Diversity in MHC class II antigen presentation

John H Robinson; Alexei A Delvig

doi:10.1046/j.0019-2805.2001.01358.x

. 2002 Mar;105(3):252–262. doi: 10.1046/j.0019-2805.2001.01358.x

Diversity in MHC class II antigen presentation

John H Robinson ¹, Alexei A Delvig ¹

PMCID: PMC1782669 PMID: 11918686

Abstract

Processing exogenous and endogenous proteins for presentation by major histocompatibility complex (MHC) molecules to T cells is the defining function of antigen-presenting cells (APC) as major regulatory cells in the acquired immune response. MHC class II-restricted antigen presentation to CD4 T cells is achieved by an essentially common pathway that is subject to variation with regard to the location and extent of degradation of protein antigens and the site of peptide binding to MHC class II molecules. These subtle variations reveal a surprising flexibility in the ways a diverse peptide repertoire is displayed on the APC surface. This diversity may have profound consequences for the induction of immunity to infection and tumours, as well as autoimmunity and tolerance.

Introduction

In over two decades of research it has been established that T-cell antigen receptors (TCR) recognize fragments of antigens bound to antigen presenting molecules coded mainly by genes of the major histocompatibility complex (MHC). CD8 and double negative T cells (expressing neither CD4 nor CD8) recognize fragments of protein or non-protein antigens bound to class Ia or class Ib MHC molecules that show variable degrees of polymorphism. However, the largest subset of T cells expresses the MHC coligand CD4, which augments the recognition of peptides of varying length associated with a small number of highly polymorphic MHC class II molecules. An extensive literature has established that the majority of peptides recognized by CD4 T cells are presented by a common pathway which is used by both professional and non-professional antigen-presenting cells (APC).¹^–⁴

The peptide epitopes recognized by CD4 T cells are mainly derived from exogenous proteins that require some form of processing before they are accessible to bind MHC class II molecules.²^,⁵^–¹⁰ Soluble antigens are internalized by APC by clathrin-dependent receptor-mediated endocytosis or clathrin-independent macropinocytosis to enter the endosomal pathway. Alternatively, particulate antigens are localized within phagosomes following receptor-mediated phagocytosis. After uptake, proteins typically undergo unfolding and disulphide reduction¹¹ followed by degradation by cysteinyl and aspartinyl proteinases with optimal activity at low pH.⁵^,⁶^,¹⁰^,¹² A number of studies have also shown that epitopes within denatured intact proteins can bind to MHC class II without prior degradation.¹^,¹¹^,¹³

MHC class II molecules are synthesized de novo in the endoplasmic reticulum (ER) where they are assembled and transported to the Golgi under the regulation of chaperones including the invariant (Ii) chain.⁴^,¹⁴^,¹⁵ MHC class II–Ii complexes are then sorted to endosomes, including multilamellar and multivesicular compartments⁹^,¹⁶^,¹⁷ or to phagosomes.¹⁸ Ii, together with the MHC class II-like chaperones DM and DO, also regulates peptide loading of MHC class II molecules.¹⁴^,¹⁵^,¹⁹^,²⁰ The Ii-derived class II invariant chain peptide (CLIP) remains associated with the MHC class II peptide binding cleft until DM catalyses the dissociation of CLIP and binding of processed antigenic peptides, optimally at low pH.²¹ DO regulates DM activity probably by enhancing the association of DM with MHC class II. MHC class II molecules bind the peptides generated in endosomes and the complexes are then exocytosed to the cell surface for presentation to CD4 T cells.⁹^,²² Endogenous proteins and peptides may also bind MHC class II molecules following transport into the endosomal pathway.²^,²³ Thus, cytosol-to-endosome transport may lead to the processing of proteins translocated into the host cytosol by intracellular pathogens such as Listeria monocytogenes.²⁴

Although late endosomes are the usual location where antigenic peptides and MHC class II molecules are able to interact, there is accumulating evidence that peptide binding occurs in other cellular compartments (see Fig. 1), which is the main focus of this review.

Where do peptides bind MHC class II molecules?

