Recent advances in antigen processing and presentation

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1 Recent advances in antigen processing and presentation Peter E Jensen Heterogeneous intracellular pathways and biochemical mechanisms are responsible for generating the glycoprotein complexes of peptide and major histocompatibility complex that are displayed on the surfaces of antigen-presenting cells for recognition by T lymphocytes. These pathways have a profound influence on the specificity of adaptive immunity and tolerance, as well as the context and consequences of antigen recognition by T cells in the thymus and periphery. The field of antigen processing and presentation has continued to advance since the publication of a focus issue on the topic in Nature Immunology in July Progress has been made on many fronts, including advances in understanding how proteases, accessory molecules and intracellular pathways influence peptide loading and antigen presentation in various cell types. Two generally distinct pathways are used by major histocompatibility complex (MHC) class I and class II molecules for the presentation of peptide antigens to CD8 + and CD4 + T cells, respectively 1 4. The MHC class I antigen presentation pathway is active in almost all cell types, providing a mechanism for displaying at the cell surface a sample of peptides derived from proteins that are being synthesized in the cell at any given time. Thus, the internal proteome is made available for surveillance by cytolytic CD8 + T cells, which have the ability to detect and kill cells expressing viral proteins or tumor antigens. The MHC class II pathway is constitutively active only in professional antigen-presenting cells (APCs), including dendritic cells (DCs), B cells, macrophages and thymic epithelial cells. The generation of peptide MHC class II complexes and the expression of costimulatory molecules and cytokines in APCs are highly regulated, reflecting the critical importance of CD4 + T cells in regulating almost all components of adaptive immunity. The peptides presented by MHC class II molecules are derived from proteins that gain access to endosomal compartments, providing a way for CD4 + T cells to respond to exogenous antigens internalized by APCs through phagocytosis, macropinocytosis, receptor-mediated endocytosis and other mechanisms. MHC class I and class II proteins use very similar peptide-binding domain structures to form complexes with peptide antigens 5 (Fig. 1). For both classes, peptides are mostly buried in the peptide-binding groove, and the peptide is an integral part of the properly folded protein. Peptides are held in place by two sets of noncovalent interactions that include sequence-dependent interactions between side chains in the peptide (anchors) and subsites or pockets in the peptide-binding groove and a conserved hydrogen-bond network formed by nonpolymorphic amino acids in MHC proteins and main-chain atoms of bound peptides. The anchor-pocket interactions determine peptide-binding specificity, whereas the hydrogen-bond networks constrain peptide conformation Department of Pathology, University of Utah, Salt Lake City, Utah 84112, USA. Correspondence should be addressed to P.E.J. (peter.jensen@path.utah.edu). Published online 18 September 2007; doi: /ni1516 and provide a basal amount of stability to the complexes. The distribution of pockets and conserved hydrogen bonds differs for MHC class I and class II molecules. In MHC class I proteins, conserved hydrogen bonds are present at each end of the peptide-binding groove, limiting the length of bound peptides to generally eight to ten residues, but allowing bulging in the middle. In contrast, the ends of the MHC class II peptidebinding groove are open, making it possible for peptides of unlimited length to bind. The hydrogen-bond network fixes the conformation of the peptide backbone throughout its length in the peptide-binding groove. For both MHC class I and class II molecules, the peptide has a substantial effect in altering and stabilizing the conformation of the peptide-binding domain 6,7. MHC class I molecules acquire peptide during initial assembly in the endoplasmic reticulum 1,2,8 (Fig. 2). Short peptides are generated from the catabolism of endogenous proteins in the cytoplasm through the action of proteasomes and other enzymes, and these peptides are actively transported into the lumen of the endoplasmic reticulum by the heterodimeric transporter associated with antigen processing (TAP). The MHC class I heavy chain assembles first with β 2 -microglobulin and then with peptide through a series of orchestrated events involving components of the MHC class I peptide-loading complex. Components include the transmembrane protein tapasin, which physically bridges the dimer of heavy chain and β 2 -microglobulin to TAP. Other components of the peptide-loading complex include the chaperone calreticulin and the thiol oxidoreductase ERp57. After successful peptide loading, MHC class I molecules are released from the peptide-loading complex and are transported through the Golgi cisternae to the cell surface through the constitutive secretory pathway. MHC class II αβ heterodimers rely on a specialized type II transmembrane chaperone protein, the invariant chain (Ii), for stable assembly in the endoplasmic reticulum 3,9,10 (Fig. 3). Ii contains an unstructured segment that fits into the MHC class II peptide-binding groove, acting as a surrogate peptide to stabilize the protein. The cytoplasmic domain of Ii contains an endosomal sorting and retention signal. Class II molecules are relatively concentrated in multivesicular and multilamellar NATURE IMMUNOLOGY VOLUME 8 NUMBER 10 OCTOBER

