- Email: [email protected]
New insights into pathways for CD1-mediated antigen presentation
New insights into pathways for CD1-mediated antigen presentation Masahiko Sugita1, Manuela Cernadas2 and Michael B Brenner3 Recent studies of CD1 structure and intracellular trafficking have demonstrated significant differences among the CD1 isoforms (CD1a, CD1b, CD1c and CD1d). The molecular and structural basis for the differential trafficking of CD1 molecules has also been delineated. These observations broaden our understanding of why the immune system has evolved multiple CD1 isoforms to survey different cellular compartments for lipid antigen presentation, to provide host defense against the microbial world and to offer immunoregulation with relevance to tumor immunity and autoimmunity. Addresses 1 Department of Microbiology and Immunology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan e-mail: [email protected] 2 Department of Pulmonary and Critical Care Medicine, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected] 3 Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Brigham & Women’s Hospital, Harvard Medical School, 1 Jimmy Fund Way, Smith Building, Room 552, Boston, MA 02115, USA e-mail: [email protected]
Current Opinion in Immunology 2004, 16:90–95 This review comes from a themed issue on Antigen processing and recognition Edited by Peter van den Elsen and Alexander Rudensky 0952-7915/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2003.11.014
Abbreviations AP adaptor protein DC dendritic cell GMM glucose monomycolate Ii invariant chain LC Langerhans cell NKT natural killer T TCR T-cell receptor
Introduction The induction of effector T cells that specifically recognize protein antigens in the context of MHC class I and class II molecules is essential for host defense against invading microbes and neoplastic tumor cells. Some microbes and tumor cells appear to have evolved evasive mechanisms that either inhibit MHC-dependent pathways of protein antigen presentation [1,2], or introduce nucleotide mutations in genes encoding antigenic peptides, referred to as antigenic drift, which can result in escape from peptidespecific T-cell and B-cell immune responses [3,4]. Current Opinion in Immunology 2004, 16:90–95
Recently, it has become clear that the immune system has evolved an independent antigen presentation system organized around the presentation of nonpeptide antigens by CD1 molecules. CD1 molecules bind lipids and enable T-cell receptor (TCR) recognition of fatty acids, glycolipids and lipopeptide antigens of foreign or self origin [5–12]. Notably, most molecules identified so far as foreign microbial antigens are presented by group 1 CD1 molecules (CD1a, CD1b, CD1c) and are derived from mycobacteria. For example, the first CD1-presented antigen to be identified was a lipid called mycolic acid, an abranched fatty acid with an extremely long acyl chain that contributes to the hydrophobic nature of the cell wall of mycobacteria [5]. As mycolic acid is essential for the survival and virulence of Mycobacterium tuberculosis, and is a target molecule for anti-tuberculosis therapy with isoniazid [13], it was hypothesized that host immune responses to such a critical antigen could efficiently monitor and control infection with virulent mycobacteria. Group 1 CD1-mediated lipid antigen presentation and Tcell activation provide the immune system with a valuable mechanism to efficiently control microbial infection. CD1a-, CD1b- and CD1c-restricted T cells specific for mycobacterial lipids are able to produce Th1 inflammatory cytokines and detect and lyse CD1þ cells infected with virulent mycobacteria [5–7,10]. The functional dichotomy in antigen sampling of MHC class I and class II molecules has been clearly appreciated, as MHC class I molecules bind peptide antigens of endogenous origin that are delivered from the cytosol, whereas MHC class II molecules traffic to lysosomes for sampling endocytosed protein antigens. Recent studies of CD1 molecules have demonstrated significant differences in the atomic structures of their antigen-binding sites and in their routes of intracellular trafficking. Thus, this article reviews the most recent advances in CD1dependent pathways for lipid antigen presentation.
Mechanisms of CD1 internalization from the plasma membrane and delivery to late endosomal/lysosomal compartments CD1 internalization and trafficking
Newly synthesized CD1b and CD1d molecules are directly delivered to the plasma membrane after assembly in the endoplasmic reticulum [14,15]. CD1b is subsequently internalized via plasma-membrane-associated clathrin-coated pits [15,16,17]. The molecular basis for this transport has been partially identified. The short cytoplasmic domain of CD1b contains a tyrosine-based sequence (YXXZ: Y, tyrosine; X, any amino acid; Z, a www.sciencedirect.com
CD1-mediated antigen presentation Sugita, Cernadas and Brenner 91
Figure 1
(a) CD1b
(b) CD1b in HPS-2
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Differential trafficking patterns of CD1 isoforms. (a) Human CD1b molecules are internalized in plasma membrane-associated clathrin-coated pits via interaction with AP-2, and transported to sorting endosomes of the early endocytic system. By virtue of the specific interaction with AP-3, CD1b molecules are subsequently transported deep into the endocytic system and reach lysosomes, where lipid antigen loading onto CD1b is proposed to occur. (b) In cells derived from AP-3 deficient Hermansky-Pudlak syndrome type 2 (HPS-2) patients, internalized CD1b is misrouted back to the cell surface without gaining access to lysosomes. (c) CD1c molecules are similarly internalized from the plasma membrane, but a majority of them gain access to recycling endosomes due to their inability to bind AP-3. A minor AP-3-independent pathway to lysosomes may also exist. (d) CD1a molecules lack a cytoplasmic tyrosine-based motif, but are internalized in plasma membrane-associated clathrin-coated pits and delivered through sorting endosomes to recycling endosomes of the early endocytic system. (e) Human CD1d has a similar trafficking pattern to human CD1c. (f) Murine CD1d traffics similarly to human CD1b. (g) In AP-3-deficient mice, internalized CD1d molecules are misrouted back to the cell surface, resulting in impaired NKT-cell development.
bulky hydrophobic amino acid) that directly interacts with the AP-2 adaptor protein complex expressed in plasmamembrane-associated clathrin-coated pits (Figure 1a; [15,16]). Further targeting of CD1b into deep endocytic compartments has been demonstrated by electron microscopic analysis of human monocyte-derived dendritic cells (DCs) that revealed the prominent expression of CD1b molecules in the MHC class II compartment (MIIC; Figure 1a). The molecular basis for the transport of CD1b to lysosomes has recently been delineated. The cytoplasmic tail of CD1b is able to bind another adaptor protein complex, AP-3, which is expressed in the early endocytic system and mediates selective protein transport to lysosomes www.sciencedirect.com
[18]. In AP-3-deficient cells derived from patients with Hermansky-Pudlak syndrome type 2 (HPS-2), CD1b accumulated in early endosomes and on the plasma membrane, and failed to efficiently gain access to lysosomes, resulting in a profound defect in antigen presentation (Figure 1b; [18]). Of note, patients with this hereditary disease suffer from recurrent bacterial infections but exhibit normal MHC class II functions [19,20], suggesting that the impaired lysosome sampling function could potentially contribute to making the host immunocompromised. Despite the fact that CD1c also contains a similar cytoplasmic tyrosine-based motif, studies detected a significant difference in intracellular localization between CD1b and CD1c [21,22]. CD1c molecules are endocytosed from the Current Opinion in Immunology 2004, 16:90–95
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cell surface in clathrin-coated pits, but the majority of them are retained in the early endocytic system that includes recycling endosomes, whereas only a small fraction reach lysosomes (Figure 1c). The molecular basis for the differential trafficking between CD1b and CD1c is determined by the cytoplasmic tail of CD1c, which is not able to bind AP-3 [18]. By contrast, CD1a molecules lack a cytoplasmic tyrosine-based motif, and instead appear to be internalized via clathrin-coated pits from the cell surface and traffic through the sorting endosome to recycling endosomes (Figure 1d; [23]). This differential intracellular trafficking of the CD1 isoforms may be critical for the efficient sampling of lipid antigens, which are delivered either to recycling endosomes or lysosomes according, at least in part, to the length of their lipid tails [24,25]. The differential trafficking of endocytosed lipids with short and long acyl chains to recycling endosomes and lysosomes, respectively, had been proposed previously, on the basis of observations made using synthetic lipid analogs [24]. Such a rule has now been shown to be applicable to CD1-restricted antigens. Natural GMM, a glucosylated form of mycolic acid with long lipid tails (C80), is endocytosed by antigen-presenting cells (APCs) and delivered to lysosomes, resulting in its efficient presentation to CD1b-restricted T cells. By contrast, a synthetic short tail (C32) version of GMM is delivered less efficiently to CD1b-containing lysosomes, presumably then following a recycling pathway of the early endocytic system [25]. Thus, it is likely that lipids with short carbon chains may be more efficiently sampled by CD1a and CD1c molecules, which are abundantly expressed in the early recycling pathway [21–23]. CD1 cytoplasmic tail motifs
Similar to humans, other mammalian species analyzed so far have multiple group 1 CD1 isoforms [26]. In guinea pigs, seven group 1 CD1 molecules have been identified on the basis of sequence homology with human CD1 molecules [27]. Interestingly, the five carboxy-terminal amino acid residues (YQDIL) of guinea pig CD1b2 are identical to human CD1c, predicting its preferential localization to early recycling endosomes due to an inability to bind AP-3. By contrast, the cytoplasmic tail of guinea pig CD1c2 contains a tyrosine-based motif followed by proline at the carboxy-terminal Y þ 4 position, which is a critical residue for the interaction of human CD1b with AP-3 [18]. As summarized in Figure 2, many group 1 CD1 molecules in mammalian species have leucine at the carboxy-terminal Y þ 4 position, but a few are found to contain proline at the corresponding position. It is likely that introducing a proline-for-leucine substitution at the carboxy-terminal position may have been a mechanism by which the immune system could evolve antigen-presenting molecules capable of sampling lipid antigens in lysosomes. Current Opinion in Immunology 2004, 16:90–95
Figure 2 Tail sequence
AP-3 binding
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YQNIP YQGIP YQDIP
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AP-3 binders and non-binders are predicted by the presence of either proline (P) or leucine (L) at the carboxy-terminal position of CD1 isoforms in humans, guinea pigs, sheep and rabbits. The AP-3 binding ability of each tail sequence was determined by yeast two-hybrid analysis. ND: not determined.
One unexplained puzzle is the unusual expression of only a single CD1 isoform in mice. Interestingly, the cytoplasmic tail of human CD1d contains a tyrosinebased motif (YQGV) followed by leucine at the carboxy-terminal Y þ 4 position, and is unable to bind AP-3 [18]. By contrast, the mouse CD1d cytoplasmic tail (YQDI and serine at the carboxy-terminal position) binds AP-3 [28,29]. Accordingly, murine CD1d molecules have evolved the capacity to localize in lysosomes (Figure 1e,f). The significance of this is underscored in mice deficient in AP-3, where cell surface expression of CD1d is increased and natural killer T (NKT) cell populations fail to develop (Figure 1g; [28,29]). The importance of lysosomal trafficking for murine CD1d was also illustrated by tail-truncated CD1d-expressing mice that have defects both in NKT cell development and in antigen presentation [30]. Given that early recycling endosomes and lysosomes may contain different arrays of lipid antigens [24,25], the differential binding ability of human and mouse CD1d to AP-3 indicates that NKTcell populations in these two species may differ significantly in size and in function. The role of MHC class II, invariant chain and endosomal proteases
Recently, the importance of endosomal trafficking of CD1d has been highlighted as other molecules and potential mechanisms have been implicated in CD1d trafficking and antigen presentation, including invariant chain (Ii), MHC class II and the endosomal proteases cathepsin S and L. MHC class II and Ii associate with human and mouse CD1d in biochemical studies, and they promote the delivery of tail-deleted CD1d to late endosomes [14,31]. In mice expressing tail-deleted www.sciencedirect.com
CD1-mediated antigen presentation Sugita, Cernadas and Brenner 93
CD1d, however, TCRa invariant CD1d-restricted T-cell numbers (NKT cells) are markedly reduced, suggesting that the association of CD1d with MHC class II–Ii complexes is not sufficient for adequate CD1d trafficking and antigen presentation [30]. In addition, Ii-deficient mice, which have increased CD1d cell surface expression on antigen-presenting cells, do not have alterations in TCRa invariant CD1d-restricted T-cell selection or development [14,29]. Mice deficient in cathepsin S and L also have reduced numbers of TCRa invariant CD1d-restricted T cells, and impaired presentation of the endosomally processed antigen a-galactosylgalactosylceramide was observed in cathepsin-S-deficient mice, suggesting a role for these endosomal proteases in CD1-mediated antigen presentation [32,33]. The importance of CD1d endosomal trafficking in TCRa invariant CD1d-restricted T-cell development is further underscored by the finding that the TCRa invariant Va14þ subset of CD1d-restricted T cells are unable to respond to cytoplasmic tail truncated CD1d or to cathepsin-L-deficient thymocytes, which have intact CD1d expression, in contrast to the diverse Va14– subset of CD1d-restricted T cells, which are responsive [30,33,34]. The molecular mechanisms by which these proteins affect CD1d trafficking and presentation have yet to be fully delineated.
Major advances in ligand-bound CD1 atomic structures The previous structural definition of the mouse CD1d antigen-binding groove revealed two hydrophobic pockets (A0 and F0 ), which were assumed to bind the lipid tails of CD1-presented antigens [35]. Now, the structures of antigen-bound CD1a and CD1b molecules have been solved. CD1b molecules contain three hydrophobic pockets (A0 , C0 and F0 ) and a fourth distinct channel, designated the T0 tunnel, which interconnects with the other pockets [36]. Thus, CD1b appears to have the potential for binding a variety of lipid tail arrangements, including lipids with multiple tails or lipids with long tails that can navigate the superchannel formed by the sequential connection of A0 , T0 and F0 channels. In addition, the C0 pocket extends to a portal opening under the a2 helix, thus providing a potential exit for a long carbon chain that cannot be fully accommodated within the pocket. By contrast, CD1a molecules contain two hydrophobic pockets (A0 and F0 ) similar to those observed in murine CD1d molecules. The CD1a A0 pocket clearly limits the size of the lipid tail that it can bind to C18–C23 [37]. Thus, similar to the differential trafficking of CD1 isoforms, the distinct antigen-binding differences of CD1 isoforms may allow the efficient sampling of an array of lipid antigens in appropriate intracellular compartments. This has resulted in the formulation of the ‘groove’ (antigen binding) and ‘tail’ (trafficking) hypotheses for evolutionary pressure on CD1 isoforms [26]. www.sciencedirect.com
Differential pathways for MHC and CD1 antigen presentation during DC maturation DCs in various tissues play a pivotal role in initiating T-cell responses to both protein and lipid antigens. During DC maturation, peptide antigen loading onto MHC class II molecules is occurs in lysosomes, which are subsequently delivered to the cell surface. Furthermore, the surface expression of T-cell co-stimulatory molecules, such as CD80 and CD86, and adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) are upregulated, resulting in the efficient activation of peptide-antigen-specific naı¨ve T cells [38]. By contrast, none of the CD1 molecules accumulate on the cell surface as prominently as MHC class II following DC maturation stimuli, suggesting that the presentation of peptide and lipid antigens might be controlled differentially during DC maturation [17,39]. Similar to MHC class II, CD1b molecules are also expressed prominently in the multilamellar lysosome of immature DCs [16]. However, the segregation of CD1b and MHC class II molecules was noted even before DC maturation occurred [17], as the majority (85%) of lysosome-resident CD1b molecules are detected on the limiting membrane, whereas most MHC class II molecules (95%) are expressed in the inner membranes of multilamellar lysosomes. Upon activation with maturational stimuli, lysosomes begin to lose the multilamellar structure to form electron dense single membrane vesicles that contain only CD1b, but not MHC class II. This lysosomal pool of CD1b in mature DCs appears to be maintained as a result of its continued recycling between the lysosome and the plasma membrane, suggesting that CD1b recycling might continue independently of DC maturation [17]. Indeed, efficient presentation of GMM to specific CD1b-restricted T cells was observed similarly in immature and mature DCs [39]. DC maturation-independent pathways for lipid antigen presentation have also been demonstrated for CD1a expressed on epidermal Langerhans cells (LCs; [40]). Immature LCs freshly isolated from human epidermis, as well as mature LCs that migrate from the epidermis, were similarly efficient in presenting lipid antigens to T cells. Given that DC maturation may take several days to occur, these observations suggest that CD1 molecules may play a dominant role, particularly at early phases of the acquired immunity, even before DCs are capable of inducing maximum activation of peptide-antigen-specific T cells.
Conclusions Differential trafficking of CD1 molecules and the molecular interactions that control these pathways have now been elucidated. The adaptins, AP-2 and AP-3, have been shown to mediate internalization and lysosomal trafficking of specific CD1 isoforms, respectively. Similar Current Opinion in Immunology 2004, 16:90–95
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trafficking patterns appear to be maintained in other mammalian species, which suggests that the immune system has evolved diverse trafficking patterns to accomplish antigen sampling by CD1 isoforms and effective activation of the immunoregulatory T-cell populations that they stimulate. MHC class II, Ii and the endosomal proteases cathepsin S and L have also been shown to interact with CD1d; however, the mechanisms by which they affect CD1 function are yet to be defined. Defects in some of these pathways significantly alter the activation and development of immunoregulatory CD1d-restricted NKT cells. The ability of CD1 to fully sample endocytic subcompartments is of special importance for the immune detection of mycobacteria-infected cells. Mycobacteria efficiently inhibit MHC-dependent pathways of peptide antigen presentation [41,42], but lipid antigens produced in phagosomes traffic out of the phagosomes, resulting in the activation of lipid antigen-specific cytotoxic T cells that have been detected in vivo [43,44]. Recently, the efficacy of lipid-based vaccines against tuberculosis has been demonstrated [45]. As independent pathways for MHC and CD1 antigen presentation are now clear, as observed in maturing DCs, the combination of protein and lipid vaccines may work synergistically.
Acknowledgements This work was supported by grants from the National Institutes of Health (to MBB) and from the Ministry of Education, Culture, Sports, Science and Technology (Grant-in-aid for Scientific Research on Priority Areas; to MS).
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40. Pena-Cruz V, Ito S, Dascher CC, Brenner MB, Sugita M: Epidermal Langerhans cells efficiently mediate CD1a-dependent presentation of microbial lipid antigens to T cells. J Invest Dermatol 2003, 121:517-521. 41. Ramachandra L, Noss E, Boom WH, Harding CV: Processing of Mycobacterium tuberculosis antigen 85B involves intraphagosomal formation of peptide-major histocompatibility complex II complexes and is inhibited by live bacilli that decrease phagosome maturation. J Exp Med 2001, 194:1421-1432. 42. Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, Haddix PL, Collins HL, Fok AK, Allen RD, Gluck SL, Heuser J, Russell DG: Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 1994, 263:678-681. 43. Beatty WL, Rhoades ER, Ullrich HJ, Chatterjee D, Heuser JE, Russell DG: Trafficking and release of mycobacterial lipids from infected macrophages. Traffic 2000, 1:235-247. 44. Kawashima T, Norose Y, Watanabe Y, Enomoto Y, Narazaki H, Watari E, Tanaka S, Takahashi H, Yano I, Brenner MB et al.: Cutting edge: major CD8 T cell response to live bacillus CalmetteGuerin is mediated by CD1 molecules. J Immunol 2003, 170:5345-5348. 45. Dascher CC, Hiromatsu K, Xiong X, Morehouse C, Watts G, Liu G, McMurray DN, LeClair KP, Porcelli SA, Brenner MB: Immunization with a mycobacterial lipid vaccine improves pulmonary pathology in the guinea pig model of tuberculosis. Int Immunol 2003, 15:915-925.
Current Opinion in Immunology 2004, 16:90–95
Current Opinion in Immunology 2004, 16:90–95 This review comes from a themed issue on Antigen processing and recognition Edited by Peter van den Elsen and Alexander Rudensky 0952-7915/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2003.11.014
Abbreviations AP adaptor protein DC dendritic cell GMM glucose monomycolate Ii invariant chain LC Langerhans cell NKT natural killer T TCR T-cell receptor
Introduction The induction of effector T cells that specifically recognize protein antigens in the context of MHC class I and class II molecules is essential for host defense against invading microbes and neoplastic tumor cells. Some microbes and tumor cells appear to have evolved evasive mechanisms that either inhibit MHC-dependent pathways of protein antigen presentation [1,2], or introduce nucleotide mutations in genes encoding antigenic peptides, referred to as antigenic drift, which can result in escape from peptidespecific T-cell and B-cell immune responses [3,4]. Current Opinion in Immunology 2004, 16:90–95
Recently, it has become clear that the immune system has evolved an independent antigen presentation system organized around the presentation of nonpeptide antigens by CD1 molecules. CD1 molecules bind lipids and enable T-cell receptor (TCR) recognition of fatty acids, glycolipids and lipopeptide antigens of foreign or self origin [5–12]. Notably, most molecules identified so far as foreign microbial antigens are presented by group 1 CD1 molecules (CD1a, CD1b, CD1c) and are derived from mycobacteria. For example, the first CD1-presented antigen to be identified was a lipid called mycolic acid, an abranched fatty acid with an extremely long acyl chain that contributes to the hydrophobic nature of the cell wall of mycobacteria [5]. As mycolic acid is essential for the survival and virulence of Mycobacterium tuberculosis, and is a target molecule for anti-tuberculosis therapy with isoniazid [13], it was hypothesized that host immune responses to such a critical antigen could efficiently monitor and control infection with virulent mycobacteria. Group 1 CD1-mediated lipid antigen presentation and Tcell activation provide the immune system with a valuable mechanism to efficiently control microbial infection. CD1a-, CD1b- and CD1c-restricted T cells specific for mycobacterial lipids are able to produce Th1 inflammatory cytokines and detect and lyse CD1þ cells infected with virulent mycobacteria [5–7,10]. The functional dichotomy in antigen sampling of MHC class I and class II molecules has been clearly appreciated, as MHC class I molecules bind peptide antigens of endogenous origin that are delivered from the cytosol, whereas MHC class II molecules traffic to lysosomes for sampling endocytosed protein antigens. Recent studies of CD1 molecules have demonstrated significant differences in the atomic structures of their antigen-binding sites and in their routes of intracellular trafficking. Thus, this article reviews the most recent advances in CD1dependent pathways for lipid antigen presentation.
Mechanisms of CD1 internalization from the plasma membrane and delivery to late endosomal/lysosomal compartments CD1 internalization and trafficking
Newly synthesized CD1b and CD1d molecules are directly delivered to the plasma membrane after assembly in the endoplasmic reticulum [14,15]. CD1b is subsequently internalized via plasma-membrane-associated clathrin-coated pits [15,16,17]. The molecular basis for this transport has been partially identified. The short cytoplasmic domain of CD1b contains a tyrosine-based sequence (YXXZ: Y, tyrosine; X, any amino acid; Z, a www.sciencedirect.com
CD1-mediated antigen presentation Sugita, Cernadas and Brenner 91
Figure 1
(a) CD1b
(b) CD1b in HPS-2
(c) CD1c
(d)
AP-2 (Clathrin-coated pit)
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(e) Human CD1d
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(f) AP-2? (Clathrin-coated pit)
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(g) Murine CD1d (AP-3 / ) – –
Murine CD1d
AP-2? (Clathrin-coated pit)
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Sorting AP-3 endosome
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Lysosome Current Opinion in Immunology
Differential trafficking patterns of CD1 isoforms. (a) Human CD1b molecules are internalized in plasma membrane-associated clathrin-coated pits via interaction with AP-2, and transported to sorting endosomes of the early endocytic system. By virtue of the specific interaction with AP-3, CD1b molecules are subsequently transported deep into the endocytic system and reach lysosomes, where lipid antigen loading onto CD1b is proposed to occur. (b) In cells derived from AP-3 deficient Hermansky-Pudlak syndrome type 2 (HPS-2) patients, internalized CD1b is misrouted back to the cell surface without gaining access to lysosomes. (c) CD1c molecules are similarly internalized from the plasma membrane, but a majority of them gain access to recycling endosomes due to their inability to bind AP-3. A minor AP-3-independent pathway to lysosomes may also exist. (d) CD1a molecules lack a cytoplasmic tyrosine-based motif, but are internalized in plasma membrane-associated clathrin-coated pits and delivered through sorting endosomes to recycling endosomes of the early endocytic system. (e) Human CD1d has a similar trafficking pattern to human CD1c. (f) Murine CD1d traffics similarly to human CD1b. (g) In AP-3-deficient mice, internalized CD1d molecules are misrouted back to the cell surface, resulting in impaired NKT-cell development.
bulky hydrophobic amino acid) that directly interacts with the AP-2 adaptor protein complex expressed in plasmamembrane-associated clathrin-coated pits (Figure 1a; [15,16]). Further targeting of CD1b into deep endocytic compartments has been demonstrated by electron microscopic analysis of human monocyte-derived dendritic cells (DCs) that revealed the prominent expression of CD1b molecules in the MHC class II compartment (MIIC; Figure 1a). The molecular basis for the transport of CD1b to lysosomes has recently been delineated. The cytoplasmic tail of CD1b is able to bind another adaptor protein complex, AP-3, which is expressed in the early endocytic system and mediates selective protein transport to lysosomes www.sciencedirect.com
[18]. In AP-3-deficient cells derived from patients with Hermansky-Pudlak syndrome type 2 (HPS-2), CD1b accumulated in early endosomes and on the plasma membrane, and failed to efficiently gain access to lysosomes, resulting in a profound defect in antigen presentation (Figure 1b; [18]). Of note, patients with this hereditary disease suffer from recurrent bacterial infections but exhibit normal MHC class II functions [19,20], suggesting that the impaired lysosome sampling function could potentially contribute to making the host immunocompromised. Despite the fact that CD1c also contains a similar cytoplasmic tyrosine-based motif, studies detected a significant difference in intracellular localization between CD1b and CD1c [21,22]. CD1c molecules are endocytosed from the Current Opinion in Immunology 2004, 16:90–95
92 Antigen processing and recognition
cell surface in clathrin-coated pits, but the majority of them are retained in the early endocytic system that includes recycling endosomes, whereas only a small fraction reach lysosomes (Figure 1c). The molecular basis for the differential trafficking between CD1b and CD1c is determined by the cytoplasmic tail of CD1c, which is not able to bind AP-3 [18]. By contrast, CD1a molecules lack a cytoplasmic tyrosine-based motif, and instead appear to be internalized via clathrin-coated pits from the cell surface and traffic through the sorting endosome to recycling endosomes (Figure 1d; [23]). This differential intracellular trafficking of the CD1 isoforms may be critical for the efficient sampling of lipid antigens, which are delivered either to recycling endosomes or lysosomes according, at least in part, to the length of their lipid tails [24,25]. The differential trafficking of endocytosed lipids with short and long acyl chains to recycling endosomes and lysosomes, respectively, had been proposed previously, on the basis of observations made using synthetic lipid analogs [24]. Such a rule has now been shown to be applicable to CD1-restricted antigens. Natural GMM, a glucosylated form of mycolic acid with long lipid tails (C80), is endocytosed by antigen-presenting cells (APCs) and delivered to lysosomes, resulting in its efficient presentation to CD1b-restricted T cells. By contrast, a synthetic short tail (C32) version of GMM is delivered less efficiently to CD1b-containing lysosomes, presumably then following a recycling pathway of the early endocytic system [25]. Thus, it is likely that lipids with short carbon chains may be more efficiently sampled by CD1a and CD1c molecules, which are abundantly expressed in the early recycling pathway [21–23]. CD1 cytoplasmic tail motifs
Similar to humans, other mammalian species analyzed so far have multiple group 1 CD1 isoforms [26]. In guinea pigs, seven group 1 CD1 molecules have been identified on the basis of sequence homology with human CD1 molecules [27]. Interestingly, the five carboxy-terminal amino acid residues (YQDIL) of guinea pig CD1b2 are identical to human CD1c, predicting its preferential localization to early recycling endosomes due to an inability to bind AP-3. By contrast, the cytoplasmic tail of guinea pig CD1c2 contains a tyrosine-based motif followed by proline at the carboxy-terminal Y þ 4 position, which is a critical residue for the interaction of human CD1b with AP-3 [18]. As summarized in Figure 2, many group 1 CD1 molecules in mammalian species have leucine at the carboxy-terminal Y þ 4 position, but a few are found to contain proline at the corresponding position. It is likely that introducing a proline-for-leucine substitution at the carboxy-terminal position may have been a mechanism by which the immune system could evolve antigen-presenting molecules capable of sampling lipid antigens in lysosomes. Current Opinion in Immunology 2004, 16:90–95
Figure 2 Tail sequence
AP-3 binding
Human
YQNIP YQGIP YQDIP
+ ND +
CD1b
YQDIL YQNIL YQGVL YQTVL YEDIL YLTIL
– – – ND ND ND
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Sheep
Rabbit
CD1b-2
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CD1b2
CD1d CD1b-3 CD1b1 CD1b-1 Current Opinion in Immunology
AP-3 binders and non-binders are predicted by the presence of either proline (P) or leucine (L) at the carboxy-terminal position of CD1 isoforms in humans, guinea pigs, sheep and rabbits. The AP-3 binding ability of each tail sequence was determined by yeast two-hybrid analysis. ND: not determined.
One unexplained puzzle is the unusual expression of only a single CD1 isoform in mice. Interestingly, the cytoplasmic tail of human CD1d contains a tyrosinebased motif (YQGV) followed by leucine at the carboxy-terminal Y þ 4 position, and is unable to bind AP-3 [18]. By contrast, the mouse CD1d cytoplasmic tail (YQDI and serine at the carboxy-terminal position) binds AP-3 [28,29]. Accordingly, murine CD1d molecules have evolved the capacity to localize in lysosomes (Figure 1e,f). The significance of this is underscored in mice deficient in AP-3, where cell surface expression of CD1d is increased and natural killer T (NKT) cell populations fail to develop (Figure 1g; [28,29]). The importance of lysosomal trafficking for murine CD1d was also illustrated by tail-truncated CD1d-expressing mice that have defects both in NKT cell development and in antigen presentation [30]. Given that early recycling endosomes and lysosomes may contain different arrays of lipid antigens [24,25], the differential binding ability of human and mouse CD1d to AP-3 indicates that NKTcell populations in these two species may differ significantly in size and in function. The role of MHC class II, invariant chain and endosomal proteases
Recently, the importance of endosomal trafficking of CD1d has been highlighted as other molecules and potential mechanisms have been implicated in CD1d trafficking and antigen presentation, including invariant chain (Ii), MHC class II and the endosomal proteases cathepsin S and L. MHC class II and Ii associate with human and mouse CD1d in biochemical studies, and they promote the delivery of tail-deleted CD1d to late endosomes [14,31]. In mice expressing tail-deleted www.sciencedirect.com
CD1-mediated antigen presentation Sugita, Cernadas and Brenner 93
CD1d, however, TCRa invariant CD1d-restricted T-cell numbers (NKT cells) are markedly reduced, suggesting that the association of CD1d with MHC class II–Ii complexes is not sufficient for adequate CD1d trafficking and antigen presentation [30]. In addition, Ii-deficient mice, which have increased CD1d cell surface expression on antigen-presenting cells, do not have alterations in TCRa invariant CD1d-restricted T-cell selection or development [14,29]. Mice deficient in cathepsin S and L also have reduced numbers of TCRa invariant CD1d-restricted T cells, and impaired presentation of the endosomally processed antigen a-galactosylgalactosylceramide was observed in cathepsin-S-deficient mice, suggesting a role for these endosomal proteases in CD1-mediated antigen presentation [32,33]. The importance of CD1d endosomal trafficking in TCRa invariant CD1d-restricted T-cell development is further underscored by the finding that the TCRa invariant Va14þ subset of CD1d-restricted T cells are unable to respond to cytoplasmic tail truncated CD1d or to cathepsin-L-deficient thymocytes, which have intact CD1d expression, in contrast to the diverse Va14– subset of CD1d-restricted T cells, which are responsive [30,33,34]. The molecular mechanisms by which these proteins affect CD1d trafficking and presentation have yet to be fully delineated.
Major advances in ligand-bound CD1 atomic structures The previous structural definition of the mouse CD1d antigen-binding groove revealed two hydrophobic pockets (A0 and F0 ), which were assumed to bind the lipid tails of CD1-presented antigens [35]. Now, the structures of antigen-bound CD1a and CD1b molecules have been solved. CD1b molecules contain three hydrophobic pockets (A0 , C0 and F0 ) and a fourth distinct channel, designated the T0 tunnel, which interconnects with the other pockets [36]. Thus, CD1b appears to have the potential for binding a variety of lipid tail arrangements, including lipids with multiple tails or lipids with long tails that can navigate the superchannel formed by the sequential connection of A0 , T0 and F0 channels. In addition, the C0 pocket extends to a portal opening under the a2 helix, thus providing a potential exit for a long carbon chain that cannot be fully accommodated within the pocket. By contrast, CD1a molecules contain two hydrophobic pockets (A0 and F0 ) similar to those observed in murine CD1d molecules. The CD1a A0 pocket clearly limits the size of the lipid tail that it can bind to C18–C23 [37]. Thus, similar to the differential trafficking of CD1 isoforms, the distinct antigen-binding differences of CD1 isoforms may allow the efficient sampling of an array of lipid antigens in appropriate intracellular compartments. This has resulted in the formulation of the ‘groove’ (antigen binding) and ‘tail’ (trafficking) hypotheses for evolutionary pressure on CD1 isoforms [26]. www.sciencedirect.com
Differential pathways for MHC and CD1 antigen presentation during DC maturation DCs in various tissues play a pivotal role in initiating T-cell responses to both protein and lipid antigens. During DC maturation, peptide antigen loading onto MHC class II molecules is occurs in lysosomes, which are subsequently delivered to the cell surface. Furthermore, the surface expression of T-cell co-stimulatory molecules, such as CD80 and CD86, and adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) are upregulated, resulting in the efficient activation of peptide-antigen-specific naı¨ve T cells [38]. By contrast, none of the CD1 molecules accumulate on the cell surface as prominently as MHC class II following DC maturation stimuli, suggesting that the presentation of peptide and lipid antigens might be controlled differentially during DC maturation [17,39]. Similar to MHC class II, CD1b molecules are also expressed prominently in the multilamellar lysosome of immature DCs [16]. However, the segregation of CD1b and MHC class II molecules was noted even before DC maturation occurred [17], as the majority (85%) of lysosome-resident CD1b molecules are detected on the limiting membrane, whereas most MHC class II molecules (95%) are expressed in the inner membranes of multilamellar lysosomes. Upon activation with maturational stimuli, lysosomes begin to lose the multilamellar structure to form electron dense single membrane vesicles that contain only CD1b, but not MHC class II. This lysosomal pool of CD1b in mature DCs appears to be maintained as a result of its continued recycling between the lysosome and the plasma membrane, suggesting that CD1b recycling might continue independently of DC maturation [17]. Indeed, efficient presentation of GMM to specific CD1b-restricted T cells was observed similarly in immature and mature DCs [39]. DC maturation-independent pathways for lipid antigen presentation have also been demonstrated for CD1a expressed on epidermal Langerhans cells (LCs; [40]). Immature LCs freshly isolated from human epidermis, as well as mature LCs that migrate from the epidermis, were similarly efficient in presenting lipid antigens to T cells. Given that DC maturation may take several days to occur, these observations suggest that CD1 molecules may play a dominant role, particularly at early phases of the acquired immunity, even before DCs are capable of inducing maximum activation of peptide-antigen-specific T cells.
Conclusions Differential trafficking of CD1 molecules and the molecular interactions that control these pathways have now been elucidated. The adaptins, AP-2 and AP-3, have been shown to mediate internalization and lysosomal trafficking of specific CD1 isoforms, respectively. Similar Current Opinion in Immunology 2004, 16:90–95
94 Antigen processing and recognition
trafficking patterns appear to be maintained in other mammalian species, which suggests that the immune system has evolved diverse trafficking patterns to accomplish antigen sampling by CD1 isoforms and effective activation of the immunoregulatory T-cell populations that they stimulate. MHC class II, Ii and the endosomal proteases cathepsin S and L have also been shown to interact with CD1d; however, the mechanisms by which they affect CD1 function are yet to be defined. Defects in some of these pathways significantly alter the activation and development of immunoregulatory CD1d-restricted NKT cells. The ability of CD1 to fully sample endocytic subcompartments is of special importance for the immune detection of mycobacteria-infected cells. Mycobacteria efficiently inhibit MHC-dependent pathways of peptide antigen presentation [41,42], but lipid antigens produced in phagosomes traffic out of the phagosomes, resulting in the activation of lipid antigen-specific cytotoxic T cells that have been detected in vivo [43,44]. Recently, the efficacy of lipid-based vaccines against tuberculosis has been demonstrated [45]. As independent pathways for MHC and CD1 antigen presentation are now clear, as observed in maturing DCs, the combination of protein and lipid vaccines may work synergistically.
Acknowledgements This work was supported by grants from the National Institutes of Health (to MBB) and from the Ministry of Education, Culture, Sports, Science and Technology (Grant-in-aid for Scientific Research on Priority Areas; to MS).
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