Late endosomes

For the majority of epitopes that have been mapped within a very large number of protein antigens to date, the site of MHC class II binding has not been investigated. However, for a representative number of soluble proteins, a requirement for antigen processing by lysosomal enzymes and peptide loading in the acidic environment of the late endosome or lysosome has been demonstrated.⁵^,⁶^,¹⁰^,¹²^,²⁵ As a direct approach, two epitopes from hen egg lysozyme (HEL)_48–61 and HEL_34–45 and one epitope from bovine pancreatic ribonuclease RNase_90–105 complexed with MHC class II have been localized to late endosomes following fractionation of endosomal compartments in HEL-pulsed APC.²⁶ The demonstration that treatment of APC with agents that raise endosomal pH prevents antigen presentation of epitopes from many proteins also provides indirect support for peptide loading in late endosomes. For example, presentation of the epitope MP_18–29 from the influenza virus matrix protein is sensitive to the vacuolar ATPase inhibitor concanamycin B²⁷ and raising endosomal pH with chloroquine has resulted in reduced antigen presentation of the epitopes HEL_34–45²⁶ and HEL_46–61.²⁶^,²⁸ Thus, it has generally been accepted that soluble proteins are processed in the acidic environment of late endosomes or lysosomes, where peptides derived from them subsequently bind MHC class II molecules.

Endoplasmic reticulum (ER)

The ER may be an alternative site for loading of newly synthesized MHC class II molecules with peptides derived from endogenous antigens, following degradation by cytosolic proteases and transporters associated with antigen processing (TAP)-dependent transport into the ER lumen.²^,²³ For example, treatment of APC expressing endogenous HEL with a proteasome inhibitor prevented MHC class II-restricted presentation of the epitope HEL_34–45.²⁹ In another study, an endogenous cytosolic peptide from influenza A virus haemagglutinin (HA_307–318) was presented to DR1-restricted T cells by TAP-sufficient but not TAP-deficient B cells.³⁰ Thus, peptides from cytosolic proteins can be delivered directly to the ER where they are available for MHC class II binding. Endogenous proteins that remain unfolded or malfolded after synthesis could also bind newly synthesized MHC class II in the ER.²³ APC transfected with HA or HEL were shown to process and present the peptide epitopes HA_306–318³¹^,³² and HEL_46–61³³^,³⁴, respectively. However, presentation of HEL_46–61 was inhibited by chloroquine and enhanced in the presence of a high level of expression of Ii chain.³³^,³⁴ The data suggests that in this case HEL was transported from the ER to endosomal compartments for processing and MHC class II binding after the Ii chain was degraded.

Peptide loading of MHC class II in the ER may occur in cells lacking the Ii chain, the presence of which would be expected to physically block the MHC class II cleft and prevent peptide loading.³⁵ Endogenous synthesis of influenza virus matrix protein produced as a short cytosolic peptide in human fibroblasts led to DR1-restricted presentation of the epitope MP_18–29, which was prevented by transfection of the fibroblasts with Ii chain cDNA.³⁶ Association of Ii chain with MHC class II molecules also inhibits loading of MHC class II molecules with partially folded or malfolded endogenous proteins.²³^,³⁵^,³⁷ Thus, in the presence of Ii chain most unfolded endogenous protein antigens are probably transported from the ER to endosomes. However, in its absence, such as in some non-professional APC³⁸ endogenous polypeptides can bind MHC class II molecules in the ER.³⁷

Early endosomes

A growing number of studies suggest that peptide epitopes can bind MHC class II molecules in early endosomes at pH above 6·5. Complexes of MHC class II bound to the bovine pancreatic ribonuclease epitope RNase_42–56 have been localized in early endosomes²⁶ and studies using APC treated with agents that prevent endosomal acidification demonstrate that antigen processing and MHC class II binding can occur independent of the low pH of late endosomes. For example, presentation of the HA_307–318 epitope from influenza hemagglutinin is resistant to the vacuolar ATPase inhibitor concanamycin B.²⁷ In similar studies, HEL_116–129²⁸ measles virus fusion protein epitope (MVFP)_317–328³⁹ RNase_42–56²⁶ and human chorionic gonadotropin (α-subunit; hCG_61–81)⁴⁰ have been shown to load MHC class II molecules at pH above those found in late endosomes. Similar conclusions can be drawn from investigation of the mechanisms of presentation of epitopes from retinal S antigen⁴¹ and a secreted antigen from Mycobacterium tuberculosis.⁴² This mode of presentation is characterized by rapid kinetics, with maximal presentation in around 15 min, compared with the 90 min for optimal antigen presentation involving late endosomes.²⁶

Degrees of antigen processing

A prerequisite for peptide loading in early endosomes is that the epitope is accessible to bind MHC class II molecules, which is influenced by several factors. First, epitopes may be exposed within flexible regions at the surface of conformationally intact proteins. For example, the epitope Aα_551–578 within a region of fibrinogen that lacks secondary structure in the intact molecule is presented without unfolding or enzymatic degradation.⁴³