2 Figure 1 MHC class I and class II peptide-binding domains. Bound peptides are in red; disulfide bonds are in yellow. Dashed lines indicate conserved hydrogen bonds between MHC amino acid side chains and bound peptides. Corresponding regions in the MHC class I α2 domain and MHC class II β1 domain (outlined) might represent targets for regulation of peptide exchange mediated by PDI (MHC class I) or HLA-DM (MHC class II). late endosomal compartments called the MHCII compartments. Ii is released through a series of proteolytic cleavage events, starting at the carboxyl terminus, including a key cleavage event, usually mediated by cathepsin S, that releases the MHC class II αβ heterodimer from the Ii cytoplasmic tail endosomal retention signal. This leaves only a short peptide from Ii, the MHC class II associated invariant-chain peptide (CLIP), bound to the peptide-binding groove and thus protected from the action of proteases. Every MHC class II molecule starts with a single self peptide, CLIP, which must be replaced by other peptides in the endosomal pathway for the system to work. For many MHC class II molecules, the rate of dissociation of CLIP is too slow to allow quantitative peptide loading before delivery to the cell surface. The catalyst chaperone protein HLA-DM has a key function by accelerating the rate of CLIP release and peptide exchange in MHCII compartments. HLA-DM is a nonpolymorphic MHC class II heterodimer that contains its own endosomal targeting signal. It does not bind peptides, but instead directly interacts with peptide MHC class II complexes to facilitate peptide exchange. HLA-DM is thought to edit the peptides presented to CD4 + T cells by catalyzing multiple rounds of peptide exchange, possibly favoring the most stable complexes. The available pool of peptide antigens is derived through the action of endosomal proteases on essentially any exogenous or endogenous proteins that gain access to the endosomal pathway. Peptide loading in the MHC class II pathway The physical mechanism underlying HLA-DM-mediated peptide exchange remains incompletely understood. The most widely accepted model is that HLA-DM binds to a transition state like conformation of peptide MHC class II complexes, in which some of the noncovalent interactions that hold peptide in place are weakened, thus accelerating peptide dissociation and exchange. The conformational changes involved may be very subtle and localized 11. Controversy exists regarding the alternative possibilities for how HLA-DM acts; these involve whether HLA-DM targets mainly pocket-anchor interactions or conserved hydrogen bonds, although both models have some experimental support 9, This is a crucial issue, as it determines the effect of HLA- DM editing on the repertoire of peptides that are available for CD4 + T cell recognition. In the first case, HLA-DM would be expected to skew the repertoire based on peptide sequences and the identity of particular anchor residues. The second mechanism would result in a general bias toward the presentation of more-stable peptide complexes, regardless of the identity of particular anchor residues. An elegant approach was recently used to determine the effect of peptide MHC class II complex stability on the specificity of CD4 + T cell responses in vivo 16. Mice were immunized with shuttle proteins with a common structural framework containing peptide variants designed to differ in their stability of MHC binding. A direct relationship was noted between immunogenicity and peptide complex stability. This result is the strongest evidence so far that the kinetic stability of peptide-mhc binding is a key variable in determining immunodominance. A follow-up in vitro study provided compelling evidence that the relative susceptibility to HLA-DM editing is directly determined by the stability of the peptide MHC class II complex, such that low-stability complexes are readily susceptible to removal by HLA-DM editing, whereas stable complexes are resistant 17. These findings support the idea that HLA-DM edits low-stability complexes, resulting in a general bias toward the presentation of more-stable complexes. Hydrogen bonds formed by the conserved MHC class II β-chain amino acids Asp82 and His81 have recently been reported to have a disproportionate function in stabilizing peptide MHC class II complexes 18 (Fig. 1). New findings have shown that a substitution at His81 not only reduces the stability of peptide complexes but also renders the complex immune to further destabilization by HLA-DM 19. Thus, the conserved hydrogen bond formed by His81 could be a chief target for disruption in the HLA-DM catalytic mechanism. Other studies have demonstrated that in addition to being a peptide editor, HLA-DM can also edit the conformation of specific peptide MHC class II complexes, removing conformational isomers that can be distinguished by T cells 20,21. In inflammatory conditions, the edited conformer can be presented to T cells in vivo, presumably through an HLA-DM-independent mechanism 21. It is possible that HLA-DM-independent presentation of normally edited self peptides and peptide-mhc conformers may be important in the pathogenesis of autoimmune disease. The potential relevance of HLA-DM-independent peptide dissociation or exchange is also emphasized by a recent report that selected noble metal complexes can induce peptide dissociation through an allosteric mechanism 22. This finding provides a potential mechanism for the therapeutic effect of gold compounds in rheumatoid arthritis, suggesting possible new strategies for treatment of autoimmune disease based on the manipulation of antigen presentation. In contrast to HLA-DM, a second nonpolymorphic accessory protein in the MHC class II pathway remains very much an enigma. HLA-DO is an intracellular MHC class II αβ heterodimer that is expressed in B cells. HLA-DO forms complexes with a substantial fraction of HLA- DM molecules in these cells, and it partially or completely inhibits the function of the bound HLA-DM protein. Most theories of HLA-DO function have centered on the idea that HLA-DM HLA-DO complexes retain some catalytic function in the more acidic environment present in late endosomal compartments of B cells. Antigens are preferentially targeted to these compartments after internalization through the B cell antigen receptor (BCR). Thus, HLA-DO might serve to further enhance the ability of B cells to selectively present antigens internalized through the BCR to CD4 + T cells. HLA-DO is not expressed in DCs generated in vitro, so it has been proposed to have a specialized function in B cell biology. However, recent studies have demonstrated that HLA-DO is expressed in primary DC populations in vivo, both in humans and 1042 VOLUME 8 NUMBER 10 OCTOBER 2007 NATURE IMMUNOLOGY

3 mice Thus, HLA-DO has a more general effect on antigen presentation than previously appreciated, and theories about its function need to be revisited. HLA-DO expression is downregulated during DC activation 23,24 and in germinal center B cells HLA-DO is also expressed in thymic medullary epithelial cells, consistent with the possibility that HLA-DO selectively affects antigen presentation by tolerance-inducing APCs in the thymus as well as periphery and is involved in immunological tolerance. Much remains to be learned about the mechanisms underlying antigen unfolding and peptide generation in the MHC class II pathway. The lysosomal thiol reductase GILT is important in the unfolding of disulfide-containing antigens, although other factors are probably involved 28. The environment in lysosomes is rich in proteases, but none have been shown to have a substantial nonredundant function in peptide generation in the MHC class II pathway. A common theme of the MHC class II and MHC class I pathways is that there is a balance between peptide generation and destruction. Recent studies have shown that the relatively limited lysosomal protease activity of DCs and B cells favors antigen presentation 29 and that the immunogenicity of protein antigens is enhanced by reducing susceptibility to lysosomal proteolysis 30. An old idea that remains viable is that MHC class II molecules initially bind to partially unfolded polypeptides and that the core peptide is protected in the peptide-binding groove during a trimming process that generates the final peptide 31. A well documented example of MHC-guided processing has recently been published 32. In B cells, antigen or selected antigenic determinants can be protected from proteolysis by binding to the BCR 33,34. These two ideas have been brought together in a recent study showing that protease nicking can be sufficient to allow large fragments of a model protein antigen to bind MHC class II and that BCR-bound nicked antigen can be passed to MHC class II molecules localized together in the same membrane through a process catalyzed by HLA-DM 35. This finding raises interesting questions about the physical basis for HLA-DM-enhanced antigen transfer between the BCR and MHC proteins. The MHC class II pathway in DCs Intense focus remains on the mechanisms that regulate antigen presentation by DCs. These cells are key in responding to environmental signals to initiate various cascades of T cell immunity or tolerance. Immature DCs are highly endocytic but relatively inefficient at antigen processing and presentation. After stimulation with Toll-like receptor (TLR) ligands or inflammatory cytokines, DCs undergo a maturation process that results in migration to lymphoid organs, remodeling of endosomal compartments, reduced endocytosis (ultimately), redistribution of MHC class II molecules from MHCII compartments to the cell surface, and upregulation of costimulatory molecules. Most of the events in the MHC class II pathway are regulated by ph and are optimal at acidic ph. Key recent findings include the observation of enhanced lysosomal acidification during DC maturation 36. In addition, antigen uptake is transiently increased in response to TLR signaling 37. It makes sense that antigen uptake should be enhanced rather than inhibited during the initial time period after contact with microbial pathogens. The unexpected observation that endogenous caspases have a regulatory function in preventing endosomal remodeling and controlling protein sorting in immature DCs has been reported 38. It was also recently discovered that surface expression and turnover rates for MHC class II are regulated by cytoplasmic domain ubiquitination in DCs and B cells 41,42. This observation helps to explain why surface expression of MHC class II molecules is low on immature DCs and provides a mechanism for the considerable increase in the half-life of surface MHC class II molecules that occurs after DC maturation, providing a means for sustained antigen presentation after migration to secondary lymphoid organs. Much remains to be learned about the molecular pathways that regulate DC endosomal acidification, actin remodeling, caspase activity and MHC class II ubiquitination in response to TLR signaling. Adding to the complexity, the efficiency of presentation of antigen internalized through phagocytosis is enhanced by the localization of TLR ligands together with antigen in the phagosome, and the generation of peptide MHC class II complexes is controlled by TLRs in a phagosome-autonomous way 43. Thus, local TLR signaling can regulate phagosome maturation 44 and the efficiency of antigen processing in individual membrane-bound compartments. No doubt further progress will continue to be made in this important area. The endogenous MHC class I pathway Early folding and oxidation of MHC class I heavy chain and assembly with β 2 -microglobulin are mediated by the chaperone calnexin (Fig. 2). These events are followed by release from calnexin and assembly with the MHC class I peptide-loading complex, which comprises many components, including the soluble chaperone calreticulin, ERp57, tapasin and TAP. A chief function of the complex is to orchestrate final assembly with peptides, delivered into the endoplasmic reticulum by TAP, and to provide quality control for exported peptide-mhc complexes 45. By analogy to the MHC class II pathway, there is strong evidence that initial peptide binding to MHC class I molecules is followed by peptide Endoplasmic reticulum β 2 M MHC class I heavy chain Calnexin? Proteasome & peptidases PDI Calreticulin ERAAP Peptide trimming Peptide loading & exchange (editing)? ERp57 TAP Tapasin Peptide-loading complex Golgi Endogenous Peptide protein antigen Proteasome Figure 2 The direct MHC class I processing pathway. MHC class I heavy chains initially assemble with β 2 -microglobulin (β 2 M), followed by recruitment into the peptide-loading complex in the endoplasmic reticulum. Endogenous peptides, generated in the cytoplasm through the action of proteasomes and other peptidases, are transported into the endoplasmic reticulum via TAP. ERAAP mediates final amino-terminal trimming of peptides, before or after initial binding to MHC class I molecules. Components of the peptideloading complex promote peptide loading and exchange, providing a quality-control mechanism for the preferential export of kinetically stable peptide MHC class I complexes to the cell surface. NATURE IMMUNOLOGY VOLUME 8 NUMBER 10 OCTOBER

4 Exogenous protein antigens Endogenous proteins exchange and editing in the endoplasmic reticulum Tapasin has been postulated to have a key function in peptide editing, although it seems that many components of the peptideloading complex participate in the qualitycontrol mechanism. A study has demonstrated that the hierarchy of presentation of a series of specific peptides, representing a wide range of affinities, corresponded to peptide half-life 48. This hierarchy was disrupted in cells lacking tapasin, but calreticulin or ERp57 had no apparent effect. This finding reinforces the idea that tapasin is critical in the selection of stable peptide complexes. A recent study has provided evidence for the involvement of tapasin in the retrieval of unstable peptide MHC class I complexes from post endoplasmic reticulum compartments 49. Thus, tapasin may contribute to quality control not only through its participation in the peptide-loading complex and through retention of unstable MHC class I molecules in the endoplasmic reticulum but also through the retrieval of complexes that escape the endoplasmic reticulum after being loaded with suboptimal peptides. ERp57 is a thiol oxidoreductase that forms a disulfide bond with tapasin 50. Given its enzymatic activity, it is possible that ERp57 may maintain proper disulfide structure in MHC molecules during peptide loading or may regulate loading by disulfide exchange 50. Indeed, a conserved disulfide bond in the α2 domain (Fig. 1) is critical for stabilizing the conformation of the peptide-binding domain. However, recent work suggests that this is not its chief function. Tapasin was demonstrated to be a preferred substrate for ERp57, forming a highly stable disulfide-linked heterodimer, thus preventing ERp57 from acting on other substrates 51. In a key study, mice were generated to be deficient in ERp57 in B cells 52. ERp57 deficiency had no effect on the oxidative state of the disulfide bonds in MHC heavy-chain molecules. ERp57, however, was found to be important for recruiting and retaining MHC molecules in the peptide-loading complex and for optimal cell surface expression of stable MHC-peptide complexes 52. Thus, ERp57 affects quality control in a way similar to tapasin. Recent findings have shown that tapasin acts as a functionally important sink for the sequestration of ERp57. In the absence of tapasin, the MHC α2-domain disulfide bond is rapidly reduced through the catalytic activity of free ERp57 (ref. 53). The integrity of this disulfide is critical for peptide loading. Tapasin interacts directly with MHC, but the ability of the isolated protein to directly catalyze peptide loading and exchange, by analogy to HLA-DM in the MHC class II pathway, has been difficult to demonstrate. A recent study has demonstrated peptide-editing function with a soluble form of tapasin engineered to have greater affinity for MHC through the use of leucine zippers 54. It seems that in physiological conditions, ERp57 provides a key structural element in promoting tapasin function. In a cell-free system, recombinant tapasin-erp57 complexes facilitated the recruitment of MHC into the peptide-loading complex, peptide binding and peptide editing, favoring the formation of more-stable peptide complexes 55. Tapasin spontaneously assembles with ERp57 with no requirement for other components of the peptide-loading complex 51. ERp57 may influence the conformation of tapasin in the heterodimer, as well as providing a second binding site with the peptide-loading complex through the direct interaction of ERp57 with calreticulin 50,52,55. Thus, Autophagy Endoplasmic reticulum Invariant chain Endocytosis Late endosomal compartments Endosomal proteases GILT MHC class I CLIP DM-catalyzed Peptide loading & exchange (editing) Peptide trimming Unfolded protein or peptide Figure 3 The MHC class II processing pathway. MHC class II molecules assemble initially in the endoplasmic reticulum with Ii, which contains an endosomal targeting signal. In endosomal compartments, Ii is released mainly through a series of protease cleavage events, leaving only the fragment CLIP occupying the peptide-binding groove. HLA-DM (DM) catalyzes the release of CLIP, the binding of antigen peptides and peptide exchange. HLA-DM edits the repertoire of peptide MHC class II complexes that are transported to the cell surface for recognition by CD4 + T cells. Exogenous proteins are internalized into the endosomal pathway by a variety of mechanisms, and unfolding and fragmentation are catalyzed by the disulfide reductase GILT and lysosomal proteases. Peptides are probably subjected to further trimming after initial binding to MHC class II molecules. it seems that no single component of the peptide-loading complex is sufficient to promote peptide loading and editing in the MHC class I pathway; instead, tapasin, ERp57 and calreticulin function in concert. The newest candidate component of the peptide-loading complex to be described is protein disulfide isomerase (PDI), an enzyme that has a general function in promoting the formation of native disulfide bonds during initial folding of proteins in the endoplasmic reticulum. PDI was reported to precipitate together with other components of the peptideloading complex and to be critical in regulating the redox state of the disulfide bond in the MHC class I α2 domain 56. Evidence has been presented indicating that this disulfide, situated in the peptide-binding groove, is in dynamic equilibrium between the oxidized and reduced states and that conversion may be catalyzed by PDI through a disulfide-exchange mechanism 56 (Fig. 1). Notably, the redox state was found to be controlled by the availability of high-affinity MHC-binding peptides. In addition to catalytic domains, PDI has a domain for binding small peptides, and substitutions in the PDI peptide-binding domain were found to impair MHC class I peptide loading. Thus, peptide loading and quality control in the MHC class I pathway might be controlled by a thiol-based redox mechanism mediated by PDI that regulates the conformation or stability of the MHC class I peptide-binding domain. In addition, PDI might function as a peptide carrier with the ability to serve as a donor or acceptor for MHC class I peptide-exchange reactions in the endoplasmic reticulum 56. These findings remain controversial, because it has been difficult for other groups to identify PDI as a component of the peptide-loading complex 51,53,55. Nevertheless, it remains possible that catalytic concentrations of PDI might influence the peptide-loading mechanism. Although much has been learned about the MHC class I peptideloading mechanism, the story continues to be written. Indeed a recently described mutant cell line showed a defect in the early assembly of MHC class I molecules, despite normal function of all known components of the MHC class I assembly pathway 57, emphasizing the idea that critical components of the antigen-processing pathways remain to be discovered VOLUME 8 NUMBER 10 OCTOBER 2007 NATURE IMMUNOLOGY

5 Most of the peptides that enter the MHC class I presentation pathway are generated by proteasome-mediated cleavage of polypeptides in the cytoplasm of cells. Strong evidence has been published supporting the idea that translation and protein folding may be error prone, that a considerable fraction of newly translated polypeptides are rapidly degraded by the proteaseome and that newly generated polypeptides, including defective ribosomal products, represent the main source of antigens entering the MHC class I loading pathway This model has been called into question by recent evidence showing that newly synthesized polypeptides are mostly protected from proteasomal degradation during and immediately after translation and that preexisting proteins represent the main proteaseome substrates 61. It is clear, however, that translational errors, including ribosomal frameshifting, can have biological relevance in generating CD8 + T cell determinants 62. In addition, T cell epitopes have been identified that represent spliced peptides generated by the proteasome, expanding the known post-translational mechanisms through which T cell determinants are generated or modified The proteasome generates peptides 2 25 amino acids in length, with most being rapidly degraded by cytoplasmic peptidases 1,2,66. A small fraction is transported into the endoplasmic reticulum by TAP. Proteasomes are thought to generate the final carboxy-terminal residues of MHC-binding peptides, but additional trimming at the amino terminus is required for most peptide epitopes. The cytoplasmic peptidase TPPII has been shown to be involved in trimming proteasomal products over 15 amino acids in length 57,67, although its quantitative contribution to the pool of MHC-binding peptides remains unclear 57. TPPII has also been shown to participate in a proteasome-independent Protein antigen Proteasome Peptide TAP MHC class I Sec61 Mannose receptor Scavenger receptor MHC class II Figure 4 Proposed pathways for cross-presentation by MHC class I molecules. (a) In the phagosome-tocytoplasm pathway, particle- or cell-associated proteins or peptides are transported from the phagosome to the cytoplasm, where they enter the direct MHC class I pathway as substrates for proteasomes. The export mechanism is unknown. (b) The endoplasmic reticulum (ER) phagosome represents an essentially autonomous compartment for generating peptide MHC class I complexes from exogenous antigens. Components of the endoplasmic reticulum are incorporated into phagosomes that contain internalized antigens. Proteins are exported to the cytoplasm by the endoplasmic reticulum derived Sec61 translocation complex, where they become substrates for locally associated proteasomes. The resulting peptides are transported back into the endoplasmic reticulum phagosome by TAP, followed by binding to MHC class I molecules and transport to the cell surface. (c) Soluble proteins can be targeted to different processing pathways after internalization through receptor-mediated endocytosis. Proteins internalized by pinocytosis or scavenger receptors are targeted to lysosomes and are excluded from cross-presentation by MHC class I molecules. Proteins internalized through mannose receptors are targeted to a stable population of early endosomes, from which they are transported to the cytoplasm, entering the direct MHC class I pathway as proteasome substrates. Additional mechanisms for cross-presentation have been demonstrated. pathway for epitope generation 68. Indeed, the proteasome destroyed the influenza nucleoprotein T cell determinant investigated in that study. The key enzyme responsible for final amino-terminal trimming of peptides in the MHC class I pathway is located in the endoplasmic reticulum. The ubiquitously expressed endoplasmic reticulum aminopeptidase ERAAP (or ERAP1) seems to be ideally suited for generating MHC class I binding peptides from longer amino-terminally extended precursors delivered into the endoplasmic reticulum by TAP It has been reported to function as a molecular ruler that recognizes the peptide carboxyl terminus and trims the amino terminus to generate peptides 8 10 residues in length 72. However, another recent report has indicated that ERAAP has the ability to further trim small peptides and thus destroy T cell determinants 73. MHC class I molecules were reported to protect peptides from destruction by binding to amino-terminally extended precursors, a mechanism analogous to that described above for MHC class II molecules 73. It will be useful to further investigate this mechanism and the potential influence of PDI and other peptide-binding endoplasmic reticulum chaperone molecules on peptide trimming. In both the MHC class I and class II pathways, accessory proteins have the ability to bind antigenic precursors, influence proteolytic processing and potentially hand off peptide precursors to the MHC peptidebinding groove, which might protect the core sequence during a final trimming step 31,35,56, Two endoplasmic reticulum aminopeptidases are expressed in human cells, ERAP1 (ERAAP) and ERAP2, and these are reported to have complementary function 77. In contrast, ERAAP is the only endoplasmic reticulum peptidase in mouse cells. It is therefore surprising that ERAAP deficiency has a relatively minor effect on MHC class I expression, CD8 + T cell selection and the ability to mount T cell responses to viral infections However, a recent study has suggested that ERAAP does have a global effect on the repertoire of peptides presented by MHC class I molecules. APCs from ERAAPdeficient mice were shown to stimulate strong T cell responses in wild-type mice and vice versa, indicating that there are sets of peptide MHC class I complexes that are uniquely presented on APCs in the presence versus the absence of ERAAP and that peptide trimming in the endoplasmic reticulum has a functionally substantial effect on CD8 + T cell repertoire selection 81. A recent study has demonstrated that cortical thymic epithelial cells uniquely express a previously unrecognized catalytic subunit of the proteasome, altering cleavage specificity and presumably influencing the repertoire of peptides that mediate positive selection of developing thymocytes 82. Mice deficient in this catalytic subunit have a substantial defect in the development of CD8 + T cells despite having normal expression of MHC class I on cortical thymic epithelial cells. These findings, coupled with a previous study demonstrating important differences in proteolytic events in the MHC class II pathway in cortical thymic epithelial cells 83, suggest that it may be critical to have distinct peptide repertoires that mediate positive versus negative selection of thymocytes. NATURE IMMUNOLOGY VOLUME 8 NUMBER 10 OCTOBER

6 Cross-presentation In addition to sampling endogenous peptides for presentation by MHC class I molecules, DCs and macrophages have the ability to present exogenous antigens internalized through the endocytic pathway to CD8 + T cells 4, The mechanisms responsible for such cross-priming or cross-presentation are critical for initiating CD8 + T cell responses to antigens that would not otherwise gain access to the MHC class I presentation pathway in DCs. There is a division of labor among the main DC subsets in mouse spleen; the CD8 + subpopulation is specialized for cross-presentation 87,88, whereas the CD8 DC subpopulation has recently been reported to be more effective in inducing CD4 + T cell responses 89. Cell- or particle-associated antigens are generally much more efficient at inducing cross-priming than are soluble antigens. It is clear that there are many pathways for cross-presentation, including TAP-dependent and TAP-independent mechanisms. The TAP-independent or vacuolar pathway may involve peptide exchange in recycling endosomes or on the cell surface, and a recent study has demonstrated that the lysosomal protease cathepsin S is important in generating peptides presented through this pathway 90. The physical form of antigen that is transferred to DCs for cross-presentation has been the subject of debate. However, recent studies have indicated that cross-presentation generally results from the transfer of proteins that require further processing 91 93, not free peptides or peptides bound to heat-shock proteins 94. TAP-dependent mechanisms seem to dominate, and they are thought to involve the transfer of precursor antigens from the endosome to the cytoplasm, where they enter the direct MHC class I presentation pathway as substrates for the proteasome (Fig. 4). As in the MHC class II and direct MHC class I processing pathways, there is a balance between peptide generation and destruction by proteolytic enzymes in cross-presentation. Mechanisms that reduce the activity of endosomal hydrolases in DCs have recently been shown to enhance the efficiency of cross-presentation 95,96. Both soluble and phagocytosed particulate antigens have been reported to access the cytoplasm through a mechanism involving molecular components of the endoplasmic reticulum associated degradation system, which transfers misfolded proteins from the endoplasmic reticulum to the cytoplasm for degradation 97,98. Soluble proteins might directly access the endoplasmic reticulum after endocytosis through a retrograde transport pathway that is active in DCs 99. A recent study has suggested that the mechanism of internalization of soluble antigen controls access to a cross-presentation pathway in DC and macrophages 100. Antigen internalized through mannose receptor mediated endocytosis is targeted to a stable population of early endosomes, resulting in efficient cross-presentation to CD8 + T cells. Presentation is dependent on proteasome function, suggested that antigen is transferred from the early endosomes to the cytoplasm, where it enters the direct MHC class I processing pathway. In contrast, antigen internalized through scavenger receptors or pinocytosis is targeted to lyosomes and is efficiently presented to CD4 + T cells but not to CD8 + T cells 100 (Fig. 4). There was considerable excitement after the discovery of the incorporation of components of the endoplasmic reticulum membrane into phagosomes after uptake of particulate antigens The findings support a model in which individual phagosomes can be self-sufficient for antigen processing and cross-presentation 102,103 (Fig. 4). In this model, antigen is transferred to the cytoplasmic side of the phagosomal membrane through the endoplasmic reticulum derived retrotranslocation machinery (the Sec61 translocation complex). Locally associated proteasomes generate peptides that are transferred back into the lumen via TAP. The functional contribution of the MHC class I peptide-loading complex and ERAAP remain to be demonstrated. Although this model is attractive, a recent study has provided strong evidence that the endoplasmic reticulum contributes very little to the phagosome membrane, which instead is derived from the plasma membrane, providing a considerable challenge to the endoplasmic reticulum phagosome model 105. Yet another pathway for cross-presentation has been demonstrated that involves direct gap junction mediated transfer of peptides from virally infected cells to professional APCs 106. The exciting recent developments in understanding cross-presentation raise many new questions for further investigation. Conclusion The MHC class I and class II processing pathways use distinct cellular compartments and accessory proteins, yet there are common principles and areas of overlap. In both pathways, peptide generation and destruction are balanced and subject to regulation. MHC proteins and accessory molecules can bind peptide intermediates and guide proteolytic processing or trimming. Accessory proteins mediate peptide exchange and editing in newly generated MHC class I and class II complexes, favoring the presentation of more-stable complexes. Exogenous antigens gain access to the MHC class I pathway through multiple cross-presentation mechanisms in professional APCs. Recent studies have demonstrated that the endosomal MHC class II loading pathway continuously receives input from endogenous cytoplasmic antigens through autophagy and other mechanisms Thus, endogenous and exogenous antigens are presented through both the MHC class I and class II pathways. There is also cross-utilization of the proteolytic machinery, as shown by the involvement of cathepsin S in cross-presentation 90 and the recent demonstration of a proteasome-dependent pathway for presentation of MHC class II restricted viral epitopes 110. There are many distinct and overlapping pathways for antigen presentation, which is not unexpected, given its central function in adaptive immunity. It is likely that unanticipated discoveries will continue to be made in this exciting area of inquiry. Future studies will improve understanding of the mechanisms of peptide loading and exchange and the effect of peptide editing on the specificity of immunity and tolerance. Much remains to be learned about distinct features of the antigen-processing pathways in different APC types, including thymic epithelial subpopulations, DCs and B cells. There is relatively little knowledge about the effect of MHC polymorphisms on interactions with the peptide-loading machinery and the implications for understanding the strong genetic associations between MHC haplotypes and disease. Indeed, it is likely that important participants in the antigenprocessing pathways remain to be discovered and that advances will be made in manipulating these pathways for the therapeutic modulation of immunity and tolerance. COMPETING INTERESTS STATEMENT The author declares no competing financial interests. Published online at Reprints and permissions information is available online at reprintsandpermissions 1. Kloetzel, P.M. Generation of major histocompatibility complex class I antigens: functional interplay between proteasomes and TPPII. Nat. Immunol. 5, (2004). 2. Rock, K.L., York, I.A. & Goldberg, A.L. Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Nat. Immunol. 5, (2004). 3. Watts, C. The exogenous pathway for antigen presentation on major histocompatibility complex class II and CD1 molecules. Nat. Immunol. 5, (2004). 4. Ackerman, A.L. & Cresswell, P. Cellular mechanisms governing cross-presentation of exogenous antigens. Nat. Immunol. 5, (2004). 5. Stern, L.J. & Wiley, D.C. Antigenic peptide binding by class I and class II histocompatibility proteins. Structure 2, (1994). 6. Glithero, A. et al. The crystal structure of H-2D b complexed with a partial peptide epitope suggests a major histocompatibility complex class I assembly intermediate. J. Biol. Chem. 281, (2006) VOLUME 8 NUMBER 10 OCTOBER 2007 NATURE IMMUNOLOGY

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