Neuroscience & Medicine, 2012, 3, 203-224
http://dx.doi.org/10.4236/nm.2012.33026 Published Online September 2012 (http://www.SciRP.org/journal/nm)
203
Initiation and Regulation of CNS Autoimmunity: Balancing
Immune Surveillance and Inflammation in the CNS
Melissa G. Harris1,2, Zsuzsanna Fabry1
1Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, USA;
2Neuroscience Training Program, School of Medicine and Public Health, University of Wisconsin, Madison, USA.
Received June 7th, 2012; revised July 4th, 2012; accepted July 15th, 2012
ABSTRACT
While the central nervous system (CNS) was once thought to be immune privileged, more recent data support that cer-
tain areas of the healthy CNS are routinely patrolled by immune cells. Further, antigen drainage is another means by
which the adaptive arm of the immune system can gain information about the health of the CNS. Altogether these en-
sure that the CNS is not beyond the scope of immune protection against viruses and tumors. However, immune surveil-
lance in the CNS has to be tightly regulated, as CNS autoimmune disease and inflammation may arise from increased
immune cell infiltration. In this review we discuss the concept and implications of CNS immune surveillance and in-
troduce the CNS antigen-presenting cells (APCs) that potentially regulate neuroinflammation and autoimmunity. We
also discuss novel animal models in which CNS disease initiation and the role of APCs in disease regulation can be
tested.
Keywords: CNS; Immune Surveillance, Autoimmunity; APCs; DCs; Oligodendrocyte Death; DAMPs; Initiation;
Regulation
1. Introduction
The immune system has evolved to help the body fight
foreign pathogens and harmful self-intruders, such as
tumors. Immunity requires continual surveillance of the
body by immune cells, primarily tissue-resident macro-
phages and dendritic cells (DCs), which initiate inflam-
matory responses that result in the recruitment of T cells
and other leukocytes to the site of infection or damage.
This process is highly restricted in the healthy central
nervous system (CNS) due to several regulatory factors
that preclude the infiltration of activated T cells from the
blood into the CNS parenchyma, thus contributing to the
immune privileged status of the CNS. In spite of this
regulation, it has been shown that limited surveillance by
T cells still promotes the health of this tissue. However,
increased immunological surveillance and immune cell
infiltration into the CNS may lead to inflammation and
autoimmune disease [1,2]. One idea is that immune cells,
particularly DCs, which accumulate in the CNS under in-
flammatory conditions may pick up and deliver myelin
antigens to lymph nodes for the priming of adaptive im-
mune responses. This process could lead to the initiation
or exacerbation of CNS autoimmune disease. Thus, an
understanding of how adaptive immunity is generated
against CNS self-antigens and how it is regulated is nec-
essary for treating diseases such as multiple sclerosis
(MS). In this review we will focus on T cell-mediated
adaptive immunity and will discuss conceptual changes
in our understanding of CNS surveillance and the role of
CNS antigen-presenting cells (APCs) in regulating adap-
tive immunity in the CNS. We will further discuss cur-
rent models of CNS autoimmune disease initiation, and
consider the potential contribution of damage-associated
molecules to the exacerbation of CNS autoimmunity.
2. CNS Immunity: Balancing Surveillance
and Autoimmunity
The CNS has historically been considered immune privi-
leged. It was originally thought that antigens within the
CNS parenchyma went unnoticed by circulating immune
cells, mainly because the blood-brain barrier (BBB) kept
them out (reviewed in [3]). This was thought to explain
how foreign tissue grafts could survive in the CNS for
long periods of time. It is now generally accepted that
immune privilege is only afforded to the parenchyma,
and not to the cerebrospinal fluid (CSF)-exposed parts of
the CNS (i.e., leptomeninges, choroid plexus, circum-
ventricular organs, and ventricles) [3]. The developed
BBB (referred to as the neurovascular unit, or NVU)
consists of not only vascular endothelial cells, but also

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS
204
the basement membrane of these cells and that of the
astrocytic endfeet (i.e., the glia limitans), which delineate
the CSF-filled perivascular space (PVS) that drains into
the leptomeningeal subarachnoid space (SAS; Figure 1)
(reviewed in [4]). Additionally, pericytes of the PVS, as
well as neurons and extracellular matrix, are all part of
the NVU (reviewed in [5]). Important to our discussion,
the SAS is an active immunological niche that is crucial
in the development and maintenance of CNS autoim-
mune disease.
Under homeostatic conditions T lymphocytes are re-
stricted in their capacity to cross endothelial cells of the
quiescent parenchymal BBB. However, activated T cells
may cross into the SAS by binding adhesion molecules
(namely, P-selectin via PSGL-1, but also ICAM-1) and
cytokines (e.g., CCL20 via CCR6) constitutively ex-
pressed by endothelial cells of the meningeal BBB or
epithelial cells of the choroid plexus, which form the
blood-cerebrospinal fluid barrier (BCSFB; [6]; reviewed
in [4,7]). Thus, activated T cells present in normal CSF
and stroma of the choroid plexus and meninges are
thought to carry out routine immune surveillance in the
SAS [6,8], which is rich in CNS antigens that drain into
the CSF from interstitial fluid. This process is vital to the
health of the CNS, as clinical reports have described pa-
tients developing opportunistic viral infections in the
CNS and subsequent progressive multifocal leukoen-
cephalopathy when T cell transmigration is inhibited
[9-11]. Of further clinical relevance, the SAS is believed
to be the initial site of CCR6-mediated entry by patho-
genic Th17 cells [12], which regulate the initiation of
experimental autoimmune encephalomyelitis (EAE), the
animal model of MS [13]. Interestingly, Th17 cells also
mediate the formation of ectopic lymphoid follicles
(eLFs) [14], which have been observed in the meninges
of both mice with EAE [14,15] and patients with secon-
dary (chronic) progressive MS [16,17]. These structures
(discussed later) are thought to be important for main-
taining chronic inflammation and may be key determi-
nants for relapse and progression in the case of CNS
autoimmune disease [17].