Second, denatured but otherwise intact proteins have been shown to bind to purified MHC class II molecules⁴⁴ suggesting that degradation is not necessary for MHC binding if the epitope is accessible on the intact molecule. Unfolding proteins in the absence of degradation allows uncleaved protein antigens to bind to MHC class II molecules on the surface of prefixed APC and subsequent presentation to CD4 T cells. This has been demonstrated by reduction of thiol bonds or exposure to low pH for beef insulin, HEL, cytochrome-c, myoglobin, ovalbumin (OVA), α-lactalbumin and Plasmodium merozoite surface protein-1 (MSP-1).⁴⁵^–⁴⁸ The same result has also been achieved by treating OVA, HEL, human transferrin and bovine serum albumin (BSA) with urea and iodoacetic acid⁴⁹ or by carboxymethylation of HEL.⁵⁰ Denaturation of HEL was used to determine the fate of unfolded proteins in the antigen presentation pathway after endocytosis.⁵¹ Partially unfolded HEL was transported to early endosomes where MHC class II binding of the epitope HEL₃₄₋₄₅ occurred. Thus, when HEL is delivered partially unfolded, the epitope HEL_34–45 binds MHC class II in early endosomes without the need for processing⁵¹ whereas from native HEL, the same epitope requires processing in late endosomes.²⁸

Third, intact proteins may require limited proteolysis in early endosomes by enzymes other than the acid hydrolases of lysosomal compartments, before MHC class II-binding is possible. Candidates that mediate this process would need to be active at pH above 6·0 and could include enzymes targeted to early endosomes from the Golgi apparatus⁵ or membrane-bound enzymes that are internalized from the cell surface.⁵²^,⁵³ Whatever the mechanism, the accessibility of peptide epitopes may be a principal factor determining whether MHC class II binding occurs in early endosomes.

Peptide epitopes that are accessible for MHC class II loading in early endosomes may be destroyed by lysosomal enzymes later in the endocytic pathway by what has been termed ‘destructive antigen processing’,¹ which would prevent subsequent loading of MHC class II molecules in late endosomes. This destructive antigen processing would explain why particular peptide epitopes are available for MHC class II binding earlier in the endosomal pathway but absent later.⁵⁴

Source of MHC class II

Antigen presentation in early endosomes is most likely to occur by peptide loading of mature MHC class II molecules recycled from the APC surface. This conclusion is based on studies of a number of epitopes that are presented preferentially in early endosomes. Presentation of influenza virus HA_307–318⁵⁵ and myelin basic protein MBP_151–170⁵⁶^,⁵⁷ is resistant to pretreatment of APC with emetine, which blocks protein synthesis including de novo synthesis of MHC class II molecules. Neither epitope was presented by fibroblasts transfected with DR1 molecules lacking the cytoplasmic domain of either α or β chains of MHC class II, which prevents recycling of MHC class II from the cell surface.⁵⁶ In another study, presentation of HEL_34–45 and HEL_116–129 from native HEL was resistant to treatment of APC with brefeldin A, which disrupts ER–Golgi transport and hence delivery of newly synthesized MHC class II to endosomal compartments²⁸ suggesting that these epitopes were presented by recycling MHC class II. Furthermore, blockade of MHC class II recycling from the cell surface by an alanine substitution in the targeting motif of the cytoplasmic domain of the MHC class II β chain inhibited presentation of both HEL_34–45 and HEL_116–129.²⁸

Additional studies demonstrating antigen presentation in the absence of protein synthesis and ER–Golgi transport suggest that a number of other epitopes preferentially load recycled MHC class II molecules. These include MSP-1_1137–1151⁴⁶ OVA_323–339⁵⁸ RNase_42–56²⁶^,⁵⁹ and the tetanus toxin epitope TT_947–967.⁶⁰ This alternative loading mechanism is a property of both professional and nonprofessional APC, including B cells¹^,²⁸ immature dendritic cells⁶⁰ monocytes⁶¹ macrophages²⁶^,⁶² intestinal epithelial cells⁶³ and cortical thymic epithelial cells.⁶⁴ Collectively, these data suggest that many T-cell epitopes have the potential to load mature MHC class II molecules recycled from the APC surface. However, the full extent of peptide loading of recycled MHC class II molecules will not be appreciated until many more epitopes have been studied.

