Neurochem Res (2007) 32:257–262
DOI 10.1007/s11064-006-9145-4
REVIEW ARTICLE
Mini Review: Immune Response to Myelin-Derived Sulfatide
and CNS-Demyelination
Ramesh C. Halder Æ A. Jahng Æ I. Maricic Æ
Vipin Kumar
Accepted: 22 August 2006 / Published online: 28 September 2006

Springer Science+Business Media, LLC 2006
Abstract Here we briefly review our understanding of
the immune response to myelin-derived glycolipids
during an inflammatory autoimmune response in the
central nervous system (CNS). We focus primarily on
the recognition of the self-glycolipid sulfatide by a
distinct population of non-invariant NK T cells. The
results of studies we have obtained so far in investi-
gating the presentation of sulfatide by CNS-resident
cells including microglia and their interactions with
T cells indicate that this pathway might be successfully
targeted for the treatment of autoimmune demyelina-
tion in multiple sclerosis.
Keywords Myelin Æ Sulfatide Æ Central nervous
system Æ Demyelination Æ CD1 Æ Glycolipids Æ Microglia Æ
Multiple sclerosis Æ EAE
Special issue of the Journal dedicated to Drs. Anthony T.
Campagnoni and Celia W. Campagnoni.
It is a privilege to contribute an article for this special occasion. It
was highly rewarding for me to participate in the Journal Club
meetings at UCLA initiated by Tony in which experts in
Neurochemistry, Neurosciences and Immunology would discuss
and learn from each other with passion. I personally enjoyed and
benefited both from these meetings and especially from the
get-togethers at their lovely home overlooking the Santa Monica
hills. I will always treasure my association and friendship with
Tony and Celia.
R. C. Halder Æ A. Jahng Æ I. Maricic Æ V. Kumar (&)
Laboratory of Autoimmunity, Torrey Pines Institute for
Molecular Studies, 3550 General Atomics Court, San Diego,
CA 92121, USA
e-mail: vkumar@tpims.org
Introduction
While much attention has focused on the manipulation
of immune responses to myelin-derived proteins for
intervention in autoimmune demyelinating diseases,
little is known about immunity to myelin glycolipids. In
contrast to most membranes, 70–85% of the dry weight
of myelin is composed of lipids, while the remainder is
comprised of proteins such as myelin basic protein
(MBP), proteolipid protein (PLP), myelin oligoden-
drocyte glycoprotein (MOG), etc. Glycolipids such as
gangliosides and galactocerebrosides are the most
abundant component of myelin. One fifth of the total
myelin galactolipid occurs in the form of sulfatide
(3¢-sulfogalactosyl ceramide), in which the 3¢-OH moiety
on galactose is sulfated and the carbohydrate moiety is
attached to ceramide (Cer) in a b-linkage (see structure
in Fig. 1). Although anti-glycolipid, including anti-sul-
fatide, antibody responses have been shown to be pres-
ent in individuals with polyneuropathy syndromes as
well as multiple sclerosis (MS) [1–5], their role in these
disease processes is not known. It has also not been
shown whether, like proteins, myelin-derived glycoli-
pids can be recognized by T cells. Here we will briefly
review our work that relates to T cell recognition of
myelin-derived sulfatide and the manipulation of this
pathway to intervene in autoimmune demyelination.
Glycolipids in CNS-Demyelination
Multiple sclerosis is a demyelinating disease mediated
by a T cell-guided autoimmune response that is initi-
ated by antigen-presenting events either in the central
nervous system (CNS) or peripherally by a systemic
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Fig. 1 Chemical structure of
myelin-derived sulfatides
molecular mimicry response [6–8]. Experimental
autoimmune encephalomyelitis (EAE) is a prototypic
T cell-mediated autoimmune disease characterized by
inflammation and demyelination in the CNS accom-
panied by paralysis following immunization with
myelin antigens, for example MBP, MOG or PLP.
EAE shares many pathological and immune abnor-
malities with human MS [9]. Recently it has become
apparent that dysfunction of regulatory T cell popula-
tions, including CD25+CD4+ T cells, CD8 T cells, NK
cells, and NK T cells [10–13] is associated with the
clinical manifestation of autoimmunity.
In MS patients increased serum levels of glycolipids
[14, 15] and anti-glycolipid antibodies have been re-
ported [1–5]. Recently lipid microarrays have con-
firmed enhanced antibody response against sulfatide
and other myelin lipids in MS patients and their
potential to enhance experimental demyelination [16].
Furthermore, T cells reactive to glycolipids have been
isolated from active MS patients, where their fre-
quency has been shown to be threefold higher than in
normal individuals [17, 18]. Recently using human T
cell clones it has been demonstrated that the ganglio-
side GM1 binds well to CD1b, whereas sulfatide binds
promiscuously to all of the CD1 (a–d) molecules [17,
18; and Gennaro De Libero, University of Basel,
Switzerland, personal communication]. In chronic-active
MS lesions, CD1 molecules are up-regulated on mac-
rophages in areas of demyelination, but not in silent
lesions in the brain [19]. Together, these observations
open the possibility that myelin glycolipids may be
presented locally during inflammation in the CNS.
CD1-Restricted T Cells
T cells recognize lipid antigens bound in the context of
CD1 molecules, which are non-polymorphic, MHC
class I-like, and are associated with b2-microglobulin
[20, 21]. Generally, professional antigen-presenting
cells such as dendritic cells, macrophages, and subsets
of B cells express CD1 molecules. Five distinct CD1
genes (isotypes) are conserved among species and can
be categorized into two groups: group 1 includes CD1a,
CD1b, and CD1c, and is present in humans but not
mice; and group 2, the CD1d molecule, which is
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Neurochem Res (2007) 32:257–262
present in most species studied, including both mice
and humans and CD1e as an intermediate. The crystal
structure of the empty CD1d molecule reveals a deep
hydrophobic ligand-binding groove about 30 Å long by
10–15 Å wide, which is well suited for a stable, non-
specific binding of long fatty-acid chains [22].
T cells recognizing antigens presented by CD1d
molecules can be categorized into two groups. One of
the major murine groups expresses an invariant TCR
(iNK T) encoded by the germline TCR a chain (mouse
Va14-Ja18, human Va24-JaQ) and diverse mouse Vb8
or human Vb11 chains [23]. Second group of CD1d-re-
stricted T cells utilize non-invariant TCR (non-iNK T)
and are also referred type II NK T cells. Activation of
murine iNK T cells in vivo by the non-mammalian ligand
a-galactosyl ceramide (a-GalCer), a glycolipid initially
isolated from a marine sponge, promptly induces a cas-
cade of events resulting in the activation of both innate
and adaptive immune components, for example NK
cells, dendritic cells, T cells, and B cells [23]. A detailed
understanding of glycolipid recognition by T cells in
mice and humans has been obtained from the use of this
lipid a-GalCer. Unlike a-GalCer, most mammalian
glycolipids have the carbohydrate moiety attached in a
b-linkage. Only very recently a glycolipid iGB3 has been
described as a natural self-ligand for the CD1d-
restricted invariant Va14+ T cells [24]. Thus, we are only
just beginning to understand self-glycolipid recognition
as a legitimate component of the immune response.
To characterize self-glycolipid-recognition by T cells
we have focused on myelin in the nervous system
because (a) the CNS is rich in glycolipids that are formed
from a common precursor Cer that has a potential
CD1d-binding domain similar to the well-studied
a-GalCer; and (b) myelin is the target of an autoimmune
process during EAE, a model for human MS, in which
the influence of myelin-derived lipid-reactive T cells can
be easily studied.
Sulfatide is the Dominant CD1d-Dependent Myelin
Lipid Antigen for T Cells
We have examined the nature of the response to myelin-
glycolipids in mice and its dependence on the CD1d
antigen presentation pathway. NK T cells proliferate
Neurochem Res (2007) 32:257–262
and produce both IFN-r and IL-4 in response to sulfatide
and gangliosides in a similar fashion to a-GalCer [12].
The response to sulfatide in CD1d-deficient mice is ab-
sent, indicating that presentation is CD1d-dependent.
The immune response to other myelin-glycolipids with
similar hydrocarbon chains and a potential capacity to
bind to CD1d molecules, such as b-galactosyl ceramide
(b-GalCer), sphingomyelin and GM1, is not detected in
naı̈ve animals. These studies indicate that sulfatide is an
immunodominant glycolipid present in myelin. Since
brain-derived sulfatide is a mixture of several molecular
species varying mostly in acyl chain lengths we have used
synthetic sulfatide analogs to further define the CD1d-
dependent recognition of individual sulfatides. We have
found that cis-tetracosenoyl form (C24:1) with a 24
carbon acyl chain carrying one unsaturation at the 8–9
position, is the immunodominant species of sulfatide for
CD1d-restricted T cells in BL/6 and SJL/J mice [25]. The
crystal structure of the CD1d-cis-tetracosenoyl sulfatide
complex at 1.9 Å reveals that the longer cis-tetracose-
noyl fatty acid chain fully occupies the A’ pocket of the
CD1d-binding groove, whereas sphingosine fills the F’
pocket. The 3¢-sulfatide galactose headgroup projects up
and away from the binding pocket and is exposed for
interaction with the TCR.
Sulfatide-CD1d-Tetramers and the Identification
of Sulfatide-Reactive Non-Invariant NK T Cells
Tetrameric CD1d molecules loaded with a-GalCer have
been utilized to define and monitor iNK T cells in both
mice and in humans [26]. We have used sulfatide-loaded
CD1d tetramers to precisely define the cell population
responsible for the proliferative and cytokine response
to sulfatide [12]. Sulfatide-reactive T cells are TCRab+,
predominantly CD4+, and comprise 4–6% of the total
mononuclear cells in liver, 0.5% in thymus and around
0.3% in spleen. In the liver and spleen most of the sul-
fatide-tetramer+ population are NK1.1+, and they are
non-overlapping with iNK T cells. These cells use a
variable or non-iNK T and are present in mice deficient
in the Ja18 gene that lack iNK T cells [12].
Sulfatide-Reactive T Cells are Enriched in the CNS
During EAE
During the course of EAE the integrity of the myelin
sheath is disrupted by infiltrating T cells and by other
inflammatory cells such as macrophages. The disrup-
tion of myelin and its subsequent phagocytosis by local
259
phagocytic cells such as microglia and macrophages
leads to the intriguing possibility that myelin lipids
might be presented to T cells by CD1 molecules
locally, at sites of inflammation. While the process of
demyelination and the autoreactivity to myelin pro-
teins by MHC II presentation has been well docu-
mented, it is unknown whether myelin lipids are in fact
presented by CD1d in the CNS and whether this
pathway might have a pathogenic or a regulatory role
during EAE. We have found that sulfatide-reactive T
cells constitute 3–4% of the infiltrating T cell popula-
tion in the CNS of diseased mice, whereas iNK T cells
constitute a minor part (0.6–0.9%) [12]. This is in
contrast to the peripheral organs of both normal and
diseased animals, where iNKT cells exceed sulfatide-
reactive T cells by a factor of 5. Sulfatide-CD1d-
tetramer+ T cells cannot be detected in the CNS of
naı̈ve mice or animals which have been immunized for
disease but display no clinical signs of EAE.
Sulfatide Administration can Prevent Induction
of EAE and Reverse Ongoing EAE
Activation of invariant NK T cells by a-GalCer can
either ameliorate or exacerbate the course of myelin
protein-induced-EAE in various animal models
depending upon the timing and the context (presence
or absence of adjuvant) of a-GalCer injection [11]. iNK
T-cell mediated protection correlates with the immune
deviation of pathogenic T cells and is dependent upon
the Th2 cytokines IL-4 and IL-10. We have found that
adjuvant-free injection (i.p.) of sulfatide (20 lg per
mouse) at the time of myelin-protein immunization
completely protects mice from EAE. This is dependent
upon the presence of CD1d-restricted T cells, as mice
deficient in CD1d are not protected. Furthermore,
protection is not dependent upon immune deviation, as
in the case of a-GalCer, but rather on inhibition of
pathogenic T cell effector function [12]. In contrast
administration of sulfatide emulsified with a strong
adjuvant such as complete Freund’s adjuvant does not
inhibit pathogenic T cells and fails to prevent antigen-
induced EAE [16]. We have recently examined whe-
ther sulfatide can modify ongoing EAE in SJL/J mice
and have found that sulfatide injected i.p. after onset is
in fact able to reverse ongoing disease (I. Maricic et al.
manuscript in preparation). In contrast a-GalCer
injection is unable to ameliorate ongoing EAE. These
data suggest that sulfatide-reactive non-iNK T cells
represent a more relevant target for attempting to
modify the course of autoimmune demyelination than
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iNK T cells. We are currently examining the possibility
that local interaction between sulfatide-reactive T cells
within the CNS and microglial presentation of sulfatide
is critical for the effective amelioration of EAE.
CD1d Expression by Microglia/Macrophages
The CD1d antigen presentation of a-GalCer has been
well documented for dendritic cells, macrophages, B
cells and thymocytes [23]. Although CNS tissue con-
tains self-glycolipid antigens that could be presented by
CD1 molecules, especially during local inflammation,
very little is known about CD1d expression on CNS-
resident cells or their ability to present myelin lipids to
T cells. Only a few studies have suggested the expres-
sion of CD1 molecules in the CNS. Immunohisto-
chemistry as well as PCR-based analysis have been
used to show CD1b and CD1d expression in cells in
chronic active lesions in MS, but not in silent lesions
[19, 27]. This suggests that activated microglia and
macrophages in MS lesions might be capable of
engulfing myelin debris and subsequently presenting its
component lipids to T cells. Indeed glycolipids
including sulfatide have been shown to be recognized
by CD1-restricted T cells in normal individuals and at
elevated levels in MS patients [17, 18]. It is likely that
lipid-transfer proteins, such as apolipoprotein E
(apoE) plays an important role in the transfer of sulf-
atides from oligodendrocytes to microglia and thus
facilitating presentation of myelin glycolipids in the
context of CD1d (see Fig. 2).
Microglia are strategically located in the CNS and
are present in the inflammatory lesions of MS and
EAE [28–30]. They function as CNS-resident antigen
presenting cells (APC) and have a significant impact on
the outcome of the immune response, particularly in
CNS-repair following tissue damage [30–32]. Microglia
also have been shown to have a surveillance function in
normal brain and hence been termed ‘‘vigilant house-
keepers‘‘ [33]. Given the elevated levels of anti-glyco-
lipid antibodies during CNS-inflammation and in EAE,
it seems likely that the myelin glycolipid-presentation
pathway of CNS-resident antigen-presenting cells is
active. A genetic polymorphism expressed in the
microglia of two rat strains with a differing suscepti-
bility to EAE has now been mapped in humans and
appears to correlate with the level of expression of a
promoter of the MHC class II transactivator in MS
patients [34, 35]. Additionally, CNS-inflammation
and EAE have been shown to be reversed using
drugs antagonizing important microglial functions,
such as hydroxy-methyl-glutaryl coenzyme A reductase
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Neurochem Res (2007) 32:257–262
ApoE
Oligodendrocyte
Microglia
CNS
Sulfatide-reactive
Non-iNKT Periphery
TCR
CD1d
Dendritic Sulfatide
Cell
Fig. 2 Activation of sulfatide-reactive NK T cells in peripheral
lymphoid organs and in the CNS. A hypothetical model
depicting presentation of sulfatide by CD1d-expressing dendritic
cells and the CNS-resident microglia to non-invariant NK T cells
is shown. Sulfatide or other myelin lipids can be acquired by
microglia from oligodendrocytes by lipid-transfer-proteins, such
as apolipoprotein E (apoE). These activation pathways of non-
iNK T cells can be targeted for immune intervention in
autoimmune demyelinating diseases
inhibitors (atorvastatin) and agonists of peroxysome
proliferator-activated receptor alpha (gemfibrozil) [36,
37]. These data suggest that antigen-presentation by
microglia can affect the course of demyelination.
As mentioned, we have found that sulfatide-reac-
tive T cells infiltrate into the CNS during the normal
course of EAE. To examine the possibility of sul-
fatide presentation within the CNS, we have analyzed
the expression of CD1d on microglia-enriched
mononuclear cells from diseased mice at different
times during the course of EAE. While both micro-
glia and macrophage/DC populations express a low
level of CD1d before onset, CD1d is significantly up-
regulated during the peak of disease before returning
to lower levels during remission. Our preliminary
experiments have shown that a microglia-enriched
population is capable of presenting glycolipids to T
cells in in vitro assays. The ability of sulfatide to
inhibit EAE may also relate to the fact that CD1d
on CNS-resident microglia is down-regulated in sul-
fatide treated mice (R. C. Halder et al., manuscript
in preparation).
Summary and Future Directions
It is clear that not only the anti-sulfatide antibody
response but also anti-sulfatide T cell responses are
Neurochem Res (2007) 32:257–262
present in both healthy individuals and in MS
patients, but are augmented in the latter. Sulfatide is
recognized in the context of CD1d in both mice and
humans by a specialized subset of NK T cells. Our
preliminary data further suggest that sulfatide is also
presented by CNS-resident APCs to activate these T
cells during demyelination and that this pathway can
be targeted for intervention in EAE (see Fig. 2). We
intend to use sulfatide human CD1d tetramer staining
to analyze human peripheral lymphocytes for the
presence of sulfatide-reactive T cells in normal indi-
viduals and in MS patients. These studies will be
important not only for understanding the biology of
CD1d expression and presentation of sulfatide by
CNS-resident APCs, but also because the macro-
phage/microglial presentation pathway of sulfatide
could provide a practical target for manipulating the
autoimmune response in humans. Since CD1 mole-
cules, unlike the classical MHC molecules, are
non-polymorphic, insight into the role of sulfatide-
presentation by microglia and their interaction with a
unique CD1d-restricted T cell population in the CNS
will be extremely valuable in the development of non-
HLA-dependent therapeutic approaches for autoim-
mune demyelinating diseases in humans.
Acknowledgements This work was supported by grants from
the National Institutes of Health (VK) and from the Multiple
Sclerosis National Research Institute (VK). Authors would like
to thank our lab colleagues, Drs. Randle Ware and Trevor Smith
for a critical reading of the manuscript.
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