While it now seems clear that the CNS is immu-
nologically monitored by activated T cells, which can be
beneficial, the question remains: how do they become
activated in the first place? With the exception of the
CNS, every tissue in the body is connected to a complex
network of lymphatic vessels. One of the key functions
of this lymphatic system is to allow for drainage/homing
of both soluble antigen and antigen-bearing cells (espe-
cially DCs) to peripheral lymphoid tissues to engage the
Figure 1. Anatomical locations supporting immune cell surveillance and entry into the CNS. Routine immune surveillance of
the CNS is thought to occur by activated memory T cells in the subarachnoid space (SAS) of the leptomeninges, which is
comprised of the arachnoid mater and the pia mater (left picture). These T cells may enter into the CSF-filled SAS either
from postcapillary venules of the leptomeninges or across the epithelial cells of the choroid plexus, which form the
blood-cerebrospinal fluid barrier (not shown). Together with neurons, the neurovascular unit (right picture) is comprised of
the endothelial cells of the blood-brain barrier (BBB) and their underlying basement membrane, the perivascular space
(PVS), and the basement membrane of the astrocytic endfeet forming the glia limitans. In the presence of neural inflamma-
tion, activated T cells may cross the endothelial cells of the BBB into the PVS, presumably where they are re-primed by cog-
nate antigen-bearing APCs that allow them to enter the CNS parenchyma.

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS 205
adaptive immune system. However, without draining
lymphatics, how do antigens that are sequestered behind
the BBB generate peripheral T cell responses? In the
context of infection, it was proposed that bacterial or
viral pathogens are allowed to persist in the CNS paren-
chyma without eliciting adaptive immune responses,
which can only be generated following peripheral subcu-
taneous challenge with certain viruses [18-21]. In con-
trast, it is not known how normal, non-pathogenic CNS
self-antigens (such as those from myelin) might drain
and become the targets of autoimmune attack, despite the
apparent immune privilege afforded to CNS pathogens.
One possible explanation is that autoreactive T cell re-
sponses might develop following delayed-type hypersen-
sitivity response to CNS infection, due to generation of
new antigens created by bystander myelin damage [19].
However, in the absence of infection, it is hard to under-
stand how this might occur.
The traditional method used to study soluble antigen
drainage from the CNS has been intracerebral antigen
injection. Using this technique, it was established that,
despite the CNS not having conventional lymphatics,
protein antigens injected intracerebrally into different
parenchymal regions (i.e., caudate nucleus, internal cap-
sule, and midbrain) and into CSF could be largely recov-
ered in the cervical lymph nodes (CLNs) [22,23]. As
reviewed by Cserr and Knopf [22], antigens may drain
from the CNS into the blood by exiting the SAS through
the arachnoid villi, which protrude into the dural sinus.
The second exit is along the cranial nerves, in particular,
along the olfactory pathway and nasal lymphatics to the
CLNs [22]. To support the functional significance of this
drainage process, it was shown that protein antigens that
drain to the periphery are capable of eliciting adaptive
immune responses [24,25], and may even be more im-
munogenic (as reflected in higher antibody titers) than
the same antigens introduced peripherally [24]. We have
also shown that both soluble and cell-bound intracere-
brally injected antigens drain to the CLNs, and this is
followed by the preferential recruitment of primed re-
sponder T cells to the CNS [26-29]. This accumulation of
effector T cells in the CNS may be important because it
has the potential to initiate and/or exacerbate autoim-
mune disease.
The technique of intracerebral antigen injection is a
relatively easy and straightforward procedure in which
antigen can be stereotaxically injected into desired loca-
tions of the brain. It is also fairly quantitative, giving the
investigator control over the concentration of antigen or
number of antigen-pulsed cells introduced. We previ-
ously reported a titration effect, in which the number of
antigen-pulsed dendritic cells (DCs) injected into the
brain positively correlated with their accumulation in the
CLNs, as well as with the numbers of activated antigen-
specific T cells recruited to the brain [26]. However, it is
difficult to control for blood-brain barrier disruption, as
minor tissue trauma from the needle injection may lead
to inadvertent but minor immune cell activation and re-
cruitment to the CNS [22]. Another limitation of this
technique is that it disconnects antigen release and cellu-
lar signals associated with cell death (i.e., damage-asso-
ciated molecular patterns, or DAMPs), thereby preclude-
ing study of the potentially immunogenic role of DAMPs
in priming CNS antigen-specific adaptive immune re-
sponses.
To overcome the above listed limitations, newer mod-
els have more recently been created to test the critical
questions of how CNS cell-specific neoantigens are rec-
ognized by the peripheral immune system, and how this
recognition leads to CNS pathology. Notably, neural
cell-specific neoantigen models have been created in
which expression of immunogenic antigens is restricted
to neurons [30,31], astrocytes [32], oligodendrocytes
(ODCs) [33,34], and both ODCs and Schwann cells [35],
and is achieved either by using Cre driver transgenic
mouse lines or by having the neoantigens under direct
neural cell-specific promoter control. These models are
being used to understand mechanisms of immune toler-
ance and reactivity to CNS antigens, the findings of
which are summarized in Table 1. We created mice with
myelinating glial cell-specific expression of major histo-
compatibility complex (MHC) class I- and MHC class
II-restricted ovalbumin neoepitopes in order to study the
mechanism of myelinating cell-specific antigen recogni-
tion by immune cells and requirements for antigen-spe-
cific CD4+ or CD8+ T cell infiltration in the CNS under
normal and inflammatory conditions. Our findings sug-
gest that myelinating cell-specific neoantigen expression
itself is not sufficient to induce neoantigen-specific T cell
accumulation into the CNS. Other signals induced by
neuroinflammation are required for the accumulation of
neoantigen-specific CD8+ T cells in the CNS. We also
found that ovalbumin neoantigen-specific CD8+ T cells
exacerbate myelin oligodendrocyte glycoprotein (MOG)-
induced inflammation in EAE (manuscript in prepara-
tion). This supports the overall hypothesis that increased
T cell surveillance could contribute to the initiation and
maintenance of CNS autoimmunity.
3. Antigen-Presenting C e l l s i n t h e C N S :
Locations, Function, and Subtypes
As discussed above, activated T cells routinely survey
the SAS of the healthy CNS, yet how and where
CNS-infiltrating T cells are initially primed in humans
and the conditions under which this leads to autoimmu-
nity are unknown. Once primed, however, these T cells
must then re-encounter their antigen in the appropriate

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS
206
Table 1. Neural cell-specific neoantige n mode ls.
Cell type Promoter or
Cre driver line
Neoantigen or
Neoantigen/Lox
line
Neoantigen
localization
(and/or site of
normal protein
expression
[Ref])
Major Finding Additional comments Reference
(s)
ODCs MOGi-Cre
Influenza
hemagglutinin
(Rosa26tm(HA)1Lib1
mice)
unspecified
(myelin sheath
[34])
ODC-targeted attack by
pre-activated
neoantigen-specific CTLs
and neurological disease
Ignorance of neoantigen by
neoantigen-specific CD8+ T
cells in Lox/Cre x CL4-TCR
mice
[34,37]
ODCs MBP
floxed ovalbumin
(ODC-OVA mice)
cytosolic
(cytoplasmic
side of
membrane [38])
Neoantigen-specific CD8+ T
cells induce ODC death and
neurological disease in
ODC-OVA x OT-I mice
Ignorance of neoantigen by
neoantigen-specific
CD4+ T cells in ODC-OVA x
OT-II mice
[33,39]
ODCs/Schwann
cells
PLP-CreERT2
(inducible)
LCMV- and
β-gal-derived CD8+
T cell neoepitopes
(ST33.396 mice)
Unspecified
(myelin sheath
[40])
Endogenous CD8+ T cell
tolerance to neoantigens
induced by DCs
- [35,41]
astrocytes and
enteric glial cells GFAP influenza hemagglutinin cytoplasm [42]
Neoantigen-specific CD4+ T
cell ignorance in GFAP-HA
x HNT-TCR mice
- [32]
neurons NSE ovalbumin
cell
surface/
membrane [43]
intracerebral infection with
Listeria monocyto-
genes-ovalbumin induces
neurological disease, medi-
ated by
SIINFEKL-specific CD8+ T
cells
No endogenous OVA323-339
CD4+ response [30]
neurons CamK-iCre
influenza
hemagglutinin
(Rosa26tm(HA)1Lib1
mice)
unspecified
(cytosolic or
anchored to
cytoskeleton,
depending on
isoform [44])
transient encephalomyelitis
but development of chronic
diabetes
insipidus due to
destruction of
hypothalamic neurons by
neoantigen-specific CTLs
- [31,45]
ODCs = oligodendrocytes; MOG = myelin oligodendrocyte glycoprotein; MBP = myelin basic protein; PLP = proteolipid protein; GFAP = glial fibrillary acidic
protein; NSE = neuron-specific enolase promoter; CamK = calcium/calmodulin-dependent kinase; CTL = cytotoxic T lymphocyte; TCR = T cell receptor; HA
= hemagglutinin.
MHC context by a functional (and as yet uncharacterized)
APC before entering the CNS parenchyma and initiating
disease [7,46]. Naïve T cells that might indiscriminately
enter the CNS once inflammation is established also re-
quire antigen in order to become activated in situ in the
CNS [47]. It was proposed that this process is limited in
the healthy CNS, however, as there is no clear evidence
that DCs, the only cells capable of activating naïve T
cells, are present in the healthy CNS parenchyma in de-
tectable numbers [3]. However, cells that carry common
features of DCs, such as OX62 [48,49], MHC class II,
and the integrin alpha X molecule CD11c [8,50], have
been shown in the healthy rodent meninges and choroid
plexus. These meningeal/choroid plexus APCs might
represent a unique subpopulation of DCs that can con-
tribute to the development and regulation of CNS auto-
immunity. Additionally, DCs do accumulate in the in-
flamed CNS [48,51-53], indicating that these cells are
important for the maintenance of chronic inflammation in
these tissues.
In this section we focus on microglia, astrocytes, and
DCs as in situ CNS APC candidates, potentially capable
of regulating the initiation of neuroinflammation. Things
to consider in evaluation of their APC candidacy are 1)
how efficiently they activate T cells through upregulation
of co-stimulatory molecules (in particular, CD40, CD80

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS 207
(B7-1), CD86 (B7-2), and ICAM-1) and also MHC class
I and II; and 2) their ability to process and present CNS
self-antigen. As CD8+ T cells are the dominant subset of
inflammatory infiltrates observed in MS lesions [54], the
ability of the candidate APCs to cross-present exoge-
nously-derived antigen to CD8+ T cells will also be
given special consideration apart from activation of
CD4+ T cells, which govern EAE pathology. Addition-
ally, CNS-associated macrophages (found in the choroid
plexus, meninges, and perivascular space), as well as
endothelial cells and pericytes, may also be involved in
antigen presentation and disease pathology [55-60], but
they will not be discussed here.
3.1. Microglia: Providers of Neuronal Support
and Parenchymal Surveillance
The “oldest” APCs that were proposed to contribute to
CNS immunity were the microglia and were first de-
scribed by Pio del Rio-Hortega (reviewed in [61]). Mi-
croglia are abundant everywhere in the CNS [61] and are
considered CNS-resident macrophages that arise from a
primitive myeloid progenitor population in the extra-
embryonic yolk sac that enters the embryonic brain as
blood vessels begin to develop (E9.5) [62]. The different-
tiation of the shared common myeloid progenitor into the
granulocyte-monocyte progenitor (which further differ-
entiates into monocytes, DCs, and macrophages) takes
place during another developmental wave in the fetal
liver (“definitive hematopoiesis”), and eventually occurs
in the bone marrow (reviewed in [63]). Additionally,
microglia can renew in situ without contribution from
circulating hematopoietic cells [62]. While microglia are
known phagocytes of cellular material in health and dis-
ease [64], one of their primary functions in the healthy
CNS is to maintain neuronal synapses, which is in part
reflected by their ramified (non-macrophage-like) mor-
phology [65]. Likewise, they are under tight regulatory
control by active neurons (reviewed in [66,67]). However,
and of relevance in terms of innate immunity, microglia
also provide routine and active surveillance of the nerv-
ous tissue and are thus immediate responders to danger.
Their production of chemokines and proinflammatory
cytokines allows for the recruitment and entry of immune
cells from the periphery [66].
In terms of their antigen-presenting capacity, resting
microglia (i.e., CD11b+ CD45low) express very low levels
of MHC class I and II and the costimulatory molecules
CD40, CD80, CD86, and ICAM-1, making them less
efficient at priming naïve T cells compared to DCs [68].
This was demonstrated in earlier in vitro experiments, in
which resting microglia isolated from neonatal mouse
brains required signaling through B7/CD28 (endowed by
the addition of IFN-
 and granulocyte-macrophage col-
ony-stiumulating factor, GM-CSF) and CD40/CD40L
in order to serve as more efficient “professional” APCs
[69]. In contrast, peripheral DCs were demonstrated to be
much more efficient APCs than activated microglia in
their ability to prime naïve T cells; however, microglia
were just as effective as DCs in their ability to prime
helper T (Th) cell lines [70]. In vivo, microglia have a
relatively limited capacity to “pick up” and present anti-
gens to naïve T cells infiltrating the inflamed CNS. Re-
sults from S. Miller’s group show that microglia isolated
from the CNS of mice with relapsing-EAE (R-EAE) re-
main relatively poor stimulators of naïve proteolipid
protein PLP139-151-specific CD4+ T cells ex vivo, and only
become strong stimulators upon addition of exogenous
antigen at a very high APC:T cell ratio (1:1) [71]. How-
ever, they could stimulate CD4+ T cell lines much more
efficiently. Recently, microglia isolated from the brain of
naïve adult wild type mice have also been shown to be
capable of TAP-dependent cross-presentation of soluble
antigen in vitro and also intracerebrally injected antigen
ex vivo to naïve CD8+ T cells and T cell lines [72]. This
ability was enhanced in microglia when stimulated with
GM-CSF or CpG oligodeoxynucleotide. However, these
results were obtained using very high concentrations of
antigen (100 - 200 M in vitro) at a very high APC:T
cell ratio (2:1), and likely do not reflect how much anti-
gen is normally taken up in vivo, which (as the data in
[71] suggests) is probably very little. Additionally, in all
of these studies it is difficult to compare the efficiency
with which microglia can stimulate effector T cell line-
ages that develop in vivo with their ability to stimulate T
cell lines in vitro, since T cell lines require very minimal
stimulation in order to become activated.
While activated microglia (i.e., CD11b+ CD45high)
characterize most neuroinflammatory diseases, their ac-
tual contribution to CNS injury or protection is contro-
versial. In response to neuroinflammation, activated mi-
croglia can upregulate all of the co-stimulatory molecules
needed for facilitating adaptive immune responses in the
CNS, which have been found in human MS tissue ([73],
and the references therein). Prior to the manifestation of
EAE clinical symptoms, microglia activation and prolif-
eration have been noted [74], and temporally coincide
with the entry of IL-17- and IFN-
 -producing T cells into
the brain [75]. At this time microglia also start to up-
regulate MHC class II, CD40, CD80, and CD86 mole-
cules, suggesting that their primary role in this early
phase is to re-activate entering T cells or to prime naïve
T cells indiscriminately entering the inflamed CNS [75].
Indeed, EAE was greatly attenuated in ganciclovir (GCV)-
treated bone marrow chimeric CD11b-HSVTK mice (i.e.,
having CD11b promoter-driven, GCV-responsive herpes
simplex virus thymidine kinase), which have paralyzed
microglia but otherwise functional CD11b-expressing
monocytic/macrophage cells [76]. Additionally, there were

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS
208
fewer lymphocytes in the CNS of these mice. These
studies illustrate that microglia contribute to the devel-
opment of CNS autoimmune disease. However, micro-
glia have also been shown to have suppressive functions,
as in vitro activated microglia presenting the immuno-
genic myelin basic protein (MBP) Ac1-11 peptide have
been shown to induce T cell anergy and death [69,77].
This tolerogenic outcome (as opposed to T cell activation)
in vivo would depend on both T cell avidity for self-an-
tigen (i.e., the number of peptide/MHC complexes, as
well as the affinity of the T cell receptor for the pep-
tide/MHC complex), which may increase under neuroin-
flammatory conditions [7], and also the local cytokine
milieu, which influences the activation level of APCs in
the CNS. Undoubtedly, the function of microglia needs
to be further studied, as these cells might be important in
both the induction and regulation of CNS autoimmunity.
Cytokines have been shown to exert a strong influence
on the phenotype acquired by peripheral monocyte-de-
rived macrophages, which have been classified as either
classically activated (pro-inflammatory M1; polarized by
lipopolysaccharide and IFN-
 ) or alternatively activated
(anti-inflammatory M2; polarized by IL-4, IL-10, IL-13,
and TGF-
 ) (reviewed in [78], and the references
therein). These phenotypes may apply to microglia as
well; however, this has not been demonstrated in vivo. It
was shown that microglia with a constitutive IL-4-driven
alternatively activated (M2-like) phenotype are actively
involved with suppression of neuroinflammation, as EAE
is very severe in bone marrow chimeric mice that lack
IL-4 cytokine in the CNS compared to control chimeric
mice [79]. Interestingly, M2 macrophages can be re-po-
larized to an M1 phenotype in vivo at the site of injury in
a spinal cord injury model [80], suggesting that factors
within the lesion itself contributed to macrophage phe-
notype polarization with corresponding pro- or anti-in-
flammatory function. Additionally, regional differences
in local microenvironmental factors may influence macro-
phage phenotype within the same lesion (or between le-
sions). This is supported by immunostaining of CNS tis-
sue from MS patients, which showed higher numbers of
macrophage/microglia with a more M2-like phenotype
(characterized by expression of CD163) within acute
active lesions and on the edge of chronic active lesions,
i.e., sites of active inflammation, than in the center of
chronic active lesions [81]. These cells also expressed
MHC class II and stained positive for myelin, indicating
that they had the capacity to present myelin antigen to T
cells and perhaps could induce a regulatory T cell re-
sponse. Collectively, these results suggest that the type of
adaptive response that is promoted by microglia is, in
part, determined by local microenvironmental cues.
New data cast doubt on the role of microglia in
chronic disease progression. Using an elegant parabiosis
technique combined with irradiation, in which blood cir-
culation from one mouse is allowed to naturally enter the
blood circulation of the irradiated partner, Ajami et al.
recently demonstrated that while activated microglia are
present at EAE disease onset, it is the monocytes that are
recruited to the CNS from the blood after this initial
phase that are required for disease progression [82]. In-
stead, at this late stage, microglia may be more involved
with tissue repair or inhibiting further T cell activation. A
recent study examined the CNS expression profiles of
various co-stimulatory signals required for T cell activa-
tion during the different phases of EAE [83]. The authors
found that B7.2 expression on non-ramified cells during
the inductive and peak phases of EAE was largely re-
stricted to areas around blood vessels, whereas ramified
B7.2+ microglia were found in increasing numbers dur-
ing the recovery phase in the perivascular areas and
somewhat in the parenchyma. Additionally, they found
an accumulation of CTLA-4+ cells near the blood vessels
in the recovery phase of EAE. These results suggest that
T cells entering the parenchyma during EAE may be in-
duced to undergo anergy, as there is very little
co-stimulatory B7.2 expression in this area at this time.
At later phases, microglia may induce inhibition in ef-
fector cells entering from the blood vessels through
CTLA-4 signaling, which has been shown to negatively
regulate T cells (reviewed in [84]). Therefore, microglia
might play a dual role in inhibiting lymphocytes and
promoting tolerance during CNS autoimmune disease.
3.2. Astrocytes: Not Antigen-Presenting Cells in
Vivo but Contributors to BBB Integrity
Astrocytes are one of the two types of CNS-resident
macroglia (the other being the oligodendrocytes) and
arise from the neuroectoderm during embryonic devel-
opment. They have many roles—chief among them is
facilitating neuronal synaptic transmission by removing
and recycling excess neurotransmitters from the ex-
tracellular space [85]. Their communication with active
neurons and close connection with blood vessels pene-
trating the CNS parenchyma also allows them to regulate
blood flow by signaling to smooth muscle cells within
the vessel walls [86]. Unlike microglia, astrocytes are not
considered immune cells. However, astrocytic endfeet
form the glia limitans, which is an essential component
of the neurovascular unit (described above) and another
barrier to T cell infiltration. The question of whether as-
trocytes can present antigens to T cells will next be con-
sidered.
It is generally accepted that non-stimulated astrocytes
are very poor APCs and, like microglia, express very low
or no constitutive levels of costimulatory and MHC
molecules. However, activated astrocytes express in-

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS 209
creased levels of MHC class II and B7-1 molecules in
vitro, but not B7-2 and CD40, which remain at baseline
levels [87]. This suggests that they would be weak in-
ducers of T cell activation at least in vitro, if not also in
vivo. Indeed, compared to activated astrocytes, naïve
astrocytes from primary cultures have almost no ability
to induce proliferation or IFN-
 production in PLP139-151-
specific CD4+ effector T cell lines [87]. Activated astro-
cytes are only slightly better in their capacity to induce
proliferation of effector CD4+ T cells from T cell lines
than are naïve astrocytes, but cannot induce proliferation
or effector cytokine production (e.g., IL-2, IL-4, IFN-
 )
in naïve CD4+ T cells at all [70]. However, activated
astrocytes have been shown to induce low IFN-  produc-
tion by effector T cells [70,87], though they seem to be
even better at inducing IL-4 and IL-10 cytokine produc-
tion, and so they may have a role in forming a Th2-po-
larizing environment [68,70].
While activated astrocytes have some capacity to
process myelin protein and present encephalitogenic
myelin antigens in vitro [88, 89], their pathogenic role in
the CNS autoimmune disease process is dubious at best.
Mice in which astrocytes constitutively express the tran-
scription factor CIITA (required for MHC class II protein
expression in astrocytes) have a similar EAE disease
course to wild type mice, despite these astrocytes having
upregulated message levels of CIITA (the transcription
factor associated with MHC class II expression) and the
components that are involved in the assembly of pep-
tide/MHC class II complexes (invariant chain (Ii) and
H-2M molecules) [90]. Finally, astrocytes have been
shown to present soluble viral peptide antigen to naïve
CD8+ T cells in vitro [91]. While astrocytes engineered
to express viral neoantigen may activate effector CD8+ T
cells in vivo and initiate disease [92], true cross-presen-
tation of viral or myelin antigens by astrocytes in vivo
has never been tested. Given their poor ability to phago-
cytose myelin antigen compared to microglia [93], it
seems unlikely that they have any significant contribu-
tion in the presentation of self-antigen to T cells recruited
to the CNS during neuroinflammation.
Based on these studies, there is no major role for as-
trocytes in inducing adaptive immune responses in the
CNS in vivo. However, undoubtedly, these cells play a
critical role in supporting BBB and neuron functions
(reviewed in [94]).
3.3. Dendritic Cells: Major Players in CNS
Immunity
In the last few years, interest has focused on DCs in the
initiation of CNS autoimmunity, as these cells have
emerged as potential targets for modulating immune dis-
eases of the nervous tissue. DCs are highly specialized,
professional APCs that reside in tissues in an immature
state, where they capture and process antigens. Anti-
gen-bearing DCs mature en route to the peripheral lym-
phoid tissues, where they play a crucial role in T cell
activation and differentiation, as well as tolerization.
They are the most efficient of all the professional APCs
at priming naïve T cells, given their ability to migrate
and rapidly upregulate the necessary costimulatory and
MHC molecules. While this knowledge comes from
studying DCs in peripheral, non-CNS tissues, until re-
cently little was known about their immunosurveillant
role in the CNS. In one of the first studies to characterize
the presence of DCs in various non-lymphoid tissues, it
was suggested that their absence in the normal rat paren-
chyma contributed to CNS immune privilege [95]. Thus,
cells within the CNS (e.g., microglia and astrocytes)
were studied for their role in autoimmune disease patho-
genesis. But then, almost three decades after their initial
description by Steinman and Cohn [96], DCs were iden-
tified in the perivascular space, choroid plexus, and
meninges in rodents [48,49], where they localized in dif-
ferent aspects of these tissues (i.e., CSF-exposed) than
macrophages [97]. Since then, both plasmacytoid and
myeloid DC subsets have been found in CSF in humans
[98].
The identification of this professional APC in
CSF-exposed parts of the CNS has radically reshaped our
ideas about the immune-privileged nature of the CNS
and the mechanism of CNS autoimmune disease initia-
tion. Upon their discovery, it was proposed that DCs in
these non-parenchymal CNS tissue areas might acquire
antigens obtained from CSF, exit the CNS via the olfac-
tory pathway and nasal lymphatics, and stimulate the
appropriate T cells within the CLNs [19,49]. Experimen-
tal support for the crucial role of DCs in the CNS auto-
immune disease process came in a landmark study, in
which Greter et al. used mice that had DC-restricted ex-
pression of MHC class II to show that DCs within the
meninges and CNS blood vessels, but not parenchymal
MHC class II+ cells (i.e., microglia or astrocytes), were
necessary and sufficient to induce EAE [99]. DCs have
also been shown to regulate the process of epitope
spreading in the CNS, in which naïve T cells are primed
against antigens that are different than the one used to
induce disease [71]. This process is thought to underlie
the relapses that patients suffer in relapsing-remitting MS.
In this study, DCs isolated from the inflamed CNS of
mice with R-EAE (induced with PLP178-191) were able to
cross-present non-immunizing epitopes that they had
picked up in vivo to prime naïve PLP139-151-specific T
cells ex vivo [71]. Additionally, studies in our lab have
demonstrated that DCs can promote T-T cell interactions,
which facilitates their entry into the CNS [100]. Thus, the
evidence is growing that DCs are critical regulators of

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS
210
adaptive immune responses in the CNS. Special consid-
eration of the role of DCs in tolerance and immunity to
CNS self-antigens will be given later in this review.
The discovery of DCs in the CSF-exposed parts of the
healthy CNS suggested that these cells might be impor-
tant in the regulation of adaptive immune responses
within the CNS. The CNS was now viewed as being
relatively, rather than absolutely, immune privileged. In
terms of disease mechanisms, the potential for develop-
ment of CNS autoimmunity arises should the DCs be
presenting neural self-antigens, yet it would be simplistic
to think that this would be the inevitable outcome. There
exist many central and peripheral tolerance mechanisms
and cellular regulators of immunity (for example, induc-
tion of T cell anergy; clonal deletion; induction of/regu-
lation by regulatory T cells, myeloid-derived suppressor
cells, and alternatively activated macrophages) that pre-
vent self-reactive T cells from becoming activated
[101-103]. The conditions in which antigens draining
from the CNS induce and/or break peripheral tolerance
are unknown but are essential to understanding how pe-
ripherally located CNS antigen-specific T cells become
pathogenic and/or contribute to autoimmune disease.
A remaining unanswered question is whether CNS an-
tigen-specific naïve T cells are primed by DCs in the
CLNs, or whether they are primed by DCs in the SAS.
McMahon and colleagues have shown that while initial
priming of naïve CD4+ T cells occurs in the periphery as
a result of the R-EAE immunization protocol, those spe-
cific for non-immunizing epitope that have newly arrived
in the CNS are primed locally by DCs [71]. However,
Walter and Albert reported that cross-presentation of
membrane-bound antigens on splenocytes lacking MHC
class I first occurs in the CLNs before responder T cell
recruitment to the CNS [104]. Collectively, these results
suggest that antigen drainage to the CLNs is one of the
first steps regulating activated T cell recruitment to the
CNS and, thus, is a key component of CNS surveillance,
but that local stimulation in the CNS may be crucial to
disease progression. For example, DCs in the SAS may
contribute both to priming of Th17 cells and to the for-
mation of eLFs by producing CXCL13 [15,17], which
binds to CXCR5 expressed on Th17 cells that may as-
sume follicular helper T cell-like functions.
Finally, there has been some recent investigation into
the origin of CNS DCs that are present under neuroin-
flammatory conditions, namely, whether they originate
from a precursor in the CNS or enter from the blood.
Microglia, for instance, can take on a DC-like phenotype
when exposed to GM-CSF, or a more macrophage-like
phenotype when exposed to M-CSF (macrophage col-
ony-stimulating factor) [105]. Mice with CD11c pro-
moter-driven expression of GFP [106] and EYFP [107]
have been used to probe the presence and distribution of
DCs in the normal CNS parenchyma [108,109], where
the reporter cells seem to have definite DC morphology
and functionality. Bulloch and colleagues identified stel-
late EYFP+ cells in areas of the normal brain lacking a
BBB (e.g., circumventricular organs), which they pro-
posed was perhaps indicative of the role of these cells in
immunosurveillance and antigen presentation [108]. In
the other model, the GFP+ cells were also identified in
several parenchymal areas, but their dendritic processes
were found to directly connect with the glia limitans,
which, again, may be related to their role in antigen
presentation in the perivascular space [109]. Functionally,
IFN-
 -activated EYFP+ cells were able to migrate and
upregulate MHC class II in vivo, and were better at
stimulating naïve CD4+ T cells than EYFP- microglia ex
vivo, consistent with established DC properties [110].
However, it must be noted that CD11c expression is not
restricted to classical myeloid DCs, and, thus, alone it
may not reliably be used to determine lineage [111]. The
data from the reporter studies show that parenchymal
GFP+ and EYFP+ reporter cells colocalize with micro-
glia/macrophage markers F4/80, and Iba-1 and myeloid
marker CD11b, suggesting that parenchymal CD11c+
cells may be a subset of resident microglia [108,109].
Using the CD11c-EYFP reporter mice, it has recently
been shown that EYFP+ cells only in the meninges and
choroid plexus (but not in the parenchyma) of the healthy
CNS expand in response to FMS-like tyrosine kinase
receptor 3 ligand (Flt3L), which is necessary for DC
lineage commitment [50]. Additionally, these DCs re-
sembled splenic DCs in terms of their mRNA profile of
several cell surface/lineage markers and transcription
factors, as well as in their ability to stimulate naïve T
cells, and were thus distinctly different from parenchy-
mal microglia. These new findings support that pre-DCs
in the meninges and choroid plexus enter from the blood
and differentiate into mature DCs in situ. Against the
idea that DCs found in the inflamed CNS are of micro-
glia origin, bone marrow chimeric mice have previously
been used to show that the majority (i.e., more than
eighty percent) of DCs present in the CNS of mice with
R-EAE are from the bone marrow [112].
In summary, DCs in the perivascular space and men-
inges are the choice cellular candidate responsible for
priming naïve and restimulating CNS antigen-specific T
cells. Once inside the parenchyma proper, activated T
cells can then interact with CNS-resident astrocytes and
microglia. Microglia may present antigen to infiltrating
effector T cells and are perhaps more involved with
negative regulation of disease.
4. Initiation of CNS Autoimmunity: The
Perfect Immunological “Storm”
Many of our ideas about the pathogenic mechanisms

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS
211
underlying chronic neuroinflammatory diseases, such as
MS, come from studying the EAE animal model. In this
model, disease may be initiated by either immunizing the
animal with a myelin antigen (“active” induction), or by
adoptively transferring activated, encephalitogenic T
cells (“passive” induction). Under both experimental
conditions, activated T cells from the periphery infiltrate
the healthy CNS and contribute to disease. Yet in hu-
mans with MS, it is difficult to determine what drives the
entry of myelin antigen-specific T cells into the CNS.
Because of the preponderance of these and macrophage
cells in active demyelinating lesions and elevated levels
of chemokines and proinflammatory Th1 cytokines in
CSF, MS is widely accepted to be a T cell-mediated
autoimmune disease [113-115]. Thus, the standard model
is that myelin-reactive T cells initiate oligodendrocyte
death and mediate further myelin destruction by solicit-
ing the recruitment of macrophages. However, given the
different histopathological patterns displayed in active
MS lesions [116], the question arises whether MS is pri-
marily an autoimmune disease, or whether adaptive im-
munity is secondary to a different underlying cause. This
is tremendously important in terms of how the disease is
treated and is a subject of intense debate.
tion, pathogens display conserved molecules (i.e., pat-
tern-associated molecular patterns, PAMPs), which can
bind to pattern recognition receptors, such as Toll-like
receptors, on APCs and induce their activation, thus fa-
cilitating efficient presentation of the pathogenic/self
antigen. Mice infected with a neurotropic virus engi-
neered to express a myelin-self-antigen develop paralytic
demyelinating disease induced by cross-reactive CD4+ T
cells [117]. In a similar study, CD8+ T cell-mediated
attack of ovalbumin (OVA)-expressing neurons was ini-
tiated following intracerebral injection with OVA-secret-
ing Listeria monocytogenes [30]. It is important to note
that in this experiment, peripheral infection alone did not
induce disease, suggesting that CNS inflammation and
breakdown of the BBB are also required. While no spe-
cific virus has been causally linked to human MS, deep
sequencing technology is now being used to detect new
viruses from MS brain samples and will likely yield
strong correlational data [118].
Another model of CNS autoimmune disease initiation
has been proposed based on the histological observation
that oligodendrocyte (ODC) apoptosis precedes immune
cell infiltration in new lesions in several cases of relaps-
ing-remitting MS [119]. The idea is that some unknown
factor that causes ODC death also results in the direct or
indirect activation of CNS APCs, leading to their migra-
tion to CLNs and the priming of naïve T cells, which
then get recruited to the CNS (Figure 2) [120]. The
power of modeling primary ODC death as an initiator of
Infection is one of several potential triggers of CNS-
targeted adaptive immune responses and has received
much attention. An infectious pathogen might drive the
cross-activation of CNS antigen-specific T cells due to
similarities in epitope sequence homology or molecular
conformation (this is called molecular mimicry). In addi-
Figure 2. Model of initiation of CNS autoimmunity. 1) An initiating factor (red arrow) may cause damage/stress to oligoden-
drocytes (ODCs); 2) Antigens or danger signals released upon injury may be carried by interstitial fluid and drain into the
CSF and either enter the blood circulation via arachnoid villi that protrude into the dural sinus or exit along the cranial
nerves (in particular, the olfactory nerve) and reach the cervical lymph nodes (CLNs) via the nasal lymphatics; 3) In the
CLNs, naïve myelin antigen-specific T cells are primed by dendritic cells (DCs) and undergo clonal expansion. Primed T cells
are recruited to areas of CNS inflammation, as BBB endothelial cells now express the appropriate adhesion molecules and
chemokines; 4) Once inside the PVS, the primed T cells are restimulated with their cognate antigen and are able to enter the
CNS parenchyma to carry out their effector functions.

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS
212
other ideas of disease initiation. For example, primary
autoimmunity is that it allows for the initial adaptive
ral/bacterial infection) or self-antigens (e.g., from minor
trauma), and therefore connects the standard model with
immune response to be against either non-self (e.g., vi
ODC death (as opposed to T cell-mediated death) itself
may result in autoimmunity to myelin antigens exposed
by death [120]. In seeming conflict with this idea, two
groups have recently and independently shown that
diphtheria toxin-induced ODC death does not elicit adap-
tive immune cell accumulation in the CNS [121,122]. In
these studies, ODCs did not die by apoptosis (the form of
cell death usually associated with MS and EAE) but in-
stead underwent vacuolation-induced death, which is
distinct from classical necrosis and apoptosis [123]. Ad-
ditionally, change in the BBB is thought to be a critical
and obligatory step for disease initiation [124], and in-
deed, contrast enhanced MRI has shown that disruption
of the BBB is one of the earliest events in patients with
MS [125]. However, BBB permeability was not altered
in the transgenic animals used in either study, presuma-
bly due to lack of inflammation, thus precluding T cell
entry. From these studies, we may conclude that vacuola-
tion-induced ODC death per se does not induce autoim-
munity; however, other types of cell death may.
Careful consideration must be given to the type of
ODC death that is induced and whether it has the ability
to initiate inflammation in the CNS (beyond microglia
activation), which determines T cell recruitment and en-
try, as well as APC activation. These factors likely de-
termine whether death induces autoimmunity or toler-
ance (or ignorance). ODC apoptosis, in particular, is im-
portant for EAE initiation, as inhibiting ODC apoptosis
has been shown to attenuate the incidence and severity of
disease [37,126]. (However, as a caveat, it could also
mean that T cell-mediated effects are blocked.) For a
long time apoptosis was considered to be an “immu-
nologically silent” form of cell death, and so precisely
how it could contribute to MS and EAE development
was (and remains) unknown and is rather interesting.
Work done by Matthew Albert and colleagues has dem-
onstrated that DCs can acquire processed antigen from
cells undergoing apoptosis and efficiently cross-present
the antigen to CD8+ T cells [127-129]. In terms of CNS
immunity, Meloni et al. demonstrated that DCs present-
ing antigens from apoptotic ODCs could stimulate IFN-

production and proliferation of MBP-specific T cell lines
[130]. Additionally, DCs have been shown to mediate
myelin epitope spreading in the CNS in vivo [71]; how-
ever, ODC cell death was not examined as a source of
spread (or non-immunizing) antigen in this study. Thus,
whether DCs acquire antigens from apoptotic ODCs and
stimulate myelin-reactive T cells in vivo remains an open
question.
In addition to dying cells being a source of immuno-
genic epitopes, they can potentially release internal
damage-associated molecular patterns (DAMPs) and
alarmins (reviewed in [131]). These signals might, in
turn, activate and mobilize APCs. In this way, ODC
death might be “sensed” by DCs and contribute to CNS
autoimmunity. Several DAMPs were described by Kono
and Rock [131], and here we present their association
with MS/EAE in Table 2. While the DAMPs presented
in Table 2 come from a variety of sources and have a
variety of actions, to the best of our knowledge they are
not released by ODC death. However, their role in di-
recting DC subtype specification and, thus, in polarizing
T cell responses against antigens released by ODC death
are only beginning to be understood. For example, heat
shock protein 70 has been shown to facilitate processing
of MBP in murine fibroblasts made to express HLA-DR
[132]. Future research will determine whether any of
these or (as yet) undiscovered DAMPs are released from
dying ODCs, or are just microenvironmental cues that
contribute to the perfect “immunological storm”.
One question that remains is why “normal” cell death
results in tolerance and not autoimmunity. Recently, it
has been shown that indoleamine 2,3-dioxygenase (IDO)
can be induced in marginal zone macrophages and is
necessary for tolerance to antigens from apoptotic cells
[133]. Importantly, IDO-/- mice injected with apoptotic
thymocytes resulted in increased autoantibody titers in
the serum, as well as lethal autoimmunity due to renal
failure [133]. Additionally, IDO has been shown to be
upregulated in activated microglia from primary cell
cultures [134]. These studies suggest that microglia may
play a role in tolerance to self-antigens exposed by cel-
lular apoptosis via IDO-dependent mechanisms. How-
ever, studies using MHC class I H-2Db-/- bone marrow
chimera mice have demonstrated that DCs are also im-
portant in establishing tolerance to CNS LCMV neo-
antigens [35]. In summary, the whole microenvironment-
tal context of cell death likely determines whether CNS
autoimmunity or tolerance results following injury.
5. Regulation of CNS Immunity: The Role of
Dendritic Cells
One of the greatest challenges in MS research is finding
ways to regulate aberrant immunity within the CNS. DCs
are critical at this juncture and can be matured and im-
printed by environmental cues both in vitro and in vivo to
be functionally either immunogenic (stimulatory) or
tolerogenic, which will be our focus in this section. Be-
cause of their functional plasticity, drugs that alter DC
functionality will enable the therapeutic use of these cells
(reviewed in [147]). There are two major DC subsets: clas-
sical myeloid DCs (mDCs) and plasmacytoid DCs (pDCs)
that arise from a common-DC progenitor (reviewed in

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS 213
Table 2. DAMPs associated with MS/EAE pathology.
DAMP Source or
localization Activity in MS/EAE
Suspected
autoantigen or
cross-reactivity
Receptor(s) Receptor
expression Reference(s)
HMGB1 microglia and
macrophage; CSF unknown -
RAGE; TLR2;
TLR4
active lesions;
blood and CSF [135]
Double-
stranded DNA
intracellular;
anti-dsDNA
antibodies in MS
active plaque and
periplaque regions
and B cells in CSF
anti-dsDNA antibodies
may promote MS lesion
formation
yes N/A N/A [136]
intracellular; both
CNS and systemic
tissue deposits of
cross-reactive
anti-dsDNA
antibodies
Areas of demyelination
observed in the CNS and
renal autoimmune
pathology
cross-reactivity
found with
MOG92-106
N/A N/A [137,138]
Extracellular
nucloeotides
(e.g., ATP,
ADP, UTP,
UDP)
intracellular
COX-2, iNOS, and
pro-inflammatory
cytokine production;
glial cell proliferation and
death
- P2
receptors
neurons, glial
cells, Schwann
cells,
CNS-infiltrating
leukocytes
reviewed in
[139]
Adenosine intracellular anti-inflammatory - P1
receptors
neurons,
microglia,
astrocytes,
leukocytes
reviewed in
[139]
Heat-shock
proteins intracellular
Hsp-CNP peptide can
protect against or
aggravate EAE,
depending on Th1 or Th2
immune response pattern
cross-reactivity
between
mycobacterial
Hsp65 and
CNP153-164
N/A N/A [140]
intracellular; binds to
certain MBP peptides
in vitro
Hsp 70 facilitates
autoantigen processing - N/A N/A [132]
S100 proteins
astrocytes and
subpopulation of
ODCs
unknown - - - [141]
Fibronectin
/Fibrinogen
ECM/plasma;
primarily localized to
microvessel walls
(fibronectin) and
lumen (fibrinogen),
but also on
mononuclear cells and
extracellular deposits
facilitate mononuclear
cell adhesion and
migration, myelin
phagocytosis, and
breakdown of BBB;
fibronectin can inhibit
myelination
- fibronectