IMMUNOLOGY                    REVIEW ARTICLEEndosomal processing for antigen presentation mediated by CD1and Class I major...
M. Boes et al.in mice and express a T-cell receptor (TCR) that contains       ing of pathogen-recognition receptors often ...
Regulated presentation of endosome-derived antigens by myeloid dendritic cellscomplexes to the cell surface.23,24 In matur...
M. Boes et al.(TAP1/2).5 Triggering of TLR4 via treatment with lipo-       excluded from cross-presentation.63 Some recept...
Regulated presentation of endosome-derived antigens by myeloid dendritic cells                                            ...
M. Boes et al.and CD1 complexes should yield insights for future thera-               18 Gautier G, Humbert M, Deauvieau F...
Regulated presentation of endosome-derived antigens by myeloid dendritic cells     determines antigen fate. Science (New Y...
M. Boes et al.73 De Libero G, Moran AP, Gober HJ et al. Bacterial infections             is instrumental for Mycobacterium...
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  1. 1. IMMUNOLOGY REVIEW ARTICLEEndosomal processing for antigen presentation mediated by CD1and Class I major histocompatibility complex: roads to display ordestructionMarianne Boes,1,2 Arie J. SummaryStoppelenburg1 and The presentation of antigen in a form that can be recognized by T lym-Fenna C. M. Sille2 ´1 phocytes of the immune system requires antigen processing and associa- Department of Pediatric Immunology, Univer- tion of antigen-derived fragments with molecules encoded by the majorsity Medical Center Utrecht, WilhelminaChildren’s Hospital, Utrecht, the Netherlands, histocompatibility complex (MHC) locus or by the CD1 locus. Muchand 2Department of Dermatology, Brigham emphasis on antigen processing and presentation in the last decades hasand Women’s Hospital and Harvard Medical focused on what we consider ‘conventional routes’ of antigen processingSchool, Boston, MA, USA and presentation, whereby extracellular antigens are processed for presen- tation via Class II MHC complexes and cytosolic antigens are presented as peptide–Class I MHC complexes. We here highlight two other path- ways in myeloid dendritic cells, those of lipid antigen presentation in association with CD1 and of peptide cross-presentation via Class I MHC complexes. Some pathogens evade immune recognition through inhibitiondoi:10.1111/j.1365-2567.2009.03078.x of antigen presentation of phagosomal origin. Deviations in endosomalReceived 14 November 2008; revised 15 antigen processing and presentation are also seen in individuals sufferingJanuary 2009, 2 February 2009; accepted 4 from glycosphingolipid lysosomal lipid storage diseases. We summarizeFebruary 2009.Correspondence: M. Boes, Department of recent developments in the endosomal antigen processing and presenta-Pediatric Immunology, University Medical tion pathway, for display as lipid–CD1 complexes to natural killer T cellsCenter Utrecht, Wilhelmina Children’s and as peptide–Class I MHC complexes to CD8 T cells.Hospital, Utrecht, the Netherlands.Email: mboes@umcutrecht.nl Keywords: CD1d; cross-presentation; endosome; major histocompatibilitySenior author: Marianne Boes complex Class I; myeloid dendritic cell chain [of approximately 43 000–49 000 molecular weightIntroduction (MW)] that assembles with b2-microglobulinThe initiation of strong adaptive immune responses that (12 000 MW) and endogenous peptide or lipid in theyield memory requires the processing and presentation of endoplasmic reticulum, respectively. Exogenous antigensantigen as peptide–major histocompatibility complex provide alternative sources of peptides for Class I MHC,(MHC) complexes or as lipid–CD1 complexes to T lym- for loading in phagosomes.5 The number of CD1 iso-phocytes.1 Class I MHC is expressed on most nucleated forms expressed varies among species: humans expresscells, whereas CD1 expression and Class II MHC expres- several antigen-presenting isoforms of CD1 – CD1a,sion are more restricted, being constitutive on profes- CD1b, CD1c and CD1d – that complement one anothersional antigen-presenting cells (APCs) [i.e. on dendritic in the sampling of antigen from various endosomal com-cells (DCs), B cells and macrophages]. Thymic selection partments,6 whereas mice only express the CD1d iso-of MHC-restricted T lymphocytes occurs by presentation form.7 Humans additionally express CD1e, which duringof peptide–MHC complexes on thymic stroma cells, while DC maturation translocates from the Golgi to lysosomes,selection of CD1-restricted natural killer T cells (NKT where CD1e is thought to facilitate the selection of anti-cells) occurs on CD1-expressing cortical thymocytes, as genic lipids for surface display via other members of theshown in mice.23 MHC-restricted T cells require clonal CD1 family.8expansion to execute key roles in adaptive immune Much of what is known to date about CD1-mediatedresponses, whereas CD1-restricted NKT cells act within antigen presentation and T-cell selection is obtained fromhours of stimulation by secreting polarizing cytokines.4 mouse-based experiments. Semi-invariant NKT cells rep-Class I MHC and CD1 molecules both contain one heavy resent approximately 80% of all CD1d-restricted T cellsÓ 2009 Blackwell Publishing Ltd, Immunology, 127, 163–170 163
  2. 2. M. Boes et al.in mice and express a T-cell receptor (TCR) that contains ing of pathogen-recognition receptors often coincidesa Va14-Ja18 assembled with Vb8, Vb7 and Vb2-contain- with the ligation of receptors to inflammatory cytokines,ing TCR b chains.9 Antigens recognized by semi-invariant for example interferon-c (IFN-c) and tumour necrosisNKT cells are derived from lipid membranes in endo- factor-a (TNF-a), on DCs. Signals integrated from thesesomes and lysosomes from foreign or host origin.9 As can receptors instigate in DCs the rearrangement of the anti-be expected from the cargo loaded into the antigen-bind- gen processing and presentation machinery in endosomesing grooves, the hydrophobic CD1d-binding groove for induced cell-surface display of antigenic peptide–contains two large cavities that facilitate the binding of MHC and lipid–CD1 complexes.non-polar alkyl chains and exposes the polar glycolipidheadgroup,10 whereas MHC molecules harbour a groove Pathogen recognition receptors as modulators ofthat is lined with charged residues to facilitate the binding endosomal antigen processingof peptide anchor residues.11,12 Some peptides can bindCD1 and these are overall hydrophobic in character. The Ligation of receptors specific for pathogen-associatedMHC locus is polygenic (> 200 genes in human) and molecular patterns (PAMPs) expressed by DCs deliver sig-exceptionally polymorphic, whereas CD1 gene products nals that can stimulate the differentiation of DCs fromare monogenic or have a very limited range of alleles. The being primarily phagocytic sentinels into potent APCssingle CD1d protein that is expressed in mice, however, capable of T-cell stimulation. These receptors are collec-can adopt different conformations that facilitate the bind- tively called pattern recognition receptors (PRRs) anding of related ceramides from endogenous and acquired include three major families: Toll-like receptors (TLRs);sources (i.e. iGb3 and alpha-Galactosyl ceramide),10 intracytoplasmic nucleotide oligomerization domainthereby allowing the presentation of multiple antigens. (NOD)-like receptors; and cell-surface C-type lectin recep-One can imagine that other CD1 isoforms may take on tors. DCs can also be activated indirectly by capture of frag-multiple conformations as mouse CD1d does: human ments of cells that died in response to infection or tissueCD1b can present glucose monomycolates that vary sig- injury. DCs express selected sets of PRRs belonging to thesenificantly in their lipid tail fine structures and overall receptor families, the composition of which helps focus thelengths,13 a capability that may be attributable to confor- type of adaptive response that can be raised by DC sub-mational flexibility. Variability in CD1 conformations types. Langerhans’ cells (LCs), for example, do not expressmay therefore increase the antigen-presentation repertoire TLR4 and TLR5, whereas dermal interstitial DCs do expresspresented to CD1-restricted T-cell clones. TLR4 and TLR5.16 There is, furthermore, integration of sig- T-cell stimulation requires instructive signals that sup- nals downstream of PRRs: the simultaneous ligation ofplement signals incited by triggering of the TCR. DCs in TLRs 3, 4 and 8 yields a 20–50-fold increase in interleukinparticular are proficient at T-cell stimulation to mount (IL)-12 p70 production compared with the single ligationthe adaptive immune responses most appropriate for the of either TLR;17,18 and TLR4 is located at the cell surface,pathogen at hand. DCs can rapidly and effectively form whereas TLRs 3 and 8 are found intracellularly, in endoso-peptide–MHC complexes or lipid–CD1 complexes derived mal compartments, thereby illuminating the fact that signalfrom encountered pathogens, and rapidly up-regulate the integration occurs distal from TLR cytosolic domains. Usesurface expression of costimulatory molecules and chemo- of divergent sets of adaptor molecules for signal transduc-kine receptors.14 The possession of an elaborate endosomal tion (i.e. TIRAP-MyD88 and TRAM-TRIF) can direct thepathway, where antigens are degraded and loaded onto TLR-induced production of selective pro-inflammatoryMHC or CD1, is likely to contribute to the success of cytokines.19 Cytosolic triggering of PRRs, through ligationDCs in stimulating antigen-specific T-cell responses. For- of NOD-like receptors, can, moreover, activate a caspase-1-eign-derived antigens are most readily acquired at barrier activating multiprotein complex called inflammasome.20surfaces with the outside environment; only when patho- NACHT, LRR, and pyrin domain-containing proteinsgens succeed at breaching the physical and chemical bar- (NALPs), which constitute the largest subfamily of theriers of skin and mucosa are they exposed to cells of the NOD-like receptors, process pro-inflammatory caspasesimmune system. It is becoming increasingly clear that and the cytokines IL-1b and IL-18 into their active forms.21DCs form a network of cell types that have specialized If combined triggering of PRRs potentiates DC activation,characteristics: DCs found in barrier tissues acquire what is the effect of the simultaneous ligation of multiplemobility when pathogen-recognition receptors exposed on TLRs on the antigen processing and endosomal transporttheir plasma membrane are triggered, whereas other DC of peptide–MHC or lipid–CD1 complexes?subtypes found in secondary lymphoid tissues (i.e. The loading of Class II MHC and of CD1d with anti-murine CD8a+ DCs) do not have significant migratory genic cargo occurs in specializations of late endosomalcapacities but are instead optimized for antigen cross-pre- and lysosomal compartments.22 Endosomal tubulation issentation.15 DCs also have a potent ability to process and an early measure of DC maturation and is thought topresent antigenic lipids in association with CD1. Trigger- facilitate the transport of peptide-loaded Class II MHC164 Ó 2009 Blackwell Publishing Ltd, Immunology, 127, 163–170
  3. 3. Regulated presentation of endosome-derived antigens by myeloid dendritic cellscomplexes to the cell surface.23,24 In maturing DCs, CD1 Dendritic cellmolecules are not mobilized to endosomal tubules and do Immature Maturenot exhibit rapid surface display as seen for Class IIMHC.25,26 The loading of Class I MHC for cross-presenta-tion can occur in early endosomes/phagosomes5,27 as wellas in the endoplasmic reticulum28 and perhaps also in ahybrid form of these two combined.29,30 The assortmentof Class I MHC molecules that are found in early endoso-mal compartments are recycling Class I MHC moleculesfrom the surface.31,32 The origin of Class I MHCcomplexes that localize to the cell surface during DC Endosomalmaturation, however, is new synthesis rather than transfer compartmentsof existing Class I MHC present in endosomal/lysosomalcompartments33 and is therefore not expected to bestrongly represented in endosomal tubulations. The DC Golgi system Class I MHCmaturation-associated disposition of Class I MHC, Class mCD1d Class II MHC Endoplasmic chainsII MHC and mouse CD1d complexes in various subcellu- reticulumlar compartments is summarized in Fig. 1. Antigen degra-dation in endosomal compartments is also regulated in Class I MHC heavy chain with β2m and peptide Endosome with transporter associated withDCs:34,35 DCs exhibit less lysosomal proteolysis than antigen processing (TAP)macrophages.36–38 In DCs, a low level production of mCD1d heavy chain with β2m and glycolipid Putative mCD1d chaperone moleculereactive oxygen species produced by NADPH oxidase Class II MHC α and β chain with partially Microbeconsumes protons in the phagosomal lumen, supporting a cleaved invariant chainnear-neutral pH environment and favouring peptide H2-DM Antigenic glycolipid and peptideretention for presentation to T cells. This delay in antigendegradation apparently promotes antigen cross-presenta- Figure 1. Intracellular distribution and trafficking of Class I majortion via Class I MHC.38 Control of antigen degradation histocompatibility complex (MHC), Class II MHC and mouse CD1dmay additionally involve regulation in spatially confined (mCD1d) in maturing dendritic cells. Complexes are assembled in the endoplasmic reticulum (ER). To allow them to fold into functionalantigen-containing compartments rather than regulation complexes in the ER, chaperone molecules are co-assembled: antigenicat a cellular level, for example by local ligation of PRRs.39 peptide–Class I MHC; invariant chain–Class II MHC; and endogenousTLRs can be triggered inside endosomal compartments by lipid–CD1d (i.e. phosphatidylinositol and glycosyl-phosphatidylinosi-phagocytosed microbes.40 Triggering of PRRs can induce tol).96,97 After arrival at the cell surface by routing through thematuration of selective PAMP-containing phagosomes and secretory pathway, Class I MHC display and CD1d molecules recyclethereby promotes the generation of peptide–MHC through early endocytic compartments, from where CD1d moleculescomplexes in PAMP-containing phagosomes.41 PRR trig- are sorted to late endocytic/lysosomal compartments for exchange ofgering promotes CD1d-mediated lipid presentation.42–44 It ER-derived lipid for antigenic lipid cargo. Most nascent invariantis not clear, however, whether NADPH oxidase activity chain–Class II MHC complexes arrive in the endosomal pathwaymodulates the generation of lipid–CD1 complexes in DCs. directly from the Golgi system for acquisition of antigenic peptide. Chaperone proteins can facilitate antigen loading in the ER (Class I loading complex for Class I MHC98 and some processes of CD1dPattern recognition receptors as modulators of assembly,99 and lipid transfer proteins for lipid loading)100 and inendosomal composition the endosomal pathway (H2-DM for Class II MHC101,102 and lipid transfer proteins for mCD1d).92,95,103 Maturation of DCs rearrangesThe ligation of TLRs induces the transcription of genes intracellular trafficking to promote the presentation of newly acquiredthat collectively facilitate the differentiation process in antigen from ER or endosomes at the cell surface, for inspection byDCs called maturation. The integration of TLR-induced appropriately restricted T cells. Arrow thickness represents the relativesignals makes use of adaptor proteins, the most studied of rate of translocation of Class I MHC, Class II MHC and mCD1dwhich is MyD88, which is involved in signal transduction complexes. b2m, beta-2-microglobulin.downstream of TLRs 1, 2, 4, 5, 6, 7 and 9 in mice.45MyD88-deficient APCs exhibit deficiencies in antigencross-presentation and are defective in eliciting functional was suggested that the cross-presentation of soluble anti-cytotoxic T lymphocytes (CTL) in vivo.46 Cross-presenta- gens which contain PAMPs is especially dependent on thetion of phagosomal antigens by myeloid DCs requires pro- loading of Class I MHC in early endosomes/phagosomes:cessing by the proteasome in most experimental systems, antigen cross-presentation required TLR4/MyD88-medi-thereby inferring the necessity to transfer protein frag- ated signals for phagosomal recruitment of transporterments from the endosomal pathway into the cytosol.47 It associated with antigen processing (TAP) heterodimersÓ 2009 Blackwell Publishing Ltd, Immunology, 127, 163–170 165
  4. 4. M. Boes et al.(TAP1/2).5 Triggering of TLR4 via treatment with lipo- excluded from cross-presentation.63 Some receptors arepolysaccharide (LPS) also stimulates, in DCs, the rear- more effective than others at targeting of antigen forrangement of endosomal compartments to exhibit tubular cross-presentation: Gram-negative bacteria (whosestructures.23,24,48,49 Class I MHC molecules are also con- uptake by DCs is facilitated by binding to complementcentrated in multivesicular bodies (MVB) of the endoso- receptor 3) are fully degraded, whereas peptide antigenmal pathway,50 which represent the structures from which expressed by bacteria internalized via binding to receptorstubular endosomes are formed.48 MyD88-deficient DCs do to the Fc portion of immunoglobulins (Fc-receptors) arenot form tubular endosomes when triggered with LPS, yet effectively cross-presented.63 Recruitment of the Rab27ado form tubular endosomes when triggered with small GTPase to phagosomal membranes is involved inCryptococcus neoformans.51 C. neoformans can ligate TLR2 this antigen cross-presentation process in DCs, which alsoin addition to TLR4, whose signaling cascades both includes NADPH oxidase recruitment.64 CD1-mediatedinvolve MyD88 as well as TIRAP and TRIF, respectively.45 antigen presentation of exogenous antigen also benefitsThe ligation of TLR3 (which is expressed on the from receptor-mediated uptake, for example via theendosomal membranes of CD8a+ DCs) with double- C-type lectins Langerin and DC-SIGN, mannose receptorstranded RNA (dsRNA) present in the cell-associated and low-density lipoprotein receptors (LDL-R),65–68form of phagocytosed virus-infected cells promotes cross- although details that link receptor-mediated uptake withpriming and induction of antigen-specific CTLs.52 endosomal processing of lipid antigens are scarce.68Co-ligation of multiple TLRs also potentiates CTL Uptake of apoptotic blebs (for example through bindingresponses in vivo.53 What is known about endosomal to b3 integrins or to CD14) can also introducemechanisms that link TLR ligation with endosomal antigenic cargo to Class I MHC and CD1 moleculesremodeling and possibly with antigen presentation via into uninfected bystander DCs, as was shown usingClass I MHC or CD1? apoptotic macrophages that harbored Salmonella typhimu- rium or Mycobacterium tuberculosis.69,70 Ceramides, lipids that are composed of a sphingosineEndosomal sorting of Class I MHC and CD1 for and fatty acid chain, are crucial for sorting lipids andantigen acquisition proteins into intravesicular membranes of exosomes andDC maturation induced by TLR ligation stimulates new MVBs.71 The endosomal-sorting mechanisms for peptidesynthesis of Class I MHC molecules and induces antigen loading of Class II MHC in MVBs are relatively wellloading of small stores of phagosomal Class I MHC.5 A established.22 In unstimulated cells, both glycosphingo-fraction of the cellular content of Class I MHC is found lipid (GSL) ligands and CD1d are also found inin late endosomal compartments.50,54 Surface display of MVBs.72 Microbial infection of susceptible hosts, how-endosomal Class I MHC via exosome release, however, is ever, rearranges the CD1-mediated antigen-presentationdown-regulated when DCs undergo maturation.55 Upon pathway to accommodate the stimulatory effects ofexposure to inflammatory stimuli, Class II MHC mole- CD1-restricted NKT-cell responses.43,44 Microbial infec-cules acquire antigen in phagosomes/lysosomes, then tions yield presentation of acquired lipids or mobilizedaccumulate on the plasma membrane to display peptides self-derived lipids by APCs. Infection with Ehrlichiato CD4 T cells as part of DC maturation.56,57 Matura- muris and Sphingomonas capsulata, for example, causestion-induced relocation of antigen-loaded Class I MHC CD1d-mediated NKT-cell activation primarily throughand CD1 from the endosomal pathway to the cell surface direct recognition of microbial lipids.43 By contrast,is relatively modest when compared with the maturation- S. typhimurium infection causes stimulation of autoreac-induced relocation of antigen-loaded Class II MHC. Stim- tive NKT cells through a combination of endogenousulation of antigen-specific CD8 T-cell clones to acquire GSL presentation via mouse CD1d and PRR-inducedcytotoxic killing of target cells requires as few as three IL-12 production.43,44 The outer membranes of M. tuber-peptide–Class I MHC complexes,58 which is one to two culosis bacilli contain lipid ligands for CD1-mediated ¨orders of magnitude less than required to stimulate naıve presentation and lipid adjuvants that induce CD1 anti-CD4 T cells.59,60 Unlike Class II MHC, the trafficking of gen-processing pathways through TLRs.26,42,70 Finally,CD1 molecules and the presentation of lipid antigens is infection of host cells can increase the synthesis ofcomparable between both immature and mature endogenous GSL and stimulate GSL-specific T cells in aDCs.25,61,62 TLR-mediated signals stimulate specific anti- CD1- and TCR-dependent manner, as shown usinggen loading of Class I MHC and CD1 complexes in the Escherichia coli, Bacilus subtilis, Staphylococcus aureus andendosomal pathway, with less consequence to the ongoing Mycobacterium bovis-bacille Calmette Guerin (BCG).73 ´surface-directed traffic. Induction of invariant NKT (iNKT)-cell responses upon Receptor-mediated uptake effectively introduces antigen viral infection in mice involves TLR9 signaling and con-into the cross-presentation pathway, whereas antigen sequent production of IL-12, while the necessity ofinternalized by way of fluid-phase uptake is mostly CD1d-mediated presentation may not be absolute.74166 Ó 2009 Blackwell Publishing Ltd, Immunology, 127, 163–170
  5. 5. Regulated presentation of endosome-derived antigens by myeloid dendritic cells Yersinia enterocolitica and Klebsiella pneumoniae).83–86Virus-infection interference with endosomal Bacterial products can inhibit the cross-presentation ofantigen presentation mediated by CD1 and Class particulate antigen via Class I MHC in a manner thatI MHC requires PAMP binding to TLRs and MyD88. InhibitionDC activation accomplished through TLR ligation, for of cross-presentation through this route occurs throughexample, is pivotal for effective antigen cross-presentation interference with phagosome maturation and antigen pro-as discussed above. Infection with certain large viruses teolysis, as shown for the M. tuberculosis 19 000 MWthat harbor ligands for TLRs can, however, also interfere lipoprotein, CpG DNA and LPS.87 Moreover, cell wall-with antigen cross-presentation. The b-herpes virus, associated alpha-glucan from M. tuberculosis can inducemouse cytomegalovirus (MCMV), contains immune- monocytes to differentiate into DCs that lack CD1 expres-evasion genes that may affect some aspects of antigen sion, fail to up-regulate CD80 and produce IL10, render-cross-presentation as it does for the direct pathway of ing them unable to prime effector T cells or present lipidClass I MHC presentation.75 Herpes simplex virus-1 antigens to CD1-restricted T cells.88(HSV-1) and herpes simplex virus-2 (HSV-2), for exam-ple, express a protein called ICP47, which blocks peptide Interference with CD1-mediated antigen loadingtransport via the TAP1/2 transporter.76 Human cytomega- in inherited diseaselovirus (HCMV) contains another TAP1/2 inhibitor,US6.77 The use of a US6-transferrin chimeric molecule Class II MHC molecules acquire their peptide cargo inwas used to infer the role of TAP1/2 in transporting anti- specialized compartments of the late endosomal pathway,genic peptide from the cytosol into phagosomes in the including MVBs, where the peptide-exchange factor HLA-process of cross-presentation of phagosomal antigen.5 DM (H2-DM in mice) localizes.89,90 In analogy, late Mouse DCs that are infected with MCMV activate endosomal compartments are enriched for lipid-bindingCD1d-restricted iNKT cells in co-culture systems and proteins, some of which may function in the exchange ofin vivo.74 Human DCs that are infected with the human endoplasmic reticulum-derived lipids for antigenic lipidscytomegalovirus (HCMV) or HSV-1 also up-regulate onto CD1 molecules (i.e. saposins A, B, C and D) andantigen presentation via CD1d, which is the only group 2 Niemann-pick type C2 protein.91,92 Saposins function inCD1 molecule.78 However, HCMV infection of human a non-enzymatic manner, the exact mechanisms of whichDCs inhibits NKT-cell activation by CD1a, b and c (the are not yet fully understood. Lack of saposin functionso-called group 1 CD1 molecules), as characterized by causes lipid storage diseases, such as a form of Krabbeaccumulation of CD1 in endosomal/lysosomal compart- disease, which develops as a result of saposin A defi-ments and by the direct measurement of CD1b-restricted ciency.93 Other known sphingolipid activator proteins areNKT-cell activation presented by infected DCs.79 One GM2 and saposins B, C and D, which are all post-transla-possible explanation for differential responses to viral tional products of the prosaposin gene.94 Mice that areinsult of group 1 and group 2 CD1 molecules in humans deficient in prosaposin lack Va14 iNKT cells, yet have alies in regulatory elements in the 50 untranslated region, normal ability to present peptide–Class II MHC com-which is conserved for group 1 CD1 and distinct for plexes.95 Deficiencies that involve only proteins for anti-CD1d.80 At high multiplicity of infection (MOI) of HSV- gen cross-presentation, while excluding those concerned1 (MOI of 5–10), however, CD1d-mediated presentation with the direct pathway of Class I MHC-mediated presen-is also blocked, possibly through inhibition of CD1d tation, are to our knowledge yet to be described. Candi-recycling to the cell surface.72,81 dates should be found amongst proteins involved with the phagosomal milieu, especially those related to antigen processing, peptide transport past the phagosomal mem-Bacterial infection interference with endosomal brane and assembly into peptide–Class I MHC complexes.antigen presentation mediated by CD1 and ClassI MHC Concluding remarksIntracellular bacteria, including mycobacteria, also haveescape mechanisms for antigen presentation mediated by The mechanisms that support the endosomal processingClass I MHC or CD1. Bacteria can evade Class II MHC machinery in professional APCs for presentation of exo-antigen presentation by infected cells through alteration genous antigen via Class I MHC or CD1 complexes areof phagosome–lysosome fusion or biosynthesis, intracellu- currently being uncovered. It is our hope that new acces-lar trafficking and surface expression of Class II MHC, as sory proteins and pivotal mechanisms are found thatrecently reviewed.82 Peptide–Class I MHC complex pre- facilitate selectively, in the endosomal microenviroment,sentation can be obstructed through interference with the the sorting of antigen, proteolysis and loading of Class Isurface expression of Class I MHC (e.g. as in infections MHC and CD1. Elucidation of the endosomal processeswith Chlamydia pneumoniae, Salmonella enteritidis, that underlie the display of antigen-loaded Class I MHCÓ 2009 Blackwell Publishing Ltd, Immunology, 127, 163–170 167
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