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Molecular features of lipid-based antigen presentation by group 1 CD1 molecules
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Review
Molecular features of lipid-based antigen presentation by group 1 CD1 molecules Jérôme Le Nours a,b , Adam Shahine a , Stephanie Gras a,b,∗ a Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia b Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
a r t i c l e
i n f o
Article history: Received 31 March 2017 Received in revised form 12 September 2017 Accepted 2 November 2017 Available online xxx Keywords: CD1 glycoproteins MHC-like molecules Lipid-based antigen presentation CD1-mediated T-cell immunity T-cell receptor recognition
a b s t r a c t Lipids are now widely considered to play a variety of important roles in T-cell mediated immunity, including serving as antigens. Lipid-based antigens are presented by a specialised group of glycoproteins termed CD1. In humans, three classes of CD1 molecules exist: group 1 (CD1a, CD1b, CD1c), group 2 (CD1d), and group 3 (CD1e). While CD1d-mediated T-cell immunity has been extensively investigated, we have only recently gained insights into the structure and function of group 1 CD1 molecules. Structural studies have revealed how lipid-based antigens are presented by group 1 CD1 molecules, as well as shedding light on the molecular requirements for T-cell recognition. Here, we provide an overview of our current understanding of lipid presentation by group 1 CD1 molecules in humans and their recognition by Tcells, as well as examining the potential differences in lipid presentation that may occur across different species. © 2017 Published by Elsevier Ltd.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Antigen presentation by group 1 CD1 molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Antigen presentation by CD1a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Antigen presentation by CD1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3. Antigen presentation by CD1c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 TCR recognition of group 1 CD1 molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. TCR recognition of CD1a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. TCR recognition of CD1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. T-cell recognition of CD1c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Evolution of group 1 CD1 glycoproteins in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Mammalian CD1a glycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Evolution of CD1b across species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.3. Evolution of CD1c across species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
∗ Corresponding author at: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. E-mail address: [email protected] (S. Gras). https://doi.org/10.1016/j.semcdb.2017.11.002 1084-9521/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: J.L. Nours, et al., Molecular features of lipid-based antigen presentation by group 1 CD1 molecules, Semin Cell Dev Biol (2017), https://doi.org/10.1016/j.semcdb.2017.11.002
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1. Introduction T-cells play critical roles in immune defence mechanisms and pathogen recognition. Heterodimeric ␣ T-cell receptors (TCRs) expressed on the surface of cytotoxic T-cells classically recognise pathogen fragments (peptides) presented by Major Histocompatibility Complex (MHC) molecules on specialised antigen presenting cells. However, some ␣TCRs also recognise non-peptidic antigens, including lipids. Lipid-based antigens are presented by MHC-like molecules termed Cluster of Differentiation or CD1 [1]. Similar to classical class I MHC molecules, CD1 consist of a membrane-bound glycoprotein composed of three extracellular domains (␣1, ␣2, and ␣3) that is non-covalently associated with the stabilising 2 microglobulin (2 m) protein. The MHC-like fold of CD1 forms a narrow hydrophobic binding cleft that accommodates lipid-based antigens. While MHC molecules show high polymorphisms, CD1 glycoproteins show limited diversity, making them an attractive target for drug design and immunotherapies. For humans, three groups of CD1 molecules are described in the literature: group 1 (CD1a, CD1b, and CD1c), group 2 (CD1d), and group 3 (CD1e). CD1e, however, does not bind lipids and its function remains unclear [2,3]. Each CD1 isoform varies in terms of tissue distribution and intracellular trafficking [4–7], and likely has unique functions. To date, most research on CD1 has focussed on CD1d, primarily because group 1 CD1 molecules are not present in rodents and are thus more difficult to investigate functionally [8–11]. However, the recent development of human group 1 CD1 tetramers technology has considerably advanced our capacity to study group 1 CD1 antigen presentation [12–24], TCR recognition [12,15] and subsequent T-cell responses [25–32]. It is now clear that group 1 CD1 glycoproteins can bind a wide spectrum of antigens from various origins including microbial lipids such as Mycobacterium tuberculosis (Mtb) [1,6,12,26,27,29,32–37]; allergens from bee venom [38,39], and poison ivy [16]; and self-lipids [21,40] such as skin-based and tumour-specific lipids [41,42]. Therefore, the antigen repertoire diversity highlights the crucial role of group 1 CD1 molecules in a broad range of diseases (e.g. microbial infection, allergy, cancer). Here, we review the available data depicting the molecular basis of lipid-antigen presentation by group 1 CD1 molecules and the first insights into their recognition by TCRs. We also explore the evolution of group 1 CD1 molecules across species. 2. Antigen presentation by group 1 CD1 molecules Over the past twenty years, the crystal structures of all group 1 CD1 glycoproteins (CD1a, CD1b and CD1c) were determined to atomic resolution [13,14,24] (Fig. 1). More recently, the ternary crystal structures of CD1a- and CD1b-lipid in complex with their respective restricted TCRs were also determined [12,15] (Table 1). Generally, the lipid-based antigens presented by group 1 CD1 molecules are amphipathic molecules with polar headgroups linked to lipid anchors formed from fatty acids or other aliphatic hydrocarbon chains (Fig. 3). The crystal structures of CD1 glycoproteins have revealed that they all possess narrow, deep, and largely hydrophobic antigen-binding clefts comprised of A’- and F’-pockets or portals (Figs. 1 and 2). However, the volume, number of pockets, and connectivity of the pockets within the cleft differ between each isoform (Fig. 1). 2.1. Antigen presentation by CD1a Among the group 1 CD1 family members in humans, CD1a contains the smallest antigen-binding cleft (∼1280 Å3 ), consisting of
a linear “tube” comprising two distinct pockets (A’ and F’) [24] (Fig. 1A). The A’-pocket forms a semi-circular bend that restricts the length of the alkyl chains (18–23 carbons) that CD1a can accommodate. However, the F’-pocket of CD1a is more versatile, and can accommodate not only alkyl chains (e.g. sulfatide, Figs. 2 A and 3 [24]) but also peptide fragments (e.g. a lipopeptide analogue of didehydroxymycobactin [DDM], Figs. 2 B and 3) [22]. Although the A’-pocket has a closed architecture suitable for lipids with small headgroups (e.g. lyso-phosphatidylcholine [LPC], Figs. 2 D and 3), CD1a can also accommodate larger headgroup lipids (e.g. sphingomyelin [SM], Figs. 2 E and 3) [15]. While these larger headgroups may disturb the “roof” of the A’-pocket, and in turn affect TCR recognition [15], subtle alterations in A’-pocket residues may allow larger antigens to be accommodated. CD1a that is predominantly expressed on Langerhans cells can also present skin-derived ‘headless’ hydrophobic antigens [43] that include squalene, wax esters, and fatty acids [15] (Figs. 2 C and 3). In addition, CD1a has been shown to play a role in the response to common allergens (such as lysophospholipids (Fig. 3) derived from bee venoms [37,38] and house dust mites [44]), and play a role in psoriasis [45]. More recently, the role of CD1a in controlling the inflammation in psoriasis and mediating recognition of the active component of poison ivy (urushiol) has been determined [15]. Here, the crystal structure of CD1a-urushiol revealed that the allergen was buried deep within the CD1a groove, and only 20% of its molecular surface was left exposed for potential TCR recognition [16] (Fig. 2F). Together, these studies indicate that, although CD1a exhibits the smallest antigen-binding cleft, it also has the ability to accommodate a wide range of chemically distinct antigens.
2.2. Antigen presentation by CD1b CD1b has the largest antigen-binding cleft within the CD1 family, with a total volume of ∼2230 Å3 (Fig. 1B). The CD1b cleft is composed of four broadly interconnected pockets or portals (A’, F’, C’, and T’), resembling a “maze for alkyl chains” [14] (Fig. 1B). This large interconnected hydrophobic network of the A’-, T’-, and F’-pockets allows CD1b to sequester long alkyl chains of 50–56 carbons in length, while the C’-pocket accommodates shorter alkyl chains (22–26 carbons). The T’-tunnel serves as an escape hatch, permitting lipid alkyl chains longer than ∼14 carbons to egress through the bottom of the pocket [14,23] (Fig. 1B). Due to its large binding cleft, CD1b can present chemically and structurally diverse lipid-based antigens (Fig. 3), ranging from large mycobacterial lipids (e.g. mycolic acid and glucose-6-Omonomycolate [GMM] [12,23], Figs. 2 H–I and 3) to lipoglycans such as phosphatidylinositol mannosides and lipoarabinomannans (Fig. 3) [46]. In addition, CD1b binds endogenous lipids such as ganglioside (GM2, Fig. 2J) and lipids that can be either endogenous or bacterial such as phospholipids like PC (Fig. 2K) [21]. Thus far, six structures of human CD1b [12,14,19,21,23] and one structure of bovine CD1b3 [20] have been determined in complex with various lipid antigens (Table 1, and Fig. 2G–L). These structures revealed that the CD1b cleft can accommodate up to a total of 80 carbons; for example, in the case of GMM-C54, the alkyl tail was found to extend from the A’-pocket through the T’-tunnel, and exit at the F’-pocket (Fig. 2H). CD1b has also the ability to bind much smaller microbial lipids (∼32–38 carbons) that include the Mtb diacylated sulfoglycolipid (Ac2 SGL, Figs. 2 L and 3) [19] and GMM-C32 [12]). Interestingly, the CD1b structures revealed the presence of endogenous “spacer lipids” (Fig. 2I). The role and nature of these spacer lipids is currently unknown, but they seem to provide stability within the groove in the absence of larger lipids.
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Fig. 1. Structural overview of group 1 CD1 molecules. The ␣1- and ␣2-domains of CD1a (A), CD1b (B), and CD1c (C) are coloured in pink, light orange, and cyan, respectively. The antigen-binding clefts of CD1a, CD1b, and CD1c are shown as molecular surfaces and coloured in salmon, pale green, and pink, respectively. The top and middle panels represent a top and side view of the grooves, respectively. Bottom panels show the surface representation of the CD1 molecules, with the lipid antigen represented as spheres. The positions of the A’-, C’-, F’-, D’/E’-, and T’-pockets are shown.
Table 1 Structures of group 1 CD1 molecules in complex with antigens. CD1a in complex with
Lipid origin
PDB code
Reference
Sulfatide Sphingomyelin Lyso-phosphatidylcholine Fatty acid Lipopeptide Urushiol
Self Self Self Self Synthetic Mycobacterium Toxicodendron
1ONQ 4X6F 4X6C 4X6D 1XZ0 5J1A
[24] [15] [15] [15] [22] [16]
CD1b in complex with
Origin
PDB code
Reference
Ganglioside monosialic 2 Phosphatidylinositol Phosphatidylcholine Phosphatidylethanolamineand Phosphatidylcholine Diacyl trehalose sulfoglcyolipid Glucose-6-O-monomycolate-C54 Glucose-6-O-monomycolate-C32
Self Self Self Self M. tuberculosis N. farcinica M. tuberculosis
1GZP 1GZQ 2H26 3L9Ra 3T8X 1UQS 5L2J
[14] [14] [21] [20] [19] [23] [12]
CD1c in complex with
Origin
PDB code
Reference
Fatty acid Mannosyl-1-phosphomycoketide Phosphomycoketide
Self M. tuberculosis M. tuberculosis
5C9J 3OV6 4ONO
[17] [13] [18]
a
bovine CD1b3 structure, PDB: Protein Data Bank.
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Fig. 2. Lipid presentation by group 1 CD1 molecules. The antigen-binding clefts of CD1a (pink), CD1b (pale orange), and CD1c (cyan) are shown as a cartoon representation. Lipid antigens are represented as white spheres and spacer lipids are coloured green.
2.3. Antigen presentation by CD1c Structural insights into antigen presentation by CD1c are limited to three structures of CD1c in complex with two Mtb lipid-based antigens (mannosyl-1-phosphomycoketide [MPM] [13,30] and phosphomycoketide [PM] [18]), and the “in vitro” refolded CD1c that revealed the presence of a small spacer lipid [SL] [17] (Table 1 and Fig. 2M–O). CD1c has a medium-sized cleft of ∼1780 Å3 , with an extra D’/E’-portal that allows the alkyl tail of the lipid to exit from the groove (Fig. 1C) [13], facilitated by the presence of small residues (G26/G28/L74). In addition, the CD1c F’-portal is more open than other group 1 CD1 isoforms (Fig. 1C), and may accommodate lipids containing larger headgroups or even lipopeptides [13]. Furthermore, while some mycobacterial lipids are wellcharacterised CD1c-restricted antigens, a recent study showed that CD1c-restricted T-cells were also responsive to the leukaemiaassociated self-lipid methyl-lysophosphatidic acid (mLPA) (Fig. 3) [42]. 3. TCR recognition of group 1 CD1 molecules Compared to group 2 CD1 molecules [11], structural data for group 1 CD1 is extremely limited: the structures of only two TCRs in complex with group 1 CD1 molecules presenting lipid antigens have been determined [12,15]. 3.1. TCR recognition of CD1a The first structure of an ␣ TCR in complex with CD1a-lipid involved an autoreactive T-cell clone named BK6 [15]. This study showed that when CD1a presented a “permissive lipid” (e.g. a phospholipid), the roof of the A’-pocket (R73/R76-E154) remains
unaltered (Fig. 4A), allowing the BK6 TCR to bind. However, presentation of “non-permissive lipids” (e.g. SM) (Fig. 4B–C) disturbs the A’-pocket roof, thus preventing BK6 TCR binding. In addition, this structure provides some explanation for the self-reactivity of BK6 T-cells: the TCR solely binds the CD1a molecule without engaging the lipid antigen [15]. This antigen-independent mode of recognition is in stark contrast with all the observed structures of TCRs engaging peptide-MHC and group 2 CD1-lipid complexes, in which the antigen is contacted [11]. Whether this is a general mechanism of autoreactivity towards all group 1 CD1 molecules (i.e., conserved with CD1b and CD1c), or it is a unique feature of CD1a, requires further investigation. 3.2. TCR recognition of CD1b Recently, the first structural determination of an ␣ TCR in complex with a Mtb derived-lipid antigen (GMM) (Fig. 3) presented by CD1b provided a major breakthrough in our understanding of CD1b-mediated T-cell immunity [12]. Here, two types of T-cell populations were identified in Mtb-infected individuals, and were classified by their high and moderate affinity towards CD1b-GMM [32]. The crystal structure of one high affinity TCR (GEM42) in complex with CD1b-GMM showed that the TCR firmly grasped the antigen (Fig. 4D), with the CDR3 loops (i.e., the complementarity determining regions) forming a “cage-like” structure around the glucose headgroup of GMM. The exposed carbohydrate moiety was flexible within the cleft of CD1b and was stabilised by the TCR upon ligation (Fig. 4E). The tight fit of the CDR3 loops (acting as “molecular tweezers”) around the lipid was crucial to drive the antigen specificity. Consequently, the GEM42 T-cell did not tolerate even minor modifications of the glucose headgroup [12]. However, the GEM42
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Fig. 3. Chemical structures of lipid-based antigens presented by group 1 CD1 molecules. Abbreviations: FA, fatty acid; TAG, triacylglyceride; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PS, phosphatidylserine; PA, phosphatidic acid; PI, phosphatidylinositol; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; SM, sphingomyelin; GM1, monosialotetrahexosylganglioside; PM, phosphomycoketide; MPM, mannosyl-1-phosphomycoketide; PIM, diacylglycerophosphoinositolmonomannosides; LAM, lipoarabinomannan; mLPA, methyllysophosphatidic acid; Ac2 SGL, diacylated trehalose sulfolipid.
T-cell could recognise either the C32 or C80 length GMM [12], suggesting that the TCR recognition was highly centred on the carbohydrate headgroup. The site-directed mutagenesis performed on CD1b revealed that the GEM42 TCR binding was altered by CD1b residues located on the roof of the A’-pocket (Fig. 4F) [12]. This was replicated in a polyclonal T-cell population, suggesting that those T-cells likely engage the CD1b-GMM complex using a docking strategy similar to the GEM42 TCR [12]. Therefore, as opposed to the antigen-independent mode of recognition observed with CD1a [15], the TCR recognition of CD1b-antigens is highly centred on the presented lipid. 3.3. T-cell recognition of CD1c Currently, there is no available structure of a TCR-CD1c-antigen and thus our understanding of the molecular recognition of CD1cantigens by T-cells is more limited. However, work has been done
on the CD1c-restricted immune response, notably in Mtb infection [13,18,27]. CD1c not only activates ␣ T-cells [18], as shown for CD1a and CD1b molecules, but also ␥␦ T-cells [10]. Therefore, more research is required to understand the molecular basis of TCR recognition of CD1c presenting lipids.
4. Evolution of group 1 CD1 glycoproteins in mammals The identification of two CD1 genes (CD1-1 and CD1-2) in chickens suggested that this class of molecules has been conserved throughout the history of evolution (∼310 million years) [47]. Despite the high degree of conservation, the occurrence and number of orthologous CD1 genes vary between mammals. In humans, CD1 proteins are largely monomorphic whereas other mammals contain numerous isoforms of the same group 1 CD1 molecules (Table 2). The presence of multiple copies of group 1 CD1 isoforms
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Fig. 4. Recognition of group 1 CD1 molecules by T-cell receptors. (A) CD1a (pink surface) presenting a permissive lipid antigen (LPC, white spheres), which allows formation of a salt bridge roof covering the A’-pocket (E154 to R73/R76; represented by black dashes). (B) Non-permissive lipid antigens (SM, cyan spheres) disrupt the roof over the A’-pocket of CD1a (cyan surface). (C) Superposition of the structures from A and B panels. (D) GEM42 TCR CDR3␣ (pink) and CDR3 (blue) loops surrounding the GMM lipid (white spheres). (E) Superposition of the unbound CD1bGMM molecule (CD1b in pale orange cartoon; GMM in white sticks) with CD1b-GMM bound to the GEM42 TCR (yellow). (F) Alanine scanning mutagenesis revealed positions of essential (red) and non-critical (black) residues required for GEM42 TCR recognition.
Table 2 Functional CD1 alleles in different mammalian species. Species
CD1a
CD1b
CD1c
Reference
Human Rabbit Guinea pig Pig Cattle Horse Dog
1 2 1 2 1 7 4
1 1 4 1 3 2 1
1 0 3 0 0 1 1
[51] [52] [53] [54,55] [56] [49] [57]
in some mammals suggests that they may have evolved to play immune functions distinct from human CD1 molecules. We investigated the sequence conservation of group 1 CD1 binding clefts across the most common mammalian species (e.g. rabbits, guinea pigs, pigs, cattles, horses, and dogs) (Table 2) to reflect on the common or divergent molecular features of their antigen binding cleft and their ability to present a more diverse antigens repertoire. For this purpose, a sequence alignment of the antigen-binding cleft (␣1-␣2 domains) was performed using the Clustal server [48]. 4.1. Mammalian CD1a glycoproteins Alignment of the antigen-binding clefts of CD1a molecules revealed that they share 14% identity and 24% homology (Fig. 5A). In huCD1a, the bottom of the A’-pocket is restricted by the con-
served bulky Phe10 and His38 residues (Fig. 5A) that provide a landing platform for the lipid tail (Fig. 5B). The A’-portal is further blocked by Phe169 and Trp63 (Fig. 5B). Across species, the Trp63 is replaced by other hydrophobic residues (Leu, Phe, Met, Ile), while Phe169 is highly conserved (Fig. 5A). Interestingly, in canCD1a2, Trp63 and Phe169 are replaced by Arg and Tyr residues, respectively, which would generate a more polar environment, and may allow canCD1a2 to accommodate different chemical classes of lipid-based antigen(s). The residues forming the F’-pocket of CD1a (Fig. 5A, orange triangles) are also highly conserved (87% homology). However, Tyr84 (located at the end of the ␣1-helix) is not conserved across species: the diverse nature of this solvent exposed residue could drive distinct ligand specificity or critical TCR contacts (Fig. 5C). The two hydrophobic residues (Phe144 and Ile81) found at the base of the F’-portal (Fig. 5C), which are thought to close the portal, are not strictly conserved; although most CD1a molecules have an aromatic residue at position 81 (76% have Phe81) and a smaller hydrophobic residue at position 144 (53% have Leu144). As such, the closed conformation of the F’-portal (which limits the size of the bound lipid tail) across species is likely conserved. Despite the abovementioned similarities, the formation of a salt bridge between Arg73/Arg76 and Glu154 (Fig. 4A–C), which forms a roof over the lipid antigen in the A’-pocket, is unique to huCD1a. This suggests that human CD1a may have evolved to adopt a distinct mode of antigen presentation and TCR recognition to other
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Fig. 5. Conservation of group 1 CD1a across species. (A) Sequence alignment of the ␣1 and ␣2 domains from functional CD1a molecules across species (including human [hu], rabbit [rab], guinea pig [gp], pig [po], cattle [bo], horse [eq], and dog [can]; ensembl.org) visualized using ESPript v3.0 [50]. Identical residues are denoted by red background; similar residues are shown as red text and white background. Sequence similarities are denoted by blue boxes. Secondary structure for the ␣1 and ␣2 helices correspond to the CD1a-sulfatide structure [24]. (B) Strictly conserved residues (F10 and H38) and polymorphic residues (W63 and F169) within the A’-pocket (green sticks) of CD1a across all species. (C) Polymorphic residues (I81, Y84, F144, and Y147) within the F’-pocket (orange sticks) of CD1a across all species.
mammals. Furthermore, humans have only one isoform of the CD1a molecule, unlike some of the other species such as horses (Table 2). The antigen-binding clefts from the seven horse CD1a proteins only share 40% identity and 30% homology. The large number of CD1a isoforms in horses is thought to be linked with the role of CD1a in the immune response to pathogens such as Rhodocossus equi [49]. This suggests that differences in CD1a molecules may have evolved to allow presentation of species-specific antigens. 4.2. Evolution of CD1b across species The mammalian CD1b molecules share ∼20% identity in their antigen-binding clefts (Fig. 6A). In the A’-pocket, residues Phe10 and His38 are highly conserved across species: Phe10 in huCD1b interacts with both antigen and spacer lipids (Fig. 6B). However, in gpCD1b1 and gpCD1b4, Phe10 and His38 are replaced by smaller residues that may allow for larger spacer lipids or antigens to be accommodated. The CD1b F’-pocket residues (Val81, Ile96, Gly98, Gly116, Phe144, Leu147, and Ile148) are highly conserved in mammals, with the exception of Phe84 (located at the end of the F’-portal) that is unique to huCD1b (Fig. 6C). The side chain of Phe84 switches position from inside the cleft when bound to GMM-C32 to outside
when bound to GMM-C54, to allow the longer tail of GMM-C54 to fit into the F’-pocket (Fig. 6C). In huCD1b, the absence of side chains from the two Gly residues at position 98 and 116 creates the T’-tunnel. Interestingly, in the three CD1b isoforms found in cattle, one glycine is replaced with either a Val/Leu/Ala, which would block the T’-tunnel. This suggests that the three bovine CD1b molecules may select shorter tail lipids than huCD1b. Similarly, in gpCD1b4, both Gly residues are replaced by Val, which would also completely obstruct the T’tunnel. This Val98-Val116 motif is unique to gpCD1b4 and is not shared by other gpCD1b isoforms, which suggests gpCD1b4 may adopt a distinct binding-cleft architecture that may accommodate a lipids repertoire of smaller size. Lipids containing two alkyl tails typically utilise both the A’- and F’-pockets; however, in CD1b, one lipid tail is usually located within the A’-pocket, while the other is located in the C’-portal (Fig. 6D). This difference of lipid tail orientation is permitted by two small residues at position 126 and 131 (Val126 and Cys131 in huCD1b). Cys131 is shared by all CD1b (Fig. 6A) and a small hydrophobic residue occupies position 126 in all but gpCD1b3, in which a bulkier residue (Phe126) is most likely to block the C’-portal. Thus, some CD1b molecules will have a smaller cleft volume than the huCD1b
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Fig. 6. Conservation of group 1 CD1b across species. (A) Sequence alignment of the ␣1 and ␣2 domains from functional CD1b molecules as per Fig. 5A. Secondary structure for the ␣1 and ␣2 helices correspond to the CD1bGMM-C32 structure [12]. (B) Conserved residues within the A’-pocket (green sticks). (C) Movement of F84 within the F’-pocket in the GMM-C32 (white) [12] and GMM-C54 (blue) [23] structures. (D) Amino acid residues involved in formation of the T’- and C’-portals (orange sticks); orange spheres represent the C␣ atom of the glycine residues.
molecule, which might lead to different antigen repertoires across species. 4.3. Evolution of CD1c across species CD1c is not present in rabbits, pigs, or cattle (Table 2). Horses and dogs contain one CD1c isoform, and three CD1c isoforms are found in guinea pigs. These six CD1c sequences share 30% identity (Fig. 7A). Among the eleven residues that form the A’-pocket, three are fully conserved (Gly28, His38, and Ile47). In the F’-pocket, six residues are similar (Ile81, Ile96, Val98, Val144, Leu147, and Leu148) and two are distinct (His84 and Val116) (Fig. 7A). Together with Phe170, the conserved His38 and Ile47 form the end of the A’-portal and support the lipid tail, which extends above Gly28 (Fig. 7B). The conservation of Gly28 across evolution would allow all CD1c molecules to present lipids with a long tail similar to CD1b molecules. However, the CD1c cleft has a smaller volume than CD1b, and lacks the long T’-tunnel (Val98/Val116, Fig. 7C). The only exception is gpCD1c3 that does have a glycine at position 116 (like CD1b molecules) that would allow longer lipid tails to fit inside the F’-pocket (Fig. 7C). The F’-pocket in CD1c is highly variable across species (Fig. 7A). Moreover, the residues forming the D’/E’-portal (Gly26, Gly28, and Leu74), are not conserved across species: while Gly28 is conserved across species, Gly26 is unique to huCD1c, and Leu74 is only con-
served in dogs (Fig. 7A). Therefore, even though there are fewer CD1c alleles compared to CD1a and CD1b, the antigen-binding cleft of CD1c varies across species in terms, and may also bind distinct lipid antigens.
5. Conclusion In recent years, fundamental insights into the role of group 1 CD1 molecules in T-cell mediated immunity have emerged. The development of CD1 tetramer technology has contributed to that effect by becoming an essential tool to identify new group 1 CD1-restricted antigens and T-cells and ascertain their mode of recognition by T-cells. As more crystal structures of lipid-reactive TCRs bound to group 1 CD1-lipid complexes emerge, we will further advance our understanding of lipid-based mediated immunity. While the hydrophobic nature of the antigen-binding cleft of group 1 CD1 molecules is clearly conserved across different species and isoforms, some key variations do exist at the molecular level that may allow to accommodate diverse lipid-based antigens. However, the impact of these variations across group 1 CD1 molecules in terms of their antigen repertoire, mechanism of lipid presentation, and impact on T-cell immunity requires further investigation.
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Fig. 7. Conservation of group 1 CD1c across species. (A) Sequence alignment of the ␣1 and ␣2 domains from functional CD1c molecules as per Fig. 5A. Secondary structure for the ␣1 and ␣2 helices correspond to the CD1c-MPM structure [13]. (B) Conserved residues within the A’-pocket (green sticks). (C) Polymorphic residues that block formation of the T’-tunnel (orange sticks) in the F’-pocket. (D) Polymorphic residues within the F’-pocket (orange sticks).
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Review
Molecular features of lipid-based antigen presentation by group 1 CD1 molecules Jérôme Le Nours a,b , Adam Shahine a , Stephanie Gras a,b,∗ a Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia b Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
a r t i c l e
i n f o
Article history: Received 31 March 2017 Received in revised form 12 September 2017 Accepted 2 November 2017 Available online xxx Keywords: CD1 glycoproteins MHC-like molecules Lipid-based antigen presentation CD1-mediated T-cell immunity T-cell receptor recognition
a b s t r a c t Lipids are now widely considered to play a variety of important roles in T-cell mediated immunity, including serving as antigens. Lipid-based antigens are presented by a specialised group of glycoproteins termed CD1. In humans, three classes of CD1 molecules exist: group 1 (CD1a, CD1b, CD1c), group 2 (CD1d), and group 3 (CD1e). While CD1d-mediated T-cell immunity has been extensively investigated, we have only recently gained insights into the structure and function of group 1 CD1 molecules. Structural studies have revealed how lipid-based antigens are presented by group 1 CD1 molecules, as well as shedding light on the molecular requirements for T-cell recognition. Here, we provide an overview of our current understanding of lipid presentation by group 1 CD1 molecules in humans and their recognition by Tcells, as well as examining the potential differences in lipid presentation that may occur across different species. © 2017 Published by Elsevier Ltd.
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5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Antigen presentation by group 1 CD1 molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Antigen presentation by CD1a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Antigen presentation by CD1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3. Antigen presentation by CD1c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 TCR recognition of group 1 CD1 molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. TCR recognition of CD1a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. TCR recognition of CD1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. T-cell recognition of CD1c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Evolution of group 1 CD1 glycoproteins in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Mammalian CD1a glycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Evolution of CD1b across species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.3. Evolution of CD1c across species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
∗ Corresponding author at: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. E-mail address: [email protected] (S. Gras). https://doi.org/10.1016/j.semcdb.2017.11.002 1084-9521/© 2017 Published by Elsevier Ltd.
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1. Introduction T-cells play critical roles in immune defence mechanisms and pathogen recognition. Heterodimeric ␣ T-cell receptors (TCRs) expressed on the surface of cytotoxic T-cells classically recognise pathogen fragments (peptides) presented by Major Histocompatibility Complex (MHC) molecules on specialised antigen presenting cells. However, some ␣TCRs also recognise non-peptidic antigens, including lipids. Lipid-based antigens are presented by MHC-like molecules termed Cluster of Differentiation or CD1 [1]. Similar to classical class I MHC molecules, CD1 consist of a membrane-bound glycoprotein composed of three extracellular domains (␣1, ␣2, and ␣3) that is non-covalently associated with the stabilising 2 microglobulin (2 m) protein. The MHC-like fold of CD1 forms a narrow hydrophobic binding cleft that accommodates lipid-based antigens. While MHC molecules show high polymorphisms, CD1 glycoproteins show limited diversity, making them an attractive target for drug design and immunotherapies. For humans, three groups of CD1 molecules are described in the literature: group 1 (CD1a, CD1b, and CD1c), group 2 (CD1d), and group 3 (CD1e). CD1e, however, does not bind lipids and its function remains unclear [2,3]. Each CD1 isoform varies in terms of tissue distribution and intracellular trafficking [4–7], and likely has unique functions. To date, most research on CD1 has focussed on CD1d, primarily because group 1 CD1 molecules are not present in rodents and are thus more difficult to investigate functionally [8–11]. However, the recent development of human group 1 CD1 tetramers technology has considerably advanced our capacity to study group 1 CD1 antigen presentation [12–24], TCR recognition [12,15] and subsequent T-cell responses [25–32]. It is now clear that group 1 CD1 glycoproteins can bind a wide spectrum of antigens from various origins including microbial lipids such as Mycobacterium tuberculosis (Mtb) [1,6,12,26,27,29,32–37]; allergens from bee venom [38,39], and poison ivy [16]; and self-lipids [21,40] such as skin-based and tumour-specific lipids [41,42]. Therefore, the antigen repertoire diversity highlights the crucial role of group 1 CD1 molecules in a broad range of diseases (e.g. microbial infection, allergy, cancer). Here, we review the available data depicting the molecular basis of lipid-antigen presentation by group 1 CD1 molecules and the first insights into their recognition by TCRs. We also explore the evolution of group 1 CD1 molecules across species. 2. Antigen presentation by group 1 CD1 molecules Over the past twenty years, the crystal structures of all group 1 CD1 glycoproteins (CD1a, CD1b and CD1c) were determined to atomic resolution [13,14,24] (Fig. 1). More recently, the ternary crystal structures of CD1a- and CD1b-lipid in complex with their respective restricted TCRs were also determined [12,15] (Table 1). Generally, the lipid-based antigens presented by group 1 CD1 molecules are amphipathic molecules with polar headgroups linked to lipid anchors formed from fatty acids or other aliphatic hydrocarbon chains (Fig. 3). The crystal structures of CD1 glycoproteins have revealed that they all possess narrow, deep, and largely hydrophobic antigen-binding clefts comprised of A’- and F’-pockets or portals (Figs. 1 and 2). However, the volume, number of pockets, and connectivity of the pockets within the cleft differ between each isoform (Fig. 1). 2.1. Antigen presentation by CD1a Among the group 1 CD1 family members in humans, CD1a contains the smallest antigen-binding cleft (∼1280 Å3 ), consisting of
a linear “tube” comprising two distinct pockets (A’ and F’) [24] (Fig. 1A). The A’-pocket forms a semi-circular bend that restricts the length of the alkyl chains (18–23 carbons) that CD1a can accommodate. However, the F’-pocket of CD1a is more versatile, and can accommodate not only alkyl chains (e.g. sulfatide, Figs. 2 A and 3 [24]) but also peptide fragments (e.g. a lipopeptide analogue of didehydroxymycobactin [DDM], Figs. 2 B and 3) [22]. Although the A’-pocket has a closed architecture suitable for lipids with small headgroups (e.g. lyso-phosphatidylcholine [LPC], Figs. 2 D and 3), CD1a can also accommodate larger headgroup lipids (e.g. sphingomyelin [SM], Figs. 2 E and 3) [15]. While these larger headgroups may disturb the “roof” of the A’-pocket, and in turn affect TCR recognition [15], subtle alterations in A’-pocket residues may allow larger antigens to be accommodated. CD1a that is predominantly expressed on Langerhans cells can also present skin-derived ‘headless’ hydrophobic antigens [43] that include squalene, wax esters, and fatty acids [15] (Figs. 2 C and 3). In addition, CD1a has been shown to play a role in the response to common allergens (such as lysophospholipids (Fig. 3) derived from bee venoms [37,38] and house dust mites [44]), and play a role in psoriasis [45]. More recently, the role of CD1a in controlling the inflammation in psoriasis and mediating recognition of the active component of poison ivy (urushiol) has been determined [15]. Here, the crystal structure of CD1a-urushiol revealed that the allergen was buried deep within the CD1a groove, and only 20% of its molecular surface was left exposed for potential TCR recognition [16] (Fig. 2F). Together, these studies indicate that, although CD1a exhibits the smallest antigen-binding cleft, it also has the ability to accommodate a wide range of chemically distinct antigens.
2.2. Antigen presentation by CD1b CD1b has the largest antigen-binding cleft within the CD1 family, with a total volume of ∼2230 Å3 (Fig. 1B). The CD1b cleft is composed of four broadly interconnected pockets or portals (A’, F’, C’, and T’), resembling a “maze for alkyl chains” [14] (Fig. 1B). This large interconnected hydrophobic network of the A’-, T’-, and F’-pockets allows CD1b to sequester long alkyl chains of 50–56 carbons in length, while the C’-pocket accommodates shorter alkyl chains (22–26 carbons). The T’-tunnel serves as an escape hatch, permitting lipid alkyl chains longer than ∼14 carbons to egress through the bottom of the pocket [14,23] (Fig. 1B). Due to its large binding cleft, CD1b can present chemically and structurally diverse lipid-based antigens (Fig. 3), ranging from large mycobacterial lipids (e.g. mycolic acid and glucose-6-Omonomycolate [GMM] [12,23], Figs. 2 H–I and 3) to lipoglycans such as phosphatidylinositol mannosides and lipoarabinomannans (Fig. 3) [46]. In addition, CD1b binds endogenous lipids such as ganglioside (GM2, Fig. 2J) and lipids that can be either endogenous or bacterial such as phospholipids like PC (Fig. 2K) [21]. Thus far, six structures of human CD1b [12,14,19,21,23] and one structure of bovine CD1b3 [20] have been determined in complex with various lipid antigens (Table 1, and Fig. 2G–L). These structures revealed that the CD1b cleft can accommodate up to a total of 80 carbons; for example, in the case of GMM-C54, the alkyl tail was found to extend from the A’-pocket through the T’-tunnel, and exit at the F’-pocket (Fig. 2H). CD1b has also the ability to bind much smaller microbial lipids (∼32–38 carbons) that include the Mtb diacylated sulfoglycolipid (Ac2 SGL, Figs. 2 L and 3) [19] and GMM-C32 [12]). Interestingly, the CD1b structures revealed the presence of endogenous “spacer lipids” (Fig. 2I). The role and nature of these spacer lipids is currently unknown, but they seem to provide stability within the groove in the absence of larger lipids.
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Fig. 1. Structural overview of group 1 CD1 molecules. The ␣1- and ␣2-domains of CD1a (A), CD1b (B), and CD1c (C) are coloured in pink, light orange, and cyan, respectively. The antigen-binding clefts of CD1a, CD1b, and CD1c are shown as molecular surfaces and coloured in salmon, pale green, and pink, respectively. The top and middle panels represent a top and side view of the grooves, respectively. Bottom panels show the surface representation of the CD1 molecules, with the lipid antigen represented as spheres. The positions of the A’-, C’-, F’-, D’/E’-, and T’-pockets are shown.
Table 1 Structures of group 1 CD1 molecules in complex with antigens. CD1a in complex with
Lipid origin
PDB code
Reference
Sulfatide Sphingomyelin Lyso-phosphatidylcholine Fatty acid Lipopeptide Urushiol
Self Self Self Self Synthetic Mycobacterium Toxicodendron
1ONQ 4X6F 4X6C 4X6D 1XZ0 5J1A
[24] [15] [15] [15] [22] [16]
CD1b in complex with
Origin
PDB code
Reference
Ganglioside monosialic 2 Phosphatidylinositol Phosphatidylcholine Phosphatidylethanolamineand Phosphatidylcholine Diacyl trehalose sulfoglcyolipid Glucose-6-O-monomycolate-C54 Glucose-6-O-monomycolate-C32
Self Self Self Self M. tuberculosis N. farcinica M. tuberculosis
1GZP 1GZQ 2H26 3L9Ra 3T8X 1UQS 5L2J
[14] [14] [21] [20] [19] [23] [12]
CD1c in complex with
Origin
PDB code
Reference
Fatty acid Mannosyl-1-phosphomycoketide Phosphomycoketide
Self M. tuberculosis M. tuberculosis
5C9J 3OV6 4ONO
[17] [13] [18]
a
bovine CD1b3 structure, PDB: Protein Data Bank.
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Fig. 2. Lipid presentation by group 1 CD1 molecules. The antigen-binding clefts of CD1a (pink), CD1b (pale orange), and CD1c (cyan) are shown as a cartoon representation. Lipid antigens are represented as white spheres and spacer lipids are coloured green.
2.3. Antigen presentation by CD1c Structural insights into antigen presentation by CD1c are limited to three structures of CD1c in complex with two Mtb lipid-based antigens (mannosyl-1-phosphomycoketide [MPM] [13,30] and phosphomycoketide [PM] [18]), and the “in vitro” refolded CD1c that revealed the presence of a small spacer lipid [SL] [17] (Table 1 and Fig. 2M–O). CD1c has a medium-sized cleft of ∼1780 Å3 , with an extra D’/E’-portal that allows the alkyl tail of the lipid to exit from the groove (Fig. 1C) [13], facilitated by the presence of small residues (G26/G28/L74). In addition, the CD1c F’-portal is more open than other group 1 CD1 isoforms (Fig. 1C), and may accommodate lipids containing larger headgroups or even lipopeptides [13]. Furthermore, while some mycobacterial lipids are wellcharacterised CD1c-restricted antigens, a recent study showed that CD1c-restricted T-cells were also responsive to the leukaemiaassociated self-lipid methyl-lysophosphatidic acid (mLPA) (Fig. 3) [42]. 3. TCR recognition of group 1 CD1 molecules Compared to group 2 CD1 molecules [11], structural data for group 1 CD1 is extremely limited: the structures of only two TCRs in complex with group 1 CD1 molecules presenting lipid antigens have been determined [12,15]. 3.1. TCR recognition of CD1a The first structure of an ␣ TCR in complex with CD1a-lipid involved an autoreactive T-cell clone named BK6 [15]. This study showed that when CD1a presented a “permissive lipid” (e.g. a phospholipid), the roof of the A’-pocket (R73/R76-E154) remains
unaltered (Fig. 4A), allowing the BK6 TCR to bind. However, presentation of “non-permissive lipids” (e.g. SM) (Fig. 4B–C) disturbs the A’-pocket roof, thus preventing BK6 TCR binding. In addition, this structure provides some explanation for the self-reactivity of BK6 T-cells: the TCR solely binds the CD1a molecule without engaging the lipid antigen [15]. This antigen-independent mode of recognition is in stark contrast with all the observed structures of TCRs engaging peptide-MHC and group 2 CD1-lipid complexes, in which the antigen is contacted [11]. Whether this is a general mechanism of autoreactivity towards all group 1 CD1 molecules (i.e., conserved with CD1b and CD1c), or it is a unique feature of CD1a, requires further investigation. 3.2. TCR recognition of CD1b Recently, the first structural determination of an ␣ TCR in complex with a Mtb derived-lipid antigen (GMM) (Fig. 3) presented by CD1b provided a major breakthrough in our understanding of CD1b-mediated T-cell immunity [12]. Here, two types of T-cell populations were identified in Mtb-infected individuals, and were classified by their high and moderate affinity towards CD1b-GMM [32]. The crystal structure of one high affinity TCR (GEM42) in complex with CD1b-GMM showed that the TCR firmly grasped the antigen (Fig. 4D), with the CDR3 loops (i.e., the complementarity determining regions) forming a “cage-like” structure around the glucose headgroup of GMM. The exposed carbohydrate moiety was flexible within the cleft of CD1b and was stabilised by the TCR upon ligation (Fig. 4E). The tight fit of the CDR3 loops (acting as “molecular tweezers”) around the lipid was crucial to drive the antigen specificity. Consequently, the GEM42 T-cell did not tolerate even minor modifications of the glucose headgroup [12]. However, the GEM42
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Fig. 3. Chemical structures of lipid-based antigens presented by group 1 CD1 molecules. Abbreviations: FA, fatty acid; TAG, triacylglyceride; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PS, phosphatidylserine; PA, phosphatidic acid; PI, phosphatidylinositol; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; SM, sphingomyelin; GM1, monosialotetrahexosylganglioside; PM, phosphomycoketide; MPM, mannosyl-1-phosphomycoketide; PIM, diacylglycerophosphoinositolmonomannosides; LAM, lipoarabinomannan; mLPA, methyllysophosphatidic acid; Ac2 SGL, diacylated trehalose sulfolipid.
T-cell could recognise either the C32 or C80 length GMM [12], suggesting that the TCR recognition was highly centred on the carbohydrate headgroup. The site-directed mutagenesis performed on CD1b revealed that the GEM42 TCR binding was altered by CD1b residues located on the roof of the A’-pocket (Fig. 4F) [12]. This was replicated in a polyclonal T-cell population, suggesting that those T-cells likely engage the CD1b-GMM complex using a docking strategy similar to the GEM42 TCR [12]. Therefore, as opposed to the antigen-independent mode of recognition observed with CD1a [15], the TCR recognition of CD1b-antigens is highly centred on the presented lipid. 3.3. T-cell recognition of CD1c Currently, there is no available structure of a TCR-CD1c-antigen and thus our understanding of the molecular recognition of CD1cantigens by T-cells is more limited. However, work has been done
on the CD1c-restricted immune response, notably in Mtb infection [13,18,27]. CD1c not only activates ␣ T-cells [18], as shown for CD1a and CD1b molecules, but also ␥␦ T-cells [10]. Therefore, more research is required to understand the molecular basis of TCR recognition of CD1c presenting lipids.
4. Evolution of group 1 CD1 glycoproteins in mammals The identification of two CD1 genes (CD1-1 and CD1-2) in chickens suggested that this class of molecules has been conserved throughout the history of evolution (∼310 million years) [47]. Despite the high degree of conservation, the occurrence and number of orthologous CD1 genes vary between mammals. In humans, CD1 proteins are largely monomorphic whereas other mammals contain numerous isoforms of the same group 1 CD1 molecules (Table 2). The presence of multiple copies of group 1 CD1 isoforms
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Fig. 4. Recognition of group 1 CD1 molecules by T-cell receptors. (A) CD1a (pink surface) presenting a permissive lipid antigen (LPC, white spheres), which allows formation of a salt bridge roof covering the A’-pocket (E154 to R73/R76; represented by black dashes). (B) Non-permissive lipid antigens (SM, cyan spheres) disrupt the roof over the A’-pocket of CD1a (cyan surface). (C) Superposition of the structures from A and B panels. (D) GEM42 TCR CDR3␣ (pink) and CDR3 (blue) loops surrounding the GMM lipid (white spheres). (E) Superposition of the unbound CD1bGMM molecule (CD1b in pale orange cartoon; GMM in white sticks) with CD1b-GMM bound to the GEM42 TCR (yellow). (F) Alanine scanning mutagenesis revealed positions of essential (red) and non-critical (black) residues required for GEM42 TCR recognition.
Table 2 Functional CD1 alleles in different mammalian species. Species
CD1a
CD1b
CD1c
Reference
Human Rabbit Guinea pig Pig Cattle Horse Dog
1 2 1 2 1 7 4
1 1 4 1 3 2 1
1 0 3 0 0 1 1
[51] [52] [53] [54,55] [56] [49] [57]
in some mammals suggests that they may have evolved to play immune functions distinct from human CD1 molecules. We investigated the sequence conservation of group 1 CD1 binding clefts across the most common mammalian species (e.g. rabbits, guinea pigs, pigs, cattles, horses, and dogs) (Table 2) to reflect on the common or divergent molecular features of their antigen binding cleft and their ability to present a more diverse antigens repertoire. For this purpose, a sequence alignment of the antigen-binding cleft (␣1-␣2 domains) was performed using the Clustal server [48]. 4.1. Mammalian CD1a glycoproteins Alignment of the antigen-binding clefts of CD1a molecules revealed that they share 14% identity and 24% homology (Fig. 5A). In huCD1a, the bottom of the A’-pocket is restricted by the con-
served bulky Phe10 and His38 residues (Fig. 5A) that provide a landing platform for the lipid tail (Fig. 5B). The A’-portal is further blocked by Phe169 and Trp63 (Fig. 5B). Across species, the Trp63 is replaced by other hydrophobic residues (Leu, Phe, Met, Ile), while Phe169 is highly conserved (Fig. 5A). Interestingly, in canCD1a2, Trp63 and Phe169 are replaced by Arg and Tyr residues, respectively, which would generate a more polar environment, and may allow canCD1a2 to accommodate different chemical classes of lipid-based antigen(s). The residues forming the F’-pocket of CD1a (Fig. 5A, orange triangles) are also highly conserved (87% homology). However, Tyr84 (located at the end of the ␣1-helix) is not conserved across species: the diverse nature of this solvent exposed residue could drive distinct ligand specificity or critical TCR contacts (Fig. 5C). The two hydrophobic residues (Phe144 and Ile81) found at the base of the F’-portal (Fig. 5C), which are thought to close the portal, are not strictly conserved; although most CD1a molecules have an aromatic residue at position 81 (76% have Phe81) and a smaller hydrophobic residue at position 144 (53% have Leu144). As such, the closed conformation of the F’-portal (which limits the size of the bound lipid tail) across species is likely conserved. Despite the abovementioned similarities, the formation of a salt bridge between Arg73/Arg76 and Glu154 (Fig. 4A–C), which forms a roof over the lipid antigen in the A’-pocket, is unique to huCD1a. This suggests that human CD1a may have evolved to adopt a distinct mode of antigen presentation and TCR recognition to other
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Fig. 5. Conservation of group 1 CD1a across species. (A) Sequence alignment of the ␣1 and ␣2 domains from functional CD1a molecules across species (including human [hu], rabbit [rab], guinea pig [gp], pig [po], cattle [bo], horse [eq], and dog [can]; ensembl.org) visualized using ESPript v3.0 [50]. Identical residues are denoted by red background; similar residues are shown as red text and white background. Sequence similarities are denoted by blue boxes. Secondary structure for the ␣1 and ␣2 helices correspond to the CD1a-sulfatide structure [24]. (B) Strictly conserved residues (F10 and H38) and polymorphic residues (W63 and F169) within the A’-pocket (green sticks) of CD1a across all species. (C) Polymorphic residues (I81, Y84, F144, and Y147) within the F’-pocket (orange sticks) of CD1a across all species.
mammals. Furthermore, humans have only one isoform of the CD1a molecule, unlike some of the other species such as horses (Table 2). The antigen-binding clefts from the seven horse CD1a proteins only share 40% identity and 30% homology. The large number of CD1a isoforms in horses is thought to be linked with the role of CD1a in the immune response to pathogens such as Rhodocossus equi [49]. This suggests that differences in CD1a molecules may have evolved to allow presentation of species-specific antigens. 4.2. Evolution of CD1b across species The mammalian CD1b molecules share ∼20% identity in their antigen-binding clefts (Fig. 6A). In the A’-pocket, residues Phe10 and His38 are highly conserved across species: Phe10 in huCD1b interacts with both antigen and spacer lipids (Fig. 6B). However, in gpCD1b1 and gpCD1b4, Phe10 and His38 are replaced by smaller residues that may allow for larger spacer lipids or antigens to be accommodated. The CD1b F’-pocket residues (Val81, Ile96, Gly98, Gly116, Phe144, Leu147, and Ile148) are highly conserved in mammals, with the exception of Phe84 (located at the end of the F’-portal) that is unique to huCD1b (Fig. 6C). The side chain of Phe84 switches position from inside the cleft when bound to GMM-C32 to outside
when bound to GMM-C54, to allow the longer tail of GMM-C54 to fit into the F’-pocket (Fig. 6C). In huCD1b, the absence of side chains from the two Gly residues at position 98 and 116 creates the T’-tunnel. Interestingly, in the three CD1b isoforms found in cattle, one glycine is replaced with either a Val/Leu/Ala, which would block the T’-tunnel. This suggests that the three bovine CD1b molecules may select shorter tail lipids than huCD1b. Similarly, in gpCD1b4, both Gly residues are replaced by Val, which would also completely obstruct the T’tunnel. This Val98-Val116 motif is unique to gpCD1b4 and is not shared by other gpCD1b isoforms, which suggests gpCD1b4 may adopt a distinct binding-cleft architecture that may accommodate a lipids repertoire of smaller size. Lipids containing two alkyl tails typically utilise both the A’- and F’-pockets; however, in CD1b, one lipid tail is usually located within the A’-pocket, while the other is located in the C’-portal (Fig. 6D). This difference of lipid tail orientation is permitted by two small residues at position 126 and 131 (Val126 and Cys131 in huCD1b). Cys131 is shared by all CD1b (Fig. 6A) and a small hydrophobic residue occupies position 126 in all but gpCD1b3, in which a bulkier residue (Phe126) is most likely to block the C’-portal. Thus, some CD1b molecules will have a smaller cleft volume than the huCD1b
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Fig. 6. Conservation of group 1 CD1b across species. (A) Sequence alignment of the ␣1 and ␣2 domains from functional CD1b molecules as per Fig. 5A. Secondary structure for the ␣1 and ␣2 helices correspond to the CD1bGMM-C32 structure [12]. (B) Conserved residues within the A’-pocket (green sticks). (C) Movement of F84 within the F’-pocket in the GMM-C32 (white) [12] and GMM-C54 (blue) [23] structures. (D) Amino acid residues involved in formation of the T’- and C’-portals (orange sticks); orange spheres represent the C␣ atom of the glycine residues.
molecule, which might lead to different antigen repertoires across species. 4.3. Evolution of CD1c across species CD1c is not present in rabbits, pigs, or cattle (Table 2). Horses and dogs contain one CD1c isoform, and three CD1c isoforms are found in guinea pigs. These six CD1c sequences share 30% identity (Fig. 7A). Among the eleven residues that form the A’-pocket, three are fully conserved (Gly28, His38, and Ile47). In the F’-pocket, six residues are similar (Ile81, Ile96, Val98, Val144, Leu147, and Leu148) and two are distinct (His84 and Val116) (Fig. 7A). Together with Phe170, the conserved His38 and Ile47 form the end of the A’-portal and support the lipid tail, which extends above Gly28 (Fig. 7B). The conservation of Gly28 across evolution would allow all CD1c molecules to present lipids with a long tail similar to CD1b molecules. However, the CD1c cleft has a smaller volume than CD1b, and lacks the long T’-tunnel (Val98/Val116, Fig. 7C). The only exception is gpCD1c3 that does have a glycine at position 116 (like CD1b molecules) that would allow longer lipid tails to fit inside the F’-pocket (Fig. 7C). The F’-pocket in CD1c is highly variable across species (Fig. 7A). Moreover, the residues forming the D’/E’-portal (Gly26, Gly28, and Leu74), are not conserved across species: while Gly28 is conserved across species, Gly26 is unique to huCD1c, and Leu74 is only con-
served in dogs (Fig. 7A). Therefore, even though there are fewer CD1c alleles compared to CD1a and CD1b, the antigen-binding cleft of CD1c varies across species in terms, and may also bind distinct lipid antigens.
5. Conclusion In recent years, fundamental insights into the role of group 1 CD1 molecules in T-cell mediated immunity have emerged. The development of CD1 tetramer technology has contributed to that effect by becoming an essential tool to identify new group 1 CD1-restricted antigens and T-cells and ascertain their mode of recognition by T-cells. As more crystal structures of lipid-reactive TCRs bound to group 1 CD1-lipid complexes emerge, we will further advance our understanding of lipid-based mediated immunity. While the hydrophobic nature of the antigen-binding cleft of group 1 CD1 molecules is clearly conserved across different species and isoforms, some key variations do exist at the molecular level that may allow to accommodate diverse lipid-based antigens. However, the impact of these variations across group 1 CD1 molecules in terms of their antigen repertoire, mechanism of lipid presentation, and impact on T-cell immunity requires further investigation.
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Fig. 7. Conservation of group 1 CD1c across species. (A) Sequence alignment of the ␣1 and ␣2 domains from functional CD1c molecules as per Fig. 5A. Secondary structure for the ␣1 and ␣2 helices correspond to the CD1c-MPM structure [13]. (B) Conserved residues within the A’-pocket (green sticks). (C) Polymorphic residues that block formation of the T’-tunnel (orange sticks) in the F’-pocket. (D) Polymorphic residues within the F’-pocket (orange sticks).
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