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109
CD1 and lipid antigens: intracellular pathways for antigen presentation
Jayanthi Jayawardena-Wolf and Albert Bendelac
Recently, different members of the CD1 family of MHC-like
molecules have been shown to sample different intracellular
compartments to present lipid and glycolipid antigens to
T cells. Emerging models suggest that CD1 may have evolved
to monitor the integrity of membrane lipids and/or to present
microbial lipid antigens to both αβ and γδ T cells.
II molecules. Here we review the recent advances in our
understanding of the biology of antigen presentation by
the two groups of CD1 proteins.
CD1: two distinct groups of lipid-presenting
molecules
CD1 comprises a family of genes that are not linked to the
MHC complex. Five CD1 genes, or isotypes, are found in
the human, and these genes can be separated into two
groups on the basis of sequence homology [1]: group 1 consists of CD1-a, -b, -c and -e; group 2 consists of CD1d. The
CD1d gene is present in all species studied to date, but
group 1 genes have not been found in rodents. The CD1
genes encode nonpolymorphic proteins that noncovalently
associate with β2-microglobulin to form a similar fold to
that of MHC class I molecules [2]; but the antigen-binding
groove of mouse CD1d is much more hydrophobic than
that of MHC class I molecules.
Addresses
Department of Molecular Biology, Schultz Laboratory, Room 416,
Princeton University, Washington Road, Princeton, NJ 08544, USA
Correspondence: Albert Bendelac;
e-mail: [email protected]
Current Opinion in Immunology 2001, 13:109–113
0952-7915/01/$ — see front matter
© 2001 Elsevier Science Ltd. All rights reserved.
Abbreviation
LAM
lipoarabinomannan
Introduction
Antigen presentation is the way in which cells present
fragments of pathogens to T cells. The most well-known
antigen-presenting proteins are the MHC molecules.
T cell recognition of peptide fragments bound to MHC
class I and II molecules is critical for effective adaptive
immunity. During the past decade, other antigen-presenting molecules have been discovered and one of the
most intriguing is the CD1 family of antigen-presenting
proteins. CD1 is a lineage of antigen-presenting proteins
that has evolved to present lipid and glycolipid antigens.
CD1 proteins are divided into two groups on the basis of
their amino-acid sequence homology and recent studies
have shown that the two groups may have different functions. Furthermore, both types of CD1 molecules have
evolved novel pathways of intracellular trafficking, which
differ from those of classical MHC class I and MHC class
The differences in the structures of CD1 and MHC class
I molecules lend support to the hypothesis that CD1 has
evolved to present glycolipids and lipids to T cells. The
current model is that the fatty-acid tails of the glycolipid
fit into two hydrophobic pockets of the binding groove of
CD1, while the polar residues protrude out of the groove
and contact the TCR. Studies of the group 1 proteins
CD1-a, -b and -c have shown that CD1 can present
microbial lipid and glycolipid antigens such as mycolic
acids, lipoarabinomannans (LAMs) and hexose-1-phosphoprenoids to T cells [3,4,5••]. Analysis of group 2
human and mouse CD1d proteins has shown that they
can present a glycolipid, α-galactosylceramide [6,7].
Thus, although group 2 CD1 might also present
hydrophobic peptides, it appears that, in general, all the
CD1 proteins have evolved to present lipids rather than
peptides [8].
Figure 1
Group 1 CD1 proteins sample different
intracellular compartments containing different
types of lipid antigens. (a) CD1 molecules are
present in different maturational stages of
mycobacterial phagosomes, so they could
bind antigens directly in phagosomes. (b) Cellsurface receptors such as the mannose
receptor could bind free mycobacterial
antigens at the cell surface and bring them into
late endosomes for presentation by CD1b.
Mycobacterial lipids could also be sorted into
either (c) recycling endosomes (for lipids with
short, unsaturated fatty-acid tails), where they
encounter CD1a, or (d) late endosomes (for
lipids with long fatty-acid tails), where they
encounter CD1b. (e) CD1c could encounter
antigens in early or late endosomes.
CD1a
(c)
Early/
recycling
endosome
(a)
Phagosome
CD1c
CD1b
(e)
(d)
Lateendosome/
lysosome
(b)
Mycobacterium
Mannose receptor
Current Opinion in Immunology
110
Innate immunity
Intersection of group 1 CD1 and lipids in
intracellular compartments
Figure 2
Non-Vα14+
T cell
Vα14+
T cell
Antigenpresenting
cell
(c)
(b)
(a)
Lateendosome/
lysosome
TGN
Golgi
ER
Current Opinion in Immunology
Group 2 CD1 molecules: sampling self-glycolipids in and out of the
endosomal compartment. (a) Newly synthesized group 2 CD1d
molecules could pick up self-antigens in the secretory pathway and
present them at the cell surface to non-Vα14+ T cells. (b) Using an
endosomal-targeting motif in its cytoplasmic tail, CD1d could then
internalize into late endosomes, where the antigen loaded in the
secretory pathway is removed and an antigen present in the
endosomal compartment is loaded. (c) After recycling back to the cell
surface, CD1d then presents the endosomally loaded antigen to
Vα14+ T cells. ER, endoplasmic reticulum; TGN, trans-Golgi network.
Presentation of mycobacterial lipids by
group 1 CD1 proteins
The ability of CD1 proteins to present microbial lipid
antigens to αβ T cells was first shown for CD1b [3]. This
molecule presents components of mycobacterial cell
walls, such as mycolic acids, glucose monomycolates and
LAMs [3,4,9]. In addition to presenting mycobacterial
glycolipids, CD1b can also present self-glycosphingolipids such as the GM1 ganglioside [10•]. Recently,
Moody et al. [5••] showed that CD1c presents mycobacterial hexose-1-phosphoprenoids.
T cell lines that are restricted by group 1 CD1 are phenotypically CD8–CD4– or CD8+CD4– and both these T cell
subsets respond by secreting IFN-γ, which protects against
intracellular pathogens [11]. The CD8+CD4– subset uses
perforin to induce apoptosis of infected macrophages and
granulysin to kill mycobacteria whereas the CD8–CD4–
T cells induce apoptosis via the Fas pathway [12]. CD1c
can also be recognized by a subset of γδ T cells; however,
the ligand being presented to these T cells has not yet
been identified. CD1c-reactive γδ T cells use both perforin and Fas-mediated cytotoxicity [13•].
Studies of several CD1b-restricted T cell lines raised
against mycobacteria have revealed that even purified
mycobacterial glycolipids need to be internalized into
antigen-presenting cells before being presented to T cells
[4]. Biophysical studies showed that the acidic pH of late
endosomes is important to open the groove of CD1b, perhaps to facilitate the loading of antigens in these
compartments [14]. A tyrosine-based motif in the cytoplasmic tail of CD1b targets the protein to late endosomes [15].
Deletion of this motif results in the failure of CD1b to bind
lipid antigens derived from phagocytosed mycobacteria and
also a failure to access late endosomes. These results suggested that access of CD1b to late endosomes is important
in antigen loading [16]. CD1c also contains a tyrosine-based
motif similar to that of CD1b but, unlike CD1b, which is
predominantly found in late endosomes, CD1c is distributed throughout the endocytic system [17•,18•]. In contrast
to CD1b, which requires an acidic pH for efficient antigenpresentation, CD1c is not dependent on vesicular
acidification for presentation [17•,18•].
CD1a is the only CD1 protein that does not possess a tyrosine-based endosome-targeting motif in its cytoplasmic tail.
As a result CD1a is present mostly on the cell surface,
although there is a portion of CD1a in the recycling pathway
[19•]. This indicates that CD1a may sample mycobacterial
antigens in early/recycling endosomes. A recent study by
Schaible et al. [20••] showed that all three group 1 CD1 molecules that were studied intersect with mycobacterial
phagosomes at different stages of maturity. CD1a and CD1c
are present in phagosomes arrested at the early endosomal
stage whereas CD1b is located in phagolysosomes.
How do mycobacterial lipids reach CD1+ compartments?
Studies by Prigozy et al. [21] have suggested that the
macrophage mannose receptor might capture extracellular
antigens such as LAM and deliver them to endocytic compartments, which contain CD1b. For intracellular
mycobacteria that are sequestered in phagosomes, however, other mechanisms must be involved. Using
fluorescently labeled mycobacteria, Schaible et al. [20••]
have suggested that LAM and phosphatidylinositol mannoside (PIM) may be exported from the phagosome into
late endosomes. Although little is known about lipid
sorting, there is some suggestion that it is dependent
on the structure of hydrophobic tails. Mukherjee et al.
[22•] found that lipids with short, unsaturated fatty-acid
chains are delivered to recycling endosomes whereas
lipids with long, saturated tails are sorted to late
endosomes. Thus, mycobacterial lipids might be
delivered into the various endocytic compartments sampled by different CD1 molecules. Finally, it is also
possible that CD1 loading might directly occur in the
different maturational stages of mycobacterial phagosome,
which contain different CD1 molecules (see summary
in Figure 1).
CD1 and lipid antigens Jayawardena-Wolf and Bendelac
Processing of glycolipid antigens
One unanswered question is whether lipid antigens undergo cleavage of covalent bonds to form smaller antigenic
fragments. For example, whereas mycobacterial LAM is a
very large glycolipid containing more than 100 carbohydrate
residues, LAM-specific T cells can be stimulated by lipomannan or PIM6, which are much smaller molecules but
possess the same core structure as LAM [4]. This suggests
that antigen-presenting cells can actually cleave this antigen
into smaller units that are recognized by T cells. A recent
study of self-glycosphingolipid binding to CD1b has shown,
however, that five or more sugars may be needed for T cell
recognition [23•]. Alternatively, it is possible that the
hydrophobic tail of the glycolipid must be processed for it to
fit into the groove of CD1. For example, mycolic acid typically contains about 80 carbons (C80), which we predict to be
too long to fit into the groove of CD1.
Lipid-presentation by CD1d molecules
To date, there is no evidence that CD1d functions in presenting bacterial lipids. Mouse CD1d does bind to LAM,
but mice lacking CD1d are resistant to tuberculosis infection [24–26]. It has also been suggested that foreign glycosyl
phosphatidylinositol (GPI) from malarial circumsporozoite
might be effectively presented to CD1d-restricted T cells
[27•]; however, a more recent analysis has shown that this
may not be the case [28•]. Although it remains entirely possible that CD1d is involved in the presentation of microbial
lipids to T cells, studies so far have been restricted to the
presentation of nonmicrobial lipids. In addition, T cells that
recognize CD1d in the absence of exogenously added foreign antigens have been isolated [29].
111
α-chain — Vα14–Jα281 in the mouse or Vα24–JαQ in the
human — that is autoreactive in vitro to CD1d [30]. NKT
cells regulate a range of conditions such as autoimmune diabetes and tumor progression [31–33]. The natural glycolipids
that bind to CD1d and stimulate NKT cells have not yet
been identified. Cellular GPIs have been suggested but not
conclusively proven to be the main ligand presented by the
CD1d molecule [34]. Some CD1d-restricted T cells can
respond to purified phospholipids such as phosphatidylinositol, which is a constituent of normal mammalian membranes
[35•]. To date, the only glycolipid that has been shown to
bind to CD1d and strongly stimulate all NKT cells is αgalactosylceramide, a glycolipid originally isolated from
marine sponges because of its antitumor properties [6]. It is
conceivable that α-galactosylceramide is a mimic of an autologous ligand that has yet to be discovered.
Interestingly, CD1d autorecognition by NKT cells depends
on its intracellular trafficking. The steady-state localization
of CD1d shows much of the protein in late-endosomes/lysosomes; however, the deletion of a tyrosine-based motif in the
cytoplasmic tail of CD1d prevents targeting of CD1d to
these compartments [36,37,38••]. Chiu et al. [38••] recently
showed that CD1d proteins that cannot access late-endosomes/lysosomes cannot stimulate Vα14+ NKT cells.
However, these tyrosine-deleted proteins are still recognized
by autoreactive T cells expressing different non-Vα14+
TCRs. This implies that two categories of antigen can be
presented by CD1d: those that are restricted to endosomes;
and those that are found outside the endosomes, possibly in
the secretory pathway (see summary in Figure 2).
Rationale for lipid-antigen presentation
A prominent CD1d-restricted T cell subset comprises
NKT cells, which express a TCR with an invariant TCR
Studies of group 1 CD1 proteins suggest that these proteins may be involved in host defense against bacterial
Figure 3
Competition between self and foreign lipid
antigens. Two hypothetical pathways to
sample endosomal antigens are shown. In
pathway 1, CD1 binds to self-lipid in the
endoplasmic reticulum (ER) and then
(a) travels to the cell surface. (b) CD1
internalizes into endosomal compartments,
where the self-lipid is removed by additional
factors and another lipid is loaded. (c) CD1
then recycles back to the surface to present
potentially foreign glycolipids. (d) In
pathway 2, a chaperone protein binds and
blocks the antigen-binding groove of CD1.
(e) The chaperone protein targets CD1
directly to the endosome after exiting the
trans-Golgi network (TGN). In the endosome,
the chaperone protein is removed and CD1
can load endosomal glycolipids.
Cell
surface
Internalization
(b)
Self or
foreign
lipid
Self
lipid
(c)
Endosome
(a)
(e)
TGN
Possible
pathway 1
Golgi
ER
Possible
pathway 2
(d)
Chaperone protein
Endogenous lipid
Current Opinion in Immunology
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Innate immunity
infections. A rationale for the presentation of foreign glycolipids is that many microbial lipids differ in structure
from mammalian lipids, providing a basis for the discrimination of infectious from non-infectious structures [39].
Presentation of lipids would help to detect mycobacteria
that persist within deacidified endosomes and which avoid
presentation by the MHC.
Mycobacterial lipids can travel within membranes to other
compartments, thereby enhancing the chance of being picked
up and presented by CD1 molecules [20••]. There is little
evidence so far that CD1d proteins are involved in presenting
microbial lipids for host defense. Instead, the existence of a
prominent, conserved subset of CD1d-autoreactive Vα14+
T cells suggests that CD1d is involved in presentation of selfglycolipids. In vivo, perhaps these T cells might monitor
carbohydrate modifications of glycolipids caused by stress or
senescence and might regulate autoimmune processes such as
diabetes and the emergence of tumors [31–33].
Missing pieces
Many unanswered questions remain about CD1 glycolipidantigen presentation. An important issue is how CD1 loads
antigens in endosomal compartments in the face of immense
competition with cellular glycolipids preloaded in the secretory pathway. One possibility is that additional factors
present in endosomal compartments help in the removal of
preloaded lipids and assist in the loading of endosomal lipids.
Alternatively, a chaperone protein might bind CD1, prevent
loading of antigens in the secretory compartments and target
CD1 directly to endosomes, thus ensuring loading of CD1
only in endosomal compartments (see summary in Figure 3).
A detailed kinetic study of the trafficking of CD1 is needed
and molecules that aid CD1 in the loading of glycolipids in
different cellular compartments have yet to be found.
Perhaps CD1 uses the cell’s glycolipid-synthesizing machinery to load glycolipids or perhaps there are specialized
molecules for this process. Analysis of mutagenized cell lines
with defects in CD1 antigen presentation could be a method
to identify the accessory molecules involved.
Conclusions
Studies have shown that different members of the CD1
family sample different intracellular compartments to pick
up glycolipid antigens located in these compartments and
present them to T cells. Although much has been learned
about the cell biology of CD1 antigen presentation, a number of issues remain to be resolved. In particular, a search
for accessory molecules such as glycolipid-processing
enzymes and trafficking chaperones is needed. The
knowledge gained from the basic studies of CD1 trafficking and antigen presentation are potentially useful for the
rational design of lipid-based vaccines and adjuvants.
Acknowledgements
We thank C Bonnerot, S Amigorena, I Mellman and members of our
laboratory, in particular K Benlagha, for helpful discussions. This work was
supported by grants from the National Institutes of Health and the
American Cancer Society.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• of special interest
•• of outstanding interest
1.
Calabi F, Jarvis JM, Martin L, Milstein C: Two classes of CD1 genes.
Eur J Immunol 1989, 19:285-292.
2.
Zeng Z, Castano AR, Segelke BW, Stura EA, Peterson PA, Wilson IA:
Crystal structure of mouse CD1: an MHC-like fold with a large
hydrophobic binding groove. Science 1997, 277:339-345.
3.
Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST,
Brenner MB: Recognition of a lipid antigen by CD1-restricted αβ+
T cells. Nature 1994, 372:691-694.
4.
Sieling PA, Chatterjee D, Porcelli SA, Prigozy TI, Mazzaccaro RJ,
Soriano T, Bloom BR, Brenner MB, Kronenberg M, Brennan PJ,
Modlin RL: CD1-restricted T cell recognition of microbial
lipoglycan antigens. Science 1995, 269:227-230.
5.
••
Moody DB, Ulrichs T, Muhlecker W, Young DC, Gurcha SS, Grant E,
Rosat JP, Brenner MB, Costello CE, Besra GS, Porcelli SA: CD1cmediated T-cell recognition of isoprenoid glycolipids in
Mycobacterium tuberculosis infection. Nature 2000, 404:884-888.
This is the first demonstration that recently infected patients mount a T cell
response to glycolipids of Mycobacterium tuberculosis. The mycobacterial
antigens identified fall into a family of isoprenoid glycolipids, whose members include components of the pathways for protein glycosylation and cellwall synthesis pathways.
6.
Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H,
Nakagawa R, Sato H, Kondo E et al.: CD1d-restricted and TCRα14 NKT cells by glycosylceramides.
mediated activation of Vα
Science 1997, 278:1626-1629.
7.
Brossay L, Chioda M, Burdin N, Koezuka Y, Castorati G, Dellabona P,
Kronenberg M: CD1d-mediated recognition of an α-galactosylceramide by natural killer T cells is highly conserved through
mammalian evolution. J Exp Med 1998, 188:1521-1528.
8.
Castano AR, Tangri S, Miller JE, Holcombe HR, Jackson MR,
Huse WD, Kronenberg M, Peterson PA: Peptide binding and
presentation by mouse CD1. Science 1995, 269:223-226.
9.
Moody DB, Reinhold BB, Guy MR, Beckman EM, Frederique DE,
Furlong ST, Ye S, Reinhold VN, Sieling PA, Modlin RL et al.:
Structural requirements for glycolipid antigen recognition by
CD1b-restricted T cells. Science 1997, 278:283-286.
10. Shamshiev A, Donda A, Carena I, Mori L, Kappos L, De Libero G:
•
Self glycolipids as T-cell autoantigens. Eur J Immunol 1999,
29:1667-1675.
This paper is the first to show that circulating T cells reactive to glycolipids
presented by CD1b were present in patients with multiple sclerosis. The glycolipids presented included self-gangliosides and the carbohydrate portion
of these gangliosides was specifically recognized by TCRs.
11. Porcelli SA, Modlin R: The CD1 system: antigen-presenting
molecules for T cell recognition of lipids and glycolipids. Annu
Rev Immunol 1999, 17:297-329.
12. Stenger S, Mazzaccaro RJ, Uyemura K, Cho S, Barnes PF, Rosat JP,
Sette A, Brenner MB, Porcelli SA, Bloom BR, Modlin RL: Differential
effects of cytolytic T cell subsets on intracellular infection.
Science 1997, 276:1684-1687.
13. Spada FM, Grant EP, Peters PJ, Sugita M, Melian A, Leslie DS,
•
Lee HK, van Donselaar E, Hanson DA, Krensky AM et al.:
Self-recognition of CD1 by gamma/delta T cells: implications for
innate immunity. J Exp Med 2000, 191:937-948.
This paper convincingly demonstrated that some human Vγ2/Vδ1 T cells were
restricted by CD1c and that these T cells were autoreactive to CD1c in vitro.
14. Ernst WA, Maher J, Cho S, Niazi KR, Chatterjee D, Moody DB, Besra GS,
Watanabe Y, Jensen PE, Porcelli SA et al.: Molecular interaction of
CD1b with lipoglycan antigens. Immunity 1998, 8:331-340.
15. Sugita M, Jackman RM, van Donselaar E, Behar SM, Rogers RA,
Peters PJ, Brenner MB, Porcelli SA: Cytoplasmic tail-dependent
localization of CD1b antigen-presenting molecules to MIICs.
Science 1996, 273:349-352.
16. Jackman RM, Stenger S, Lee A, Moody DB, Rogers RA, Niazi KR,
Sugita M, Modlin RL, Peters PJ, Porcelli SA: The tyrosine-containing
cytoplasmic tail of CD1b is essential for its efficient presentation
of bacterial lipid antigens. Immunity 1998, 8:341-351.
CD1 and lipid antigens Jayawardena-Wolf and Bendelac
113
17.
•
NKT cells and ensured a strong antibody response. However, these results
were contradicted in [28•].
18. Sugita M, van der Wel M, Rogers RA, Peters PJ, Brenner MB: CD1c
•
molecules broadly survey the endocytic system. Proc Natl Acad
Sci USA 2000, 97:8445-8450.
See annotation to [17•].
28. Molano A, Park SH, Chiu YH, Nosseir S, Bendelac A, Tsuji M: Cutting
•
edge: the IgG response to the circumsporozoite protein is MHC
class II-dependent and CD1d-independent: exploring the role of
GPIs in NK T cell activation and antimalarial responses. J Immunol
2000, 164:5005-5009.
This paper contradicts [27•] by showing the antibody response to the malarial circumsporozoite protein was independent of CD1d and is dependent
instead on MHC class II. This paper casts serious doubts on the idea that
glycosyl phosphatidylinositol (GPI) or GPI-anchored proteins can be presented by CD1d.
Briken V, Jackman RM, Watts GF, Rogers RA, Porcelli SA: Human
CD1b and CD1c isoforms survey different intracellular
compartments for the presentation of microbial lipid antigens.
J Exp Med 2000, 192:281-288.
These two studies [17•,18•] elegantly described the intracellular localization of
CD1c. They found that CD1c has a broad endocytic distribution whereas CD1b
is predominantly located in late endosomes. In addition, CD1c is different to
CD1b because it does not require vesicular acidification for antigen presentation.
19. Sugita M, Grant EP, van Donselaar E, Hsu VW, Rogers RA, Peters PJ,
•
Brenner MB: Separate pathways for antigen presentation by CD1
molecules. Immunity 1999, 11:743-752.
This paper was the first to provide a detailed study of the localization of CD1a.
The authors showed that CD1a was primarily located in recycling or early
endosomes whereas CD1b is in late endosomes. In addition, unlike CD1b,
antigen presentation by CD1a was independent of vesicular acidification.
29. Bendelac A, Lantz O, Quimby ME, Yewdell JW, Bennink JR,
Brutkiewicz RR: CD1 recognition by mouse NK1.1+ T lymphocytes.
Science 1995, 268:863-865.
20. Schaible UE, Hagens K, Fischer K, Collins HL, Kaufmann SHE:
•• Intersection of group I CD1 molecules and mycobacteria in
different intracellular compartments of dendritic cells. J Immunol
2000, 164:4843-4852.
This paper is very important because it was the first to describe the intracellular localization of group 1 CD1 molecules in cells infected with
mycobacteria. CD1a and CD1c gain access to phagosomes arrested at the
early endosomal stage whereas CD1b trafficks to phagolysosomes.
31. Hammond KJL, Poulton LD, Palmisano LJ, Silveira PA, Godfrey DI,
Baxter AG: Alpha/beta-T cell receptor (TCR)+CD4–CD8– (NKT)
thymocytes prevent insulin-dependent diabetes mellitus in
nonobese diabetic (NOD)/Lt mice by the influence of interleukin
(IL)-4 and/or IL-10. J Exp Med 1998, 187:1047-1056.
21. Prigozy T, Sieling P, Clemens D, Stewart P, Behar S, Porcelli SA,
Brenner MB, Modlin R, Kronenberg M: The mannose receptor
delivers lipoglycan antigens to endosomes for presentation to
T cells by CD1b molecules. Immunity 1997, 6:187-197.
22. Mukherjee S, Soe TT, Maxfield FR: Endocytic sorting of lipid
•
analogues differing solely in the chemistry of their hydrophobic
tails. J Cell Biol 1999, 144:1271-1284.
The authors use fluorescently labeled lipids to show that lipids with long, saturated tails are sorted to late endosomes; but lipids with shorter, saturated tails,
or those with unsaturated tails, are found mainly in the endocytic recycling compartment. This paper is important because it lends support to the idea that lipids
can be sorted differently on the basis of the nature of their hydrophobic tails.
23. Shamshiev A, Donda A, Prigozy T, Mori L, Chigorno V, Benedict CA,
•
Kappos L, Sonnino S, Kronenberg M, De Libero G: The T cell
response to self-glycolipids shows a novel mechanism of CD1b
loading and a requirement for complex oligosaccharides.
Immunity 2000, 13:255-264.
This paper argues against the conventional idea that CD1b loads antigens
in compartments with an acidic pH; this study demonstrates that CD1b can
bind glycosphingolipids on the cell surface at neutral pH. In addition, internalization and processing are not needed for recognition.
24. Benlagha K, Weiss A, Beavis A, Teyton L, Bendelac A: In vivo
identification of glycolipid antigen-specific T cells using
fluorescent CD1d tetramers. J Exp Med 2000, 191:1895-1903.
25. Sousa AO, Mazzaccaro RJ, Russell RG, Lee FK, Turner OC, Hong S,
Van Kaer L, Bloom BR: Relative contributions of distinct MHC class
I-dependent cell populations in protection to tuberculosis
infection in mice. Proc Natl Acad Sci USA 2000, 97:4204-4208.
26. D’Souza CD, Cooper AM, Frank AA, Ehlers S, Turner J, Bendelac A,
Orme IM: A novel nonclassic β2-microglobulin-restricted
mechanism influencing early lymphocyte accumulation and
subsequent resistance to tuberculosis in the lung. Am J Respir
Cell Mol Biol 2000, 23:188-193.
27.
•
Schofield L, McConville MJ, Hansen D, Campbell AS, Fraser-Reid B,
Grusby MJ, Tachado SD: CD1d-restricted immunoglobulin G
formation to GPI-anchored antigens mediated by NKT cells.
Science 1999, 283:225-229.
This paper implied that glycosyl phosphatidylinositol (GPI)-associated
antigens such as malarial circumsporozoite could be presented by CD1d to
30. Bendelac A, Rivera MN, Park SH, Roark JH: Mouse CD1-specific
NK1 T cells: development, specificity, and function. Annu Rev
Immunol 1997, 15:535-562.
32. Lehuen A, Lantz O, Beaudoin L, Laloux V, Carnaud C, Bendelac A,
Bach JF, Monteiro RC: Overexpression of natural killer T cells
α14– Jα
α281 transgenic nonobese diabetic mice against
protects Vα
diabetes. J Exp Med 1998, 188:1831-1839.
33. Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M,
Kawano T, Pelikan SB, Crowe NY, Godfrey DI: Differential tumor
surveillance by natural killer (NK) and NKT cells. J Exp Med 2000,
191:661-668.
34. Joyce S, Woods AS, Yewdell JW, Bennink JR, De Silva AD,
Boesteanu A, Balk SP, Cotter RJ, Brutkiewicz RR: Natural ligand of
mouse CD1d1: cellular glycosylphosphatidylinositol. Science
1998, 279:1541-1544.
35. Gumperz JE, Roy C, Makowska A, Lum D, Sugita M, Podrebarac T,
•
Koezuka Y, Porcelli SA, Cardell S, Brenner MB, Behar SM: Murine
CD1d-restricted T cell recognition of cellular lipids. Immunity 2000,
12:211-221.
This paper shows that purified phospholipids such as phosphatidylinositol
can be recognized by some NKT cell hybridomas. This is an important result
because it implies that normal lipid constituents of mammalian membranes
can be potential self-antigens presented by CD1d.
36. Rodinov DG, Nordeng TW, Pedersen K, Balk SP, Bakke O: A critical
tyrosine residue in the cytoplasmic tail is important for CD1d
internalization but not for its basolateral sorting in MDCK cells.
J Immunol 1999, 163:1488-1495.
37.
Brossay L, Tangri S, Bix M, Cardell S, Locksley R, Kronenberg M:
Mouse CD1-autoreactive T cells have diverse patterns of
reactivity to CD1+ targets. J Immunol 1998, 160:3681-3688.
38. Chiu Y-C, Jayawardena J, Weiss A, Lee D, Park S-H, Dautry-Varsat A,
•• Bendelac A: Distinct subsets of CD1d-restricted T cells recognize
self-antigens loaded in different cellular compartments. J Exp Med
1999, 189:103-110.
This paper is the first convincing demonstration of two different pathways of
antigen presentation for mouse CD1d. The authors show that antigen presentation to Vα14+ NKT cells requires endosomal targeting of CD1d
through a tyrosine-based motif in the cytoplasmic tail of CD1. Antigen presentation to a second subset of non-Vα14+ T cells does not require endosomal trafficking of CD1 and this subset possibly recognizes antigens
loaded in the secretory pathway.
39. Lee RE, Brennan PJ, Besra GS: Mycobacterium tuberculosis cell
envelope. Curr Top Microbiol Immunol 1996, 215:1-27.