Ii chain and DM dependence

Another feature of the loading of peptides in early endosomes is the apparent lack of direct involvement of Ii chain or DM. In the studies described above, the epitopes HA_307–318, MBP_151–170, HEL_34–45 and HEL_116–129 were each presented in the absence of Ii chain.²⁸^,⁵⁵–57 Additionally, presentation of partially folded HEL, RNase_42–56 and MBP_151–170 occurred in the absence of DM.²⁶^,⁵¹^,⁵⁷ However, it has also been demonstrated that a pool of DM expressed on the surface of B cells is involved in peptide editing of recycling MHC class II molecules in some circumstances.²¹^,⁶⁵^–⁶⁷ Also, determining the role of DM is hampered by the fact that the efficiency of DM in CLIP exchange reactions is dependent on the MHC class II allelle or haplotype. For example, the H-2^k haplotype in the murine model described above²⁸ and elsewhere²⁶^,⁵¹^,⁵⁹^,⁶⁸ is unusual in that A^k is characterized by Ii chain-independent assembly⁶⁹ and DM-independent peptide loading due to the low affinity of A^k for CLIP.⁷⁰ Clearly, studies of mice of some MHC class II haplotypes could underestimate the role of Ii chain and DM in presentation by recycling MHC class II molecules across the spectrum of known haplotypes.

Another factor to consider is the possible role of alternative splice variants of Ii chain, which could exert differential effects on antigen presentation.¹⁴^,¹⁵ In Ii chain and DM double knock-out mice expression of the p41 but not the p31 Ii isoform partially restored antigen presentation, suggesting that p41 may facilitate the exchange of its own CLIP for antigenic peptides in the absence of DM.⁶⁷ Thus p41 may play a role in DM-independent peptide loading in early endosomes, consistent with morphological evidence that p41 colocalizes with mature MHC class II molecules in early endosomes.⁷¹

Phagosomes

Proteins associated with particulate antigens may be processed and bind MHC class II molecules within the phagocytic pathway.¹^,⁷²^,⁷³ The source of MHC class II molecules in phagosomes has been investigated in macrophages treated with brefeldin A. Approximately two-thirds of all phagosomal MHC class II was newly synthesized and one-third recycled from the cell surface, both participating in presentation following phagocytosis of antigen-coupled latex beads.¹⁸ Purified phagosomes containing OVA-coupled latex beads have also been shown to directly activate OVA_323–339-specific T cell hybridomas¹⁸^,⁷² suggesting that MHC class II loading occurs within the phagosomal pathway. Other likely examples of MHC class II binding in phagosomes include the observed presentation of peptides from recombinant antigens expressed by E. coli, Salmonella typhimurium or Streptococcus gordonii following uptake of viable bacteria by macrophages⁷⁴^–⁷⁶ or dendritic cells.⁷⁷^,⁷⁸

We have studied antigen processing of the surface fibrillar M5 protein from viable Streptococcus pyogenes in macrophages. Treatment of APC with metabolic inhibitors was used to show that presentation of the M protein epitope M5_308–319 was dependent on low pH and transport from early to late compartments.⁶²^,⁷⁹ Presentation was also resistant to pretreatment of macrophages with brefeldin A and cycloheximide suggesting that peptide loading occurred largely on newly synthesized MHC class II molecules.⁶² Investigation with a range of enzyme inhibitors further showed that processing of this particular epitope was dependent on the activity of serine, aspartic and cysteine proteinases.⁸⁰ Taken together, the data indicate that M5_308–319 required processing in compartments with the properties of late phagosomes.

Investigation of another epitope of the streptococcal M5 protein has provided evidence for peptide loading of recycling MHC class II in early phagosomes. We showed that the epitope M5_17–31 was processed and presented from viable S. pyogenes independent of low pH and transport from early to late phagosomes, indicative of peptide loading in early phagosomes.⁶² Resistance of presentation to treatment of APC with brefeldin A and cycloheximide suggested that this epitope was presented by mature MHC class II molecules, which occurred with rapid kinetics.⁶² We treated APC with enzyme inhibitors to investigate how this epitope was processed from streptococci and demonstrated the involvement of serine, but not aspartic or cysteine, proteinases.⁸⁰ Collectively, our data suggests that M5_17–31 is processed from streptococci and binds recycled MHC class II in early phagosomes. As M5_17–31 is located in the flexible amino terminus of the M5 protein⁸¹ it is likely that this epitope is accessible to bind MHC class II without denaturation or extensive degradation of the M protein. In another study, processing and presentation of epitopes from Mycobacterium tuberculosis bacilli by human monocytes was shown to occur in the presence of lysosomotropic agents⁶¹ again suggesting peptide loading at a pH characteristic of early phagosomes.

We have also studied antigen processing of viable S. typhimurium by macrophages, and showed that presentation of the natural epitope SipC_381–394 from the Salmonella invasion protein C (SipC) was required actin-dependent uptake but occurred in the presence of lysosomotropic agents, brefeldin A or the protein synthesis inhibitor cycloheximide (Musson et al., manuscript submitted). The data suggests that SipC is present in early phagosomes where the epitope SipC_381–394 is available to bind MHC class II recycled from the cell surface.

Thus, peptides derived from particulate antigens may preferentially bind newly synthesized MHC class II molecules in late phagosomes or, alternatively, may bind recycled MHC class II in early phagosomes, showing similarities with peptide loading in the endosomal pathway, described above. However, it is not entirely clear whether the majority of peptides remain within the phagosomal pathway or are transported out of phagosomes and into to endosomal compartments where MHC class II binding occurs.

Plasma membrane

There is abundant evidence that MHC class II molecules on the surface of fixed APC can directly bind and present synthetic peptide epitopes, although requiring higher doses than for unfixed cells.⁵¹^,⁸²^,⁸³ Also, fixed APC have been shown to present denatured proteins, as described above.⁴⁵^–⁴⁸ Therefore, MHC class II molecules on the surface of APC are capable of binding proteins or peptides denatured or degraded by the activity of extracellular enzymes present in the inflammatory exudate. A number of proteins have been reported to bypass intracellular processing, leading to efficient presentation by surface MHC class II, including two different malaria circumsporozoite proteins⁸⁴^,⁸⁵ as well as MBP_68–86 from guinea pig myelin basic protein⁸⁶ although the participation of extracellular enzymes in the degradation of these proteins was not excluded in these studies. Cleavage by serum proteinases was implicated in the serum-dependent extracellular processing of soluble Hepatitis δ antigen (HDAg) leading to presentation of HDAg_106–121 at the surface of B cells.⁸⁷ Presentation was inhibited by a trypsin proteinase inhibitor, favouring the involvement of extracellular processing. In addition, immature DC have been shown to express ectoproteinases at the cell surface⁸⁸ and to secrete serine proteases which cleave proteins into antigenic peptides.⁸⁹

Peptides generated by extracellular processing may bind cell surface MHC class II molecules under the control of DM expressed on the surface of professional APC such as B cells and immature DC, as shown for MBP_111–129 and MBP_87–99 or type II collagen COL_259–273.⁶⁵ It was suggested that both B cells and immature DC, by virtue of high DM expression on the cell surface, facilitate loading of peptides at sites of inflammation rescuing those peptides that are easily degraded when processed by endosomal proteases.

How might diversity in antigen presentation influence the immune response?

Immunity to infection

A number of peptides derived from viral, bacterial and protozoan proteins have been shown to load recycled MHC class II molecules in early endosomes or phagosomes for presentation to CD4 T cells (Table 1). For example, presentation of hepatitis B virus nucleocapsid protein core antigen was shown to be resistant to brefeldin A,⁹⁰ suggesting independence of newly synthesized MHC class II molecules. Similarly, presentation of epitopes of the measles virus fusion protein⁹¹ and influenza virus haemagglutinin⁵⁶ has been shown to depend on MHC class II molecules recycled from the cell surface. Examples from antigen presentation of bacterial antigens include an epitope of the secreted SipC protein of Salmonella typhimurium (Musson et al., manuscript submitted), as well as antigens of M. tuberculosis⁶¹ which were shown to be presented to CD4 T cells independent of newly synthesized MHC class II molecules or endosomal acidification. Furthermore, presentation of unidentified M. tuberculosis antigens to CD4 T-cell clones was demonstrated to be independent of cysteine and aspartic proteinases for the majority of T-cell clones⁹² suggesting a bypass of lysosomal processing for many epitopes from viable M. tuberculosis.⁶^,⁹³ Presentation by recycling MHC class II molecules was recently reported to be characteristic for the C-terminal fragment of MSP-1 protein of the mouse malaria parasite Plasmodium chabaudi chabaudi⁴⁶ suggesting that early endosomes are also used for processing of protozoan proteins for presentation to CD4 T cells.

Table 1. Summary of epitopes shown to bind MHC class II in alternative sites.

Protein antigen	Location of epitope	MHC restriction	Reference
hCG, α-subunit	61–81	A^d	40
Fibrinogen Aα chain	551–578	E^k	43
HEL	34–45	A^k	28,29,51
	46–61^*	A^k	33,34
	116–129	A^k	28,51
HDAg	106–121	DRB1	87
Hepatitis B nucleocapsid (core) antigen	81–105	DR14	90
Influenza virus A (HA)	306–318	DR1	30–32,55,56
Influenza virus A (MP)	18–29	DR1	36
Malaria circumsporozoite R32NS1 protein	N/A	H-2^b	84
Malaria circumsporozoite 46000 MW SPZ protein	N/A	H-2^d	85
Malaria MSP-1	1137–1151	H-2^d	46
MVFP	317–328	DR1	39,91
Mycobacterium tuberculosis	N/A	N/A	61,92
M. tuberculosis/M. leprae 30/31000 MW protein	56–65	DR17	42
MBP	68–86	RT1	86
	87–99	DR4	65
	111–129	DR4	65
	151–170	DR1	56,57
OVA	323–339	A^b	58
Retinal S-antigen	N/A	N/A	41
Ribonuclease (RNase)	42–56	A^k	26,59
Salmonella typhimurium SipC protein	381–394	A^d	N/A
Streptococcus pyogenes M5 protein	17–31	E^d	62,80
TT	947–967	DR	60
Collagen	259–273	DR4	65

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N/A- not available.

hCG, human chorionic gonadotrophin; HEL, hen egg lysozyme; HDAg, hepatitis δ antigen; HA, haemagglutinin; MP, matrix protein; MSP-1, malaria merozoite surface protein-1; MVFP, measles virus fusion protein; MBP, myelin basic protein; OVA, ovalbumin; TT, tetanus toxoid.

When HEL is expressed endogenously.

Several intracellular pathogens are known to evade phagocytic killing by preventing phagosomal maturation and lysosomal fusion, such as Salmonella⁹⁴^,⁹⁵ and mycobacteria.⁹⁶^,⁹⁷ In these situations, microbial antigens are unlikely to be delivered to late endosomes or phagolysosomes for lysosomal processing and presentation by newly synthesized MHC class II molecules. Thus, the use of the alternative sites for loading MHC class II, such as early endosomes or phagosomes, may be a host adaptation to induce CD4 T-cell-mediated responses against these pathogens. However, it has yet to be demonstrated whether epitopes presented in this way dominate the specificity of protection against any intracellular pathogen. The demonstration of protection mediated by epitopes that bind MHC class II in alternative sites would have important implications for developing new generation vaccines based on selective targeting of candidate immunogens to the relevant intracellular compartment.

T-cell selection

There is growing evidence to suggest compartmentalisation of thymocyte selection to distinct anatomical sites within the thymus and association with distinct stromal APC types.⁹⁸^,⁹⁹ These populations of stromal cells have been shown to present at least partially different self-antigen pools, possibly reflecting: (i) different enzymes participating in antigen and Ii chain processing; (ii) differential expression and function of MHC class II chaperones; and (iii) use of different endosomal compartments for processing of endogenous antigens.

Cortical thymic epithelial cells (cTEC) have been described to play a pivotal role in positive selection of T cells.¹⁰⁰ To this end, cTEC possess unique antigen processing machinery that allows for efficient processing of endogenous antigens and very poor processing of exogenous antigens.¹⁰¹^,¹⁰² cTEC have been shown to generate diverse sets of short self peptides in small low-density (early) endosomal compartments containing MHC class II, Ii chain and DM.⁶⁴^,¹⁰³ cTEC also possess unique enzymes, such as a thymus-specific serine protease¹⁰⁴ and cathepsin L¹⁰⁵ which could participate in antigen processing. However, the lack of fully acidic luminal conditions in these endosomes results in the slow degradation of Ii chain, poor function of DM, and acquisition of an unstable conformation by MHC class II molecules⁶⁴ reminiscent of the floppy MHC class II αβ heterodimers observed in DM-deficient mice.¹⁰⁶ In addition, cTEC are essentially devoid of DO molecules²⁰ which can also contribute to the less stringent control of loading MHC class II molecules with peptides. These observations are consistent with the hypothesis that cTEC use largely early endosomes for processing of endogenous antigens and DM-independent binding of antigenic peptides to MHC class II molecules. This antigen-processing pathway may account for the broad repertoire of self-peptides displayed on the cell surface necessary for positive selection. Moreover, maintenance of the peripheral CD4 T-cell repertoire was recently shown to be sustained by low affinity MHC class II–peptide complexes in a similar way to thymic positive selection⁹⁸^,¹⁰⁷ suggesting a role for the early endosomal pathway of MHC class II presentation in the development and maintenance of peripheral T-cell tolerance.

Many studies implicate medullary thymic epithelial cells (mTEC) and medullary haematopoietic cells, most notably DC, as major mediators of negative selection of T cells in the thymus.¹⁰⁸^–¹¹⁰ In mTEC, peptides are generated in high-density acidic (late) endosomes for loading on MHC class II molecules in exchange for CLIP in the presence of functional DM.⁶⁴ Thus mTEC cells appear to engage late endosomes for antigen processing and DM-dependent MHC class II loading to generate MHC class II–peptide complexes for negative selection of T cells. Consistent with this hypothesis, DO is strategically positioned in late endosomes of mTEC and dendritic cells⁷⁰^,¹⁰⁸^,¹¹⁰ where it could facilitate selection of a high-affinity peptide repertoire, which is an important regulatory mechanism in negative selection.

Autoimmunity

T cells are implicated in the pathogenesis of organ-specific and systemic autoimmunity, which has led to the identification of candidate autoantigens and mechanisms precipitating these diseases. It has been hypothesized that an altered array of self peptides, to which the T-cell repertoire has not previously been exposed, is presented on the cell surface in association with MHC class II in the absence of Ii chain and DM regulation, thus potentially breaking self-tolerance.²³ As described above, loading of MHC class II molecules in early endosomes is less strictly regulated by Ii chain or DM, which permits association between MHC class II molecules and unfolded endogenous proteins. In this way, cryptic self-epitopes may be generated in some nonprofessional APC, which lack Ii chain expression.³⁸ Therefore, it is possible that cellular compartments, such as early endosomes that permit Ii chain- and DM-independent loading of MHC class II molecules, play an important role in the generation of autoepitopes implicated in the pathogenesis of autoimmune diseases.

This hypothesis is supported by studies of myelin basic protein (MBP), a major autoantigen implicated in the pathogenesis of multiple sclerosis.¹¹¹ It has been shown that APC from Ii chain-deficient MBP_84–105 transgenic mice could present additional self-epitopes from the MBP fragment, compared to T cells from Ii chain-sufficient MBP_84–105 transgenic mice.¹¹² Moreover, MBP_84–105 has been shown to load surface and recycling MHC class II molecules independent of DM.⁵⁶^,⁵⁷ Recently, two human DR4-restricted immunodominant MBP autoepitopes MBP_111–129 and MBP_87–99 involved in multiple sclerosis¹¹³ were also shown to be presented on MHC class II molecules in a DM-independent pathway in immature DC and B cells.⁶⁵ Furthermore, DM was found to inhibit presentation of an immunodominant autoepitope from type II collagen COL_259–273 implicated in rheumatoid arthritis.⁶⁵

Several other autoantigens have been described to be processed independently of newly synthesized MHC class II molecules and endosomal acidification. Thus, presentation of the retinal S-antigen, involved in the pathogenesis of endogenous posterior uveoretinitis, was resistant to cycloheximide and chloroquine.⁴¹ In addition, processing of S-antigen was independent of cysteine proteinases and other lysosomal enzymes with the notable exception of the serine proteinase plasmin.¹¹⁴ These observations suggest that S-antigen is not processed for binding to newly synthesized MHC class II in late endosomes. Importantly, the authors speculated that since two out of three conserved putative uveitogenic epitopes include a cathepsin B cleavage site, these epitopes are likely to be forwarded for destructive processing in late endosomes, unless rescued by MHC class II molecules recycling from the cell surface.¹¹⁴

In another system, presentation of unidentified autoepitopes on A20 B lymphoma cells to autoreactive T cells was shown to be resistant to brefeldin A and cycloheximide.¹¹⁵ Truncation of the cytoplasmic domain of MHC class II β chains markedly impaired the ability of transfected B lymphoma cell lines to activate autoreactive T hybrids.¹¹⁶ An attractive interpretation of these observations¹¹⁶ is that autoreactive T cells in these studies were stimulated by peptides presented by recycling MHC class II molecules in early endosomes.

The extent to which the binding of autoepitopes to recycling MHC class II molecules is localized to early endosomes cannot yet be assessed. However, the examples presented above suggest that at least some self peptides are presented to autoreactive T cells by recycling MHC class II molecules, indicating a possible role of this MHC class II pathway in the induction of autoimmunity. Clearly, this emphasizes the necessity for studies of the mechanisms of MHC class II antigen presentation of more candidate autoantigens.

Tumour immunity

The importance of MHC-class II-restricted antigen recognition by CD4 T cells in antitumour immunity has been demonstrated in several animal models, as well as for some human tumours, such as squamous cell, breast, laryngeal and colorectal carcinoma.¹¹⁷^,¹¹⁸ It is thought that activation of tumour-specific CD4 T cells results in long-lasting antitumour immunity due to CD4 T-cell-dependent activation of CD8 cytotoxic T cells.¹¹⁹ Therefore, enhancement of MHC class II expression on tumour cells, for instance by transfection of tumour cells with MHC class II¹²⁰ has been shown to produce effective cell-based cancer vaccines, which could protect against primary and metastatic tumours. The primary mechanism underlying the efficiency of cell-based cancer vaccines is thought to be their ability to function as APC that present tumour-specific antigens to CD4 T cells. In this context it is important that MHC class II-positive tumour cells use largely an Ii chain- and DM-independent MHC class II pathway for presentation of tumour antigens¹¹⁷ which suggests this pathway is of primary importance for the development of antitumour immunity. In addition, the immunogenicity of tumour cellular vaccines was found to be abrogated by truncation of the cytoplasmic domains of MHC class II molecules¹²¹ strongly suggesting the involvement of recycling MHC class II molecules in presentation of at least some tumour antigens.

In support of these ideas, enhanced expression of Ii chain in several types of human tumours has been suggested as one of the mechanisms of escape from immune surveillance.¹¹⁹ Indeed, coexpression of DM and Ii chain with MHC class II molecules in mouse sarcoma cells resulted in decreased immunogenicity of APC vaccines.¹²² In line with these observations, suppression of Ii chain expression¹²⁰ or lack of both Ii chain and DM expression¹²³ enhanced immunogenicity of sarcoma cells. Other examples of inhibition of Ii chain expression leading to successful anticancer vaccine development include colon adenocarcinoma, melanoma, lymphoma and prostate adenocarcinoma.¹¹⁹ These observations suggest that it may be common for tumour-specific epitopes to be loaded on recycling MHC II molecules independently of DM and Ii chain regulation in early endosomes.

Tumour antigens or peptides targeted deliberately to the DM- and Ii chain-deficient cellular compartments, such as early endosomes or the plasma membrane, may induce antitumour CD4 T cell immunity most effectively. As one approach, the immunogenicity of peptides is known to be increased by coupling to transferrin, which targets peptide–transferrin complexes to early endosomes via the transferrin receptor.¹²⁴ Clearly, further studies are required to determine whether the majority of tumour antigens are presented by alternative mechanisms, which may give insights into the development of effective antigen-based cancer vaccines.

Conclusions

Previous reviews of MHC class II-restricted antigen presentation strongly advocate that immunodominant epitopes are largely confined to the narrow limits of a pathway dependent on lysosomal degradation and peptide binding of newly synthesized MHC class II molecules occurring in acidic endosomal compartments. It is consequently accepted that the chaperones Ii, DM and DO are necessary to control the efficiency of antigen presentation in part by editing the peptide repertoire on the basis of affinity of peptide-MHC class II binding in these acidic compartments. However, these conclusions, drawn mainly from studies of relatively few experimental protein antigens with a globular structure, may not be generally applicable to the structurally more diverse antigens in the real world. This alternative view is supported by the large body of evidence we have reviewed, which point to a much greater variability in the location and extent to which protein antigens are processed, as well as in the sites where the resulting peptide epitopes bind MHC class II molecules.

The second part of the review catalogues many examples of the potential impact of the diversity in antigen presentation on immunity to infection, thymic selection, autoimmunity and tumour immunity. Furthermore, our interpretation of this body of published data gives fresh insights into several aspects of applied immunology. These include host mechanisms to induce CD4 T-cell responses against intracellular pathogens, for the long held view that altered antigen presentation may trigger autoimmune disease, and novel approaches to augment tumour immunity. However, studies of the precise mechanisms of antigen presentation of many more epitopes from microbial, autoimmune and tumour antigens need to be performed and the functional consequences determined before the impact of the diversity in MHC class II-restricted antigen presentation can be more fully evaluated.

Acknowledgments

The authors' research on antigen presentation is supported by The Wellcome Trust and UK MOD.

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PERMALINK

Diversity in MHC class II antigen presentation

John H Robinson

Alexei A Delvig

Abstract

Introduction

Figure 1.

Where do peptides bind MHC class II molecules?

Late endosomes

Endoplasmic reticulum (ER)

Early endosomes

Degrees of antigen processing

Source of MHC class II

Ii chain and DM dependence

Phagosomes

Plasma membrane

How might diversity in antigen presentation influence the immune response?

Immunity to infection

Table 1. Summary of epitopes shown to bind MHC class II in alternative sites.

T-cell selection

Autoimmunity

Tumour immunity

Conclusions

Acknowledgments

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Diversity in MHC class II antigen presentation

John H Robinson

Alexei A Delvig

Abstract

Introduction

Figure 1.

Where do peptides bind MHC class II molecules?

Late endosomes

Endoplasmic reticulum (ER)

Early endosomes

Degrees of antigen processing

Source of MHC class II

Ii chain and DM dependence

Phagosomes

Plasma membrane

How might diversity in antigen presentation influence the immune response?

Immunity to infection

Table 1. Summary of epitopes shown to bind MHC class II in alternative sites.

T-cell selection

Autoimmunity

Tumour immunity

Conclusions

Acknowledgments

References

ACTIONS

PERMALINK

RESOURCES

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