Cross-presentation of exogenous antigens on MHC I molecules

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ScienceDirect Cross-presentation of exogenous antigens on MHC I molecules Jeff D Colbert, Freidrich M Cruz and Kenneth L Rock In order to get recognized by CD8 T cells, most cells present peptides from endogenously expressed self or foreign proteins on MHC class I molecules. However, specialized antigenpresenting cells, such as DCs and macrophages, can present exogenous antigen on MHC-I in a process called crosspresentation. This pathway plays key roles in antimicrobial and antitumor immunity, and also immune tolerance. Recent advances have broadened our understanding of the underlying mechanisms of cross-presentation. Here, we review some of these recent advances, including the distinct pathways that result in the cross-priming of CD8 T cells and the source of the class I molecules presenting exogenous peptides.

Acquiring exogenous antigens for XPT

Address Department of Pathology, University of Massachusetts Medical School, United States

The mechanism that most efficiently delivers antigens for XPT is phagocytosis, presumably because of the large quantity of antigen ingested, as well as the presence of XPTing machinery in phagosomes, as will be described below. Consequently, XPT of particulate antigens is much more efficient than soluble ones [6]. Since one of the pathophysiologic substrates for phagocytosis are dying cells, XPT of cell-associated antigens allows the CD8 T immune system to monitor injured cells for pathological processes, such as viral infection of malignant transformation, and hence is important for immune surveillance [1,2]. Dendritic cells may similarly acquire cellular antigens for XPT by ingesting exosomes [21] or even by taking a ‘bite’ out of living cells [22,23].

Corresponding author: Rock, Kenneth L ([email protected])

Current Opinion in Immunology 2020, 64:1–8 This review comes from a themed issue on Antigen processing Edited by Shastri Nilabh and D Amigorena Sebastian

https://doi.org/10.1016/j.coi.2019.12.005 0952-7915/ã 2019 Elsevier Ltd. All rights reserved.

Introduction MHC I molecules in most cells do not present antigens that are present in the external environment but instead focus exclusively on displaying peptides derived from the intracellular catabolism of a cell’s own proteins. However, some antigen-presenting cells, such as dendritic cells, are able to present on their MHC I molecules not only peptides from their own proteins, but also ones derived from exogenous (extracellular) sources, through a process called cross-presentation (XPT). XPT plays a key role in how dendritic cells are able to collect antigens from other cells in tissues, including ones that are cancerous or infected with viruses, and report them to CD8 T cells in ways that initiate [1,2] or in some situations prevent (tolerize) responses [3,4]. This review will focus on the dominant mechanisms by which cells are able to crosspresent (XPT) exogenous antigens. www.sciencedirect.com

Cells that XPT acquire extracellular antigens through endocytic mechanisms. Soluble antigens, which are internalized through fluid phase pinocytosis can be crosspresented (XPTed), although rather inefficiently, in part due to the small quantity of protein that is ingested [5,6]. Receptor-mediated endocytosis, for example, via the mannose receptor for soluble proteins [7] or via Clec9a for dead cells [8], can increase antigen uptake and augment XPT. This has led to interest in targeting antigens to a variety of receptors or other means of enhancing uptake into dendritic cells for vaccines [9–20].

Most if not all cells that are phagocytic can cross-present. While cross-presentation by dendritic cells (for immune surveillance/tolerance) [1,2,24] and macrophages (for elimination of chronically infected cells) [25–27] fulfills important physiological roles, the significance of XPT by some other phagocytes, for example, neutrophils [28,29] and myeloid cells [30,31] is unclear. Interestingly, if a receptor that confers phagocytic ability is transfected into non-phagocytic cells, it allows such cells to XPT antigens from exogenous particles [32]. Therefore, the ability to phagocytize can confer the ability to XPT antigens. Nevertheless, while phagocytosis may be sufficient to allow some XPT, there are additional specific mechanisms in ‘professional’ cross-presenting cells, such as dendritic cells, that increase the efficiency of XPT, as will be discussed below. Preservation of XPTed antigens in phagosomes

After a phagocyte ingests proteins into phagosomes, these vacuoles fuse with lysosomes, acidify and become catabolic. In situations where antigen is released from the phagosome to the cytosol (termed the phagosome-to-cytosol pathway Current Opinion in Immunology 2020, 64:1–8

2 Antigen processing

of XPT), proteolysis in phagosomes is not generally needed to generate XPTed peptides, but rather can destroy them [33]. Consequently, pharmacological agents or gene knock outs that reduce endosomal catabolism can increase XPT [34–36]. Dendritic cells can reduce antigen destruction in phagosomes, using Sec22b [37–39] and VAMP8 [40]dependent mechanisms to recruit NOX2/NADPH oxidase to phagosomes. The NADPH oxidase complex produces reactive oxygen species (ROS) that lead to an elevated pH within phagosomes, which in turn reduces the activity of acid-optimal proteases [33,41,42]. In addition, there are other mechanisms that delay endosome/phagosomal maturation, reduce lysosomal fusion, and/or reduce intravacuolar protein degradation [43–45]. While the reduction in phagosomal protein hydrolysis can enhance XPT, significant presentation still occurs in the absence of NOX2, Sec22b and VAMP8 [33,38,39,46], and in one report loss of NOX2 actually increased XPT [47]. Transfer of antigens to the cytosol and generation of XPTed peptides

In order to be XPTed, an internalized antigen must be hydrolyzed and the resulting oligopeptides then bound to and displayed by MHC I molecules. There are multiple pathways/mechanisms by which this can occur. This review focuses primarily on one of these mechanisms, the phagosome-to-cytosol (P2C) pathway, because it is the pathway that is thought to be most dominant in immune surveillance in vivo [48]. To generate XPTed peptides via the P2C pathway (Figure 1a and b), antigens are transferred to the cytosol, where they are hydrolyzed by proteasomes and the resulting peptides transported to MHC I molecules in the ER or phagosomes. Transfer of antigen from phagosomes to the cytosol is well documented [25,49–51] and assays have been developed to measure this event [52,53]. How this transfer is accomplished is not completely understood and there may be more than one mechanism. Most work has focused on transport through a channel, with one candidate for this being an endoplasmic reticulum-associated degradation (ERAD)-like pathway (Figure 1a). In ERAD, proteins in the ER are ubiquitinated through ER-associated E3-ligases and then, with the aid of a cytosolic ATPase (p97), are transferred to the cytosol through a channel formed by, for example, Derlin-1 [54]; once in the cytosol the proteins are degraded by proteasomes. The possibility that an ERAD pathway might operate in phagosomes was raised when a subset of ER-resident proteins, including TAP, Calnexin and Syntaxin 18, were found associated with and/or in phagosomes [55], raising the possibility that ERAD-components might also be transferred to phagosomes. As noted above, Sec22b is involved in transfer of some ER proteins to phagosomes [37] and was needed for optimal cross-presentation, in some [37,38] but not all Current Opinion in Immunology 2020, 64:1–8

reports [39]. Sec22b is a SNARE protein that promotes fusion between vesicles, which in XPT are thought to be transport vesicles from the ER fusing with endosomes/ phagosomes. How Sec22b+ vesicles are trafficked from the ER/golgi compartment to these peripheral vacuoles had been unknown, but recently the vesicular transport protein Rab39a, which is needed for optimal P2C XPT, was implicated in this process [56]. Interestingly, loss of Sec22b inhibited, among other things, P2C antigen transfer out of phagosomes [37]. These data suggested that molecules from the ER participate in the antigen translocation process, although which ones are not fully resolved. The Sec61 translocon, which Sec22b helps deliver to phagosomes, imports nascent membrane and secreted proteins into the ER and has also been implicated in both ERAD [57,58] and XPT [51,59]; however, it is not entirely clear whether Sec61 is contributing to these processes indirectly, by importing proteins needed for P2C antigen transfer [60], or directly as a retro-translocation channel [51,59,61]. The cytosolic ATPase p97 is involved in ERAD, associates with phagosomes and has been implicated in P2C antigen transfer [62–65]. However, other ERAD components, such as Hrd1, gp78, HERP and Derlin-1, are not required for XPT [51,61,64] and therefore the classical ERAD pathway is unlikely to be involved in the P2C antigen transfer. Another possible mechanism for P2C antigen transfer is rupture of vesicles. Phagosome rupture can occur [66] and rupture of vesicles is sufficient to allow internalized antigens to be XPTed (Figure 1b) [67]. Reactive oxygen species, which are generated by NADPH oxidase in phagosomes, can cause lipid peroxidation and this has been suggested as a mechanism to lead to vesicular rupture [46,68]. As noted above, loss of NOX2 partially reduces XPT but whether this is due to reduced vesicular rupture and/or acidification of these vacuoles (see above), is not clear. Loss of NADPH oxidase has also been reported to have the opposite effect of enhancing XPT [47]. Other sources of ROS may also promote XPT [69]. Once transferred into the cytosol, antigens are degraded into oligopeptides by proteasomes/immunoproteasomes, in the same manner as endogenously synthesized proteins [49]. This is a biologically important feature of the P2C pathway because by using the same proteolytic system to generate presented peptides as all other cells, the XPTed peptides that prime CD8 T cell responses will match those in the target cells that effector CD8 T cells need to eliminate. The peptides produced by proteasomes will include mature epitopes and also N-terminally extended precursors that can be subsequently trimmed to appropriate size for binding to MHC I molecules [70–72]. www.sciencedirect.com

MHC I cross-presentation Colbert, Cruz and Rock 3

Figure 1

exogenous antigen MHC I

PM P2C (rupture)

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Current Opinion in Immunology

Cross-presentation pathways. Professional antigen-presenting cells internalize exogenous antigens into phagosomes and endosomes. In dendritic cells, Nox2 is recruited (blue) and produces ROS, which then results in an increase in endocytic pH and a reduction in proteolytic hydrolysis. (a) Antigen may escape into the cytosol (P2C pathway) through channels found on endosomes/phagosomes (perhaps via an ERAD-like mechanism) or (b) due to rupture of phagosomal membranes. Once in the cytosol antigen is targeted for degradation by the ubiquitin-proteasome pathway and the resulting peptides are then translocated via TAP transporters on the ER or (c) endocytic compartments (P2C2P pathway). (d) Some antigens remain within the vacuolar compartment (vacuolar pathway) where peptides are cleaved by hydrolytic proteases (for example, cathepsin S) and loaded on MHC I molecules. Peptide-MHC I complexes then transit to the PM for recognition by CD8 T cells. Dashed lines with arrows indicate incompletely understood or postulated aspects in the pathway. Abbreviations: PM: plasma membrane, ER: endoplasmic reticulum, ERGIC: ER-golgi intermediate compartment, PLC: peptide loading complex.

Transport and trimming of XPTed peptides

After peptides are produced in the cytosol, they need to be transported into compartments that contain MHC I molecules. Loss of TAP, the peptide transporter that pumps peptides from the cytosol to ER, inhibits P2C XPT [2,73]. Thus, it is thought that a fraction of the peptides generated in the cytosol is transported to peptide-receptive MHC I molecules in the ER, in the same manner as occurs for the presentation of peptides from endogenous proteins. That the ER is an important compartment for MHC I-loading of XPTed peptides is further supported by the finding that loss of ERAP1 (ERAAP), the ER-resident aminopeptidase that trims N-terminally extended precursor peptides, is needed for a substantial portion of XPT [74,75]; this strongly suggests that many XPTed peptides are being trimmed and loaded in the ER. TAP is also present in phagosomes and is delivered there at least in part by a Sec22b-dependent mechanism [37]. TAP is active in purified phagosomes and can transport www.sciencedirect.com

peptides into purified vacuoles (Figure 1c) [76]. It has been reported that a second as yet unidentified peptide transporter is involved in transferring some peptides into purified phagosomes [77]. TAPL, a relative of TAP that is resident in endosomes was an obvious candidate for such an activity, but silencing TAPL did not affect XPT [78]. That phagosomes are a bone-fide destination for XPTed proteasome-generated peptides is supported by the finding that Rab39a, which converts phagosomes into MHC I peptide-loading compartments, is required for optimal P2C XPT [56]. Moreover, IRAP, an endosomal resident aminopeptidase related to ERAP1, participates in XPT. IRAP can trim N-terminally extended peptide precursors to mature epitopes and loss of IRAP reduces a portion of XPT for antigens that likely are presented by the P2C pathway [79]; this strongly suggests that many XPTed peptides are being trimmed and loaded in phagosomes. MHC I molecules in phagosomes

MHC I molecules are present in phagosomes and are thought to bind and XPT peptides that are present in Current Opinion in Immunology 2020, 64:1–8

4 Antigen processing

these vacuoles. How such XPTing MHC I molecules get to phagosomes is incompletely understood. These MHC I molecules may come from the cell surface as a consequence of the invagination of plasma membrane during the formation of phagosomes and/or by transport after the phagosome is formed (Figure 2a). The intracytoplasmic tail of MHC I molecules contains a tetrapeptide sorting motif (YXXw) that promotes MHC I trafficking to endosomes and contributes to XPT [80]. It is proposed that the ubiquitination status of the MHC-I tail, modified by the deubiquitinase UCH-L1, affects MHC-I localization and recycling [81]. In infection, a Toll-like receptor stimulated pathway can stimulate the delivery of MHC I from an endosomal recycling compartment (ERC) to endosomes in a Snap23-dependent manner [82] (Figure 2b). Rab3b/Rab3c have been implicated in recycling of surface MHC I molecules and XPT, although whether this is the case for P2C XPT is unclear, as the antigen studied in these experiments tends to be presented by the vacuolar pathway [83]. Alternatively, or in addition, XPTing MHC I molecules may traffic to phagosomes from the ER. The vesicular transport protein Rab39a increases intraphagosomal levels of peptide-empty MHC I molecules and this process is blocked by Brefeldin A, which inhibits transport out of

the ER/golgi [56] (Figure 2c). In addition, the invariant chain, which binds to and directs the trafficking of MHC II molecules, also binds MHC I molecules in the ER and can transport these complexes to endosomes [84,85] (Figure 2d); the loss of invariant chain inhibited XPT in one study [86] but not another one [48]. The MARCH9 ubiquitin ligase has been implicated in routing MHC I molecules from the trans-golgi to endosomes [87] (Figure 2e). Other mechanisms for transporting MHC I molecules from the ER to phagosomes have not yet been described. Regardless of the origin of the MHC I molecules in phagosome, how they become and/or are maintained in a peptide-receptive state and loaded with peptides in these vesicles is also incompletely understood. The mechanism by which MHC I complexes in phagosomes are trafficked to the cell surface is also incompletely understood. Other XPT mechanisms

In addition to the P2C mechanism, there are other pathways of XPT. The best characterized is the vacuolar pathway, which is one that is more analogous to the MHC class II antigen presentation pathway (Figure 1d). In the vacuolar pathway, internalized antigens are cleaved into peptides by proteases, such as cathepsin S, within the

Figure 2

(Phagocytosis) (ARF6-mediated endocytosis)

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Current Opinion in Immunology

Source of MHC I in phagosomes. (a) Class I molecules may traffic from the PM following ARF6-mediated internalization or phagocytosis. (b) Class I molecules may be stored in the endosomal recycling compartment following a UCH-L1-depedent de-ubiquitination step. TLR activation results in a phospho-SNAP-23-dependent fusion of these vesicles with the phagosome. Alternatively, newly synthesized class I molecules may traffic directly to the endocytic compartment via Rab39a-mediated vesicle transport (c) or chaperoned by the invariant chain (brown) (d). (e) Another pathway involves transport from the TGN to endosomes that is dependent on MARCH9-mediated ubiquitination. Dashed lines with arrows indicate incompletely understood aspects in the pathway. Abbreviations: EE: early endosomes, TLR: toll-like receptor. Current Opinion in Immunology 2020, 64:1–8

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MHC I cross-presentation Colbert, Cruz and Rock 5

phagosome itself [48]. The resulting peptides are thought to be bound to intraphagosomal MHC I molecules. The XPTed peptides are never in the cytosol and therefore do not need a peptide transporter to access phagosomes; consequently, this form of XPT is TAP-independent in most cases. Nevertheless, in some cases TAP may contribute to this or other XPT pathways indirectly by allowing the egress of MHC I molecules from the ER [88]. This vacuolar pathway is operative in vivo, although where examined it is a more minor contributor to cross priming [48]. The vacuolar pathway can generate and present at least some of the same immunodominant peptides as proteasomes [48,88,89], but since the cathepsins may make different cleavages than proteasomes, many of the peptide products generated by the vacuolar proteases are not likely to be identical to those made by proteasomes; thus, the vacuolar pathway has the potential to prime T cells to peptides that won’t be encountered on the ultimate target cells that need to be eliminated. However, it is possible that there are mechanisms that minimize such peptidemismatching. Interestingly in this context, it was recently discovered that proteasomes can be found inside of phagosomes and can be catalytically active [90]. This raises the possibility that intraphagosomal proteasome-generated peptide could contribute to cross-presentation via the vacuolar pathway or other cross-presentation pathways, such as proteasome-dependent but TAP-independent XPT [77,91].

Acknowledgement This review was supported by Grants AI114495 and AI145932 from the National Institutes of Health.

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Phagosomes as a nexus for XPT, an incomplete story that is still evolving In accordance with the findings reviewed above, one of the themes that have emerged in the XPT field is that a phagosome is not just a point of entry for antigens destined to be XPTed, but also becomes a nexus for XPT. These vacuoles evolve into cross-presenting organelles which in current parlance could be termed ‘cross-presentasomes’. There are many molecular and vesicular trafficking events that contribute to the formation of this XPTing nexus, some of which are known and others likely to yet be discovered. Sec22b [37,38], Rab39a [56], Rab14 [92,93] Rab22 [44,94,95], Rab34 [43], and Rab43 [96] are among the known vesicular trafficking molecules implicated in aspects of XPT. The calcium sensor STIM1 affects phagosomal maturation/content through unknown mechanisms [97,98]. There are also proteins such as WDFY4 [99], that may be involved in vesicular trafficking events, but whose exact role in this pathway is not yet elucidated. Looking to the future, we anticipate that there will be more molecules identified and further insights into underlying mechanisms of XPT.

Conflicts of interest statement Nothing declared. www.sciencedirect.com

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MHC I cross-presentation Colbert, Cruz and Rock 7

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