembly is proposed to occur in a sequential fashion, with a matched b-chain being selected by thea-chain–invariant chain ‘scaffold’ complex that is formed first. This sequential assembly is a prerequisite for subsequent intracellular transport of the a-chain–invariant chain–b-oligomer and its matu-ration into a functional peptide receptor.

Inherited polymorphisms result in novel protein–protein interactions

It is estimated that60 000 single nucleotide polymorph-isms of the human genome are contained within genes[1]. This diversity generates a large number of genes that occur in several alleles. Due to the random combination of parental alleles in every generation of offspring, poly-morphic gene products are essentially expressed in a novel environment. In molecular terms, this means that the functional life span of a polymorphic protein is accom-panied by numerous novel interactions with other proteins. An extremely variable region of the genome, the MHC region, is an example of a highly regulated assembly of polymorphic proteins [2]. The MHC class II (MHCII) region encodes a great variety of proteins that serve the immune system by presenting antigenic peptides to CD4+helper T cells[3]. Evolutionary selection pressure by pathogenic microorganisms has ensured that MHCII genes display an extremely high level of polymorphism.[4]. To date, more than 870 MHCII allotypes have been ident-ified in the human population (European Bioinformatics Institute;www.ebi.ac.uk), from which600 proteins were expressed. This high polymorphism produces a great diver-sity of peptide receptors and enables the species to survey an amazing variety of peptide sequences derived from the multitude of pathogenic organisms.

The polymorphic MHCII a- and b-subunits combine

with the non-polymorphic invariant chain (Ii) to form a premature peptide receptor. The present model of MHCII subunit assembly suggests that a- and b-chains form a heterodimer, which binds to the trimer of Ii[5]. This model, however, does not explain how mismatched pairing, which

might occur between some of the polymorphic a- and

b-chains, is prevented. Here, we introduce a revised concept of how the enormous variety of MHCII subunits is matched by interaction with Ii to form functional peptide receptors.

Isotypic and haplotypic pairing of MHCII molecules

The human MHC consists of two regions, one containing the class IA,BandCgenes and one containing the class II

Dgenes. The class II region is divided into three subregions

that encode a- and b-subunits of the DP, DQ and DR

isotypes (note, in the mouse H2 region, two class II sub-regions encodea- andb-subunits of isotypes I-A and I-E; I denotes ‘immune response genes’). The duplication of genes, resulting in MHCII isotypes, has created additional diversity to the codominantly expressed alleles, at the level of individuals. In the sequence of MHCII, most polymorph-isms are concentrated in the first domain ofb-chains. DP and DQa-chains show some moderate allelic variations at the N-terminus of thea1 domain, whereas the DRa -encod-ing gene exhibits unremarkable genetic diversity. The mouse orthologs for DR (I-E) and DQ (I-A) exhibit a com-parable polymorphism.

The MHCIIab heterodimers present antigens (which

have been harvested in endocytic compartments and deliv-ered to the cell surface) for recognition by CD4+ T cells. During antigen loading, the cohort of MHCII receptors binds to a large array of peptides that contain certain motifs. An antigenic sequence of eight to ten amino acid residues contained within a peptide of 13 to 18 residues in length is lodged in a groove formed by the association of MHCIIa- and b-glycoproteins. One to four (anchor) resi-dues of the peptide sequence enable binding of the peptide into the polymorphic pockets of theb-sheet of the MHCII groove. The peptide-binding groove protects the core pep-tide from further proteolysis.

MHCII a-subunits show a distinct preference for

combining with their matched isotype b-subunit (i.e.

DQa prefers to combine with DQb). However, in trans-fected cells, some of the MHCII isotype subunits might Corresponding author:Koch, N. (norbert.koch@uni-bonn.de).

Available online 5 November 2007.

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combine to give rise to mixed heterodimeric complexes, creating a genetically unpredicted diversity [6], but it is unclear whether the mixed isotype complexes exist under normal conditions within the cell. Expression of mixed isotype combinations of the MHCII peptide receptors would be expected to increase the repertoire of antigens presented by a single antigen-presenting cell (APC). How-ever, this is not necessarily the case because formation of misfolded MHCII complexes by aberrant association of subunits could severely impair antigen presentation. Furthermore, inter-isotypic MHCII pairing in human APCs would strongly reduce the amount of the less abun-dantly expressed DP and DQ molecules (compared with DR) and possibly abolish the unique role of these two isotypes. Thus, regulation of matched isotype a- and b -chain pairing could be required to ensure optimal immune responsiveness (Figure 1).

Similar to isotype matching, allotypic class II subunit pairs have to be examined to determine if they match to form peptide receptors. Allotypic MHCII variants differ in their assembly efficiency. For assembly of some allotypic combinations, coexpression of Ii is strictly required, whereas other combinations assemble efficiently even if expression of Ii is omitted[7]. Mouse H2-Aa- andb-chains that are encoded on a single chromosome seem to be evolutionarily selected for heterodimer formation [8]. Mixed haplotype pairing occurs whena- andb-chains of the same isotype, but encoded from genes expressed on the allelic chromosome, combine to form functional units. In inbred mouse strains, these combinations of polymorphic MHCII subunits are not found on parental cells and are unique in APCs from F1 hybrid mice. Indeed, in mice it has been shown that H2-A subunits encoded by some mixed haplotypes show an absolute dependence on the Ii chaper-one for optimal folding and transport of the resultant heterodimer[8].

The chaperone role of li in MHCII subunit assembly

Upon biosynthesis, proteins are translocated into the endoplasmic reticulum (ER) and there pass a quality

control system that involves interaction with chaperones. Most known ER-resident chaperones transiently bind to a wide array of proteins, which appear after translation. Discrete transport competent multiprotein complexes are formed upon selective folding and assembly of protein subunits. Newly synthesized MHCII glycoproteins pass through a transiently aggregated phase[9,10]. These aber-rantly mixed MHCII subunits are temporarily complexed with chaperones, such as the ER-resident membrane protein calnexin, or the soluble immunoglobulin heavy chain binding protein (BiP) and possibly other, not yet defined, chaperones [11–13]. Immediately following the aggregated phase, Ii binds to the MHCII chains, promoting folding and subsequent export of the class II complex out of the ER [14]. An additional role of Ii is to sort MHCII molecules into endocytic compartments, where Ii is degraded. An MHCattached fragment of Ii, class II-associated Ii peptide (CLIP), is released upon interaction with the class II-like DM molecules [HLA-DM (human), H2-DM (mouse)] and replaced by antigenic peptide [15]. Although Ii is essential for the optimal expression of

sur-face MHCII, a- and b-chains can form dimers in the

absence of Ii[9]. For example,in vitro translateda- and b-chains form dimers in the presence of microsomes, which are essential for the assembly of the MHCII membrane-bound subunits [16]. Therefore, it was suggested that a preformeda–bheterodimer binds to Ii[16,17]. Because an interaction of Ii with individual MHCII subunits has also been reported[18–20], this issue remained controversial. Although Ii is not required for the presentation of all antigens [21], the absence of Ii often causes defective

MHCII export [22]and aberrant association of DM with

MHCII subunits in the ER (DM catalyses the acquisition of peptides by the MHCII heterodimer)[23]. Ii-dependency of MHCII function is explained by the role of Ii to promote the assembly of MHCII subunits and by targeting the MHCII– Ii complex to peptide-loading compartments.

The Ii chain occupies the MHCII groove and

prevents the binding of proteins that appear after biosyn-thesis in the ER. In MHCII-transfected Ii-free cells, newly

Figure 1. A model for matched isotype MHCII subunit assembly. MHCII isotypes derive from duplicated genes, which encodea- andb-chains. Assembly of thea- andb -subunits to MHCII peptide receptors is regulated in an APC yielding matched intra-isotype, rather than inter-isotype, combinations. The matched isotypes are subsequently expressed on the cell surface as peptide receptors (middle arrow). (a) DR, DP and DQa-chains (green, red and blue, respectively) assemble in the presence of the invariant chain, Ii (yellow), with matched isotype DP, DQ and DRb-chains (green, red and blue, respectively) to form functional peptide receptors. Ii regulates matched isotype pairing. Following the maturation of MHCII oligomers, Ii is degraded, and the Ii-derived fragment CLIP (grey) is replaced by an antigenic peptide (light brown). (b) In the absence of Ii, thea- andb-isotype subunits form mixed complexes. The fate of the mixed-isotype MHCII heterodimers is unclear. The excess of DR subunits might result in the formation of matched isotype heterodimers, which are exposed as peptide receptors on the cell surface.

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synthesized MHCII molecules are not significantly loaded with peptide but associate with misfolded polypeptides in the ER[24]. Presumably, the loading conditions in the ER are not optimal for MHCII peptide binding[25].

Ii binds to the enormous number of polymorphic class II glycoproteins without any reported exception. Interaction of Ii with the MHC isotypes DP, DQ and DR is strong, whereas binding to the nonclassical MHCII molecules DM and DO and to the class Ib molecule CD1d can only be detected in lysates using mild detergent[26,27]

Conserved Ii-binding sites on MHCII chains

Three Ii chains form a trimer [28], to which MHCII

subunits are attached. The multicomponent framework of the MHCII–Ii structure suggests several interaction sites [29]. It has been reported that the transmembrane domains of MHCII and Ii are capable of self-association

[30]. However, this interaction is only stable in mild deter-gent and is complemented by association of other parts of the molecules[31,32]. Ii utilizes a sequence encompassing residues 91 to 99 to bind to the groove of MHCII peptide receptors. The peptide backbone of this Ii sequence pro-vides an additional promiscuous binding site to conserved amino acid residues in the peptide-binding groove of MHCII heterodimers[33].

Interaction of Ii with distinct non-polymorphic

sequences on MHCII subunits is required for the promiscu-ous binding of Ii to the large family of MHCII glycoproteins. Individual MHCII a-chains efficiently coisolate with Ii, whereas individual b-chains exhibit only a low-affinity interaction with Ii [34]. Ii residues Met91, Ala94 and Met99 bind to pockets 1, 4 and 9 of the MHCII (DR3 allotype) groove[33]. The first pocket (P1) is predominantly

formed by conserved DRa residues (Figure 2a). A

Met91->Gly mutant (which is the anchor for P1) of Ii completely abolished co-isolation of Ii with individual DRa chains [34]. This result suggests that Ii is docked to conserved residues of DRa. Binding of thea-subunit to Ii might suggest interaction with non-polymorphic residues, which explains the promiscuous binding of Ii to all MHCII allo- and isotypes. It is important that the singleb-chain does not bind efficiently to Ii because the large molar excess of Ii, which is expressed in APCs, would impair assembly of a–Ii–bcomplexes and preferentially producea–Ii andb–Ii pairs. The detection of a preformeda–Ii complex suggests a sequential binding ofa- andb-subunits to the Ii trimer. By metabolic labelling experiments, it was demonstrated that thea-chain attaches to Ii within 5 minutes[34]. Thisa–Ii scaffold subsequently binds to the b-subunit. Consistent

with this finding, a–b dimer intermediates were not

observed[5].

How does thea–Ii complex promiscuously interact with matched MHCIIb-chains? The extra-cytoplasmic part of

DRb consists of a highly polymorphic b1 and a more

conserved b2 domain. One study identified a novel motif in the sequence of the DRbchain, which is defined by two tryptophan residues separated by 22 amino acids[35]. This ‘WW MHC class II’ (WWCII) sequence is conserved in the MHCIIb2 domains of vertebrate species. In the DRbchain, Trp153 and Tyr123, which are located within the WWCII sequence, form a pocket-like structure and, in conjunction with Asp152, mediate interaction with a proline-rich region of Ii found adjacent to the groove-binding sequence of Ii (Figure 2b).

Editing of matched MHCII subunits by li

Unlike MHC-I, MHCII heterodimers do not acquire peptides in the ER. Therefore, at the stage of assembly,

Figure 2. Conserved MHCII binding sites for li. Two binding sites of Ii to conserved sequences of DRaand DRbchains are depicted. One of the binding sites directs docking of Ii residue Met91 to DRa. The second binding site is located on DRb. Binding of a proline-rich sequence of Ii to this WWCII sequence on DRbaccomplishes the formation of the MHCII–Ii complex. (a) Pocket 1 of the DR3–CLIP complex with residues Phe32 and Trp43 (both yellow) of DRabinds to Met91 (light-brown) of the Ii-derived fragment CLIP (grey ribbon). In this figure, DRais depicted as a ribbon, and DRbis depicted as a backbone. (b) The same complex rotated 90 degrees anticlockwise relative to the plane of the page. In this view, it is DRbthat is depicted as the ribbon, and DRaas a backbone. Lys83 and Pro82 (light brown) at the N-terminus of CLIP were modelled into this structure to demonstrate a potential interaction of Ii residues with Trp153, Tyr123 and Asp152 of the DRbchain (all yellow). Turns betweenb-sheets or betweena- tob -structures are depicted as green and coils are grey [Protein Database (PDB) accession 1A6A]. Data from[33].

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the a- and b-subunits are not examined by antigenic peptides to form functional peptide receptors. Based on

novel data [34,35], we propose a new model for MHCII

subunit assembly whereby the MHCIIa–Ii complex forms a scaffold to which a matched b-glycoprotein is selectively bound (Figure 3a). Thea–Ii matrix can bind to any MHCII b-chain. However, in the presence of the isotype-matched b-subunit, a transport-competent a–Ii–b oligomer is formed. This a–Ii–b complex is qualified to mature into aa–bpeptide receptor.

Within the transient a–Ii–b complex, the b-chain is examined as a potential subunit of the MHCII peptide receptor complex. The groove-binding sequence of Ii has the role of a master peptide. Interaction of some poly-morphic residues of the MHCIIb-chain with the Ii master peptide sequence and with thea1 domain might test the ability of the b-chain to fit into the complex. The poly-morphic residues of the MHCIIb-chain might determine the conversion of transient to stable MHCII complexes. In addition, a recently described hydrogen bond between the conserved His81 of theb-chain and a carbonyl group of the peptide backbone stabilizes the complex[36]. If interaction of the b-chain to the master sequence is inefficient, it is replaced by one of the various MHCIIb-chains expressed in APCs. Interaction of the b-chain with a–Ii is accom-plished by binding of a proline-rich region of Ii to WWCII on theb-chain. A WWCII mutant of the DRbchain that still binds to Ii and to DRawas transported intracellularly

and subsequently expressed on the cell surface[35]. In the presence of wild-type DRb, however, association of the WWCII mutant to DRaand Ii was abolished. It was there-fore suggested that the chaperone role of Ii is regulated by interaction of Ii with the WWCII domain on the DRbchain. The conformation of the MHCII peptide receptor is influenced by its interaction with Ii. A conformational change of thea–bheterodimer, observed in the presence of Ii, is maintained following Ii degradation in endosomes and MHCII expression on the cell surface[37]. The struc-ture of thea–Ii–bcomplex could be different from a

com-plex that would be produced by preformed a–b that

associates with the Ii trimer [Figure 3b(i)]. The ‘classic’ model suggests that a–b heterodimers are required to insert into a loop contained in the Ii trimer [38]. By con-trast, our revised model suggests that thea- andb-chains form a sandwich-like structure with the Ii trimer [Figure 3b(ii)]. An advantage of this sandwich model is that a mismatchedb-chain can still dissociate from thea– Ii matrix and be replaced by a matchedb-chain. In contrast toa–Ii–b[Figure 3b(ii)], an exchange of theb-chain in the a–b–Ii complex [Figure 3b(i)] containing preformed a–b dimers requires several steps of dissociation and reassoci-ation.

Concluding remarks

In contrast to the previously described model (outlined in Figure 3), our new model suggests that Ii is required Figure 3. Models for the assembly of MHCII subunits with Ii. A single APC expresses up to 11a- andb-subunits of various allo- and isotypes. The model presented here, in contrast to the opposed ‘classic model’, might explain how functional peptide receptors are selected out of the various transiently generateda- andb-associates. (a) The various MHCIIb-chains expressed in an APC are capable of transiently binding to thea–Ii scaffold. Allo- and isotypicb-chains then compete for binding toa–Ii. Ii edits transiently expresseda–Ii–bcomplexes for matcheda–bheterodimers. Subsequently, matched MHCII heterodimers exit the ER and travel to class II peptide-loading compartments. (b) Two models for MHCII subunit assembly. (i) The ‘classic’ model: a preformeda–bheterodimer is inserted into a loop formed by the Ii trimer (the segment of Ii that generates CLIP is labelled in grey). (ii) Our new ‘revised’ model: an Ii trimer first binds to the MHCIIa-chain. Subsequently, theb-chain associates with the matrix (or ‘scaffold’) formed bya–Ii, and it is at this stage that the isotype is checked as a match for thea-subunit.

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to select polymorphic b-chains in the formation of peptide-binding units. Given the numerousa- andb -allo-types encoded by the human genome, not all a–bdimers will form functional peptide receptors. This is particularly

important for DQ and DP subunits because both a- and

b-chains of these isotypes are polymorphic. A novel com-bination of polymorphic MHCIIa- andb-subunits in every offspring needs to be examined as a functional peptide-binding unit. The ‘classic’ model of a preformed a–b het-erodimer does not explain how matching subunits are efficiently selected out of the various MHCII glycoproteins expressed in a given APC. The requirement for selective assembly is evident when one considers the number of potential combinations of isotype subunits and the result-ing intra-isotype heterodimers[39]. We suggest that in this selection process, Ii functions as a unique chaperone for MHCII isotype subunit assembly. Ii promotes the

for-mation of DR, DP and DQ a–bheterodimers and deters

inter-isotypic MHCII pairing. At present, there is no evi-dence for MHCII peptide receptors other than DR, DP or DQ heterodimers. It is, however, conceivable that, out of the great variety of MHCII molecules, some mixed isotype a–b heterodimers are assembled, which form functional peptide receptors.

Matched or aberrantly assembled MHCII subunits can be distinguished by their ability (or inability) to enter the MHCII processing pathway. It is still unclear which struc-tural requirement enables export of the MHCII molecules from the ER.

An additional question concerns the stoichiometry of MHCII oligomers. Are there several MHCII isotypes con-tained in one complex with the Ii trimer? For mouse MHCII, it has been demonstrated that I-A and I-E hetero-dimers form distinct complexes with Ii[40,41]. This ques-tion has not been resolved for human MHCII isotypes.

Acknowledgements

This work has been supported by a grant from the Deutsche Forschungsgemeinschaft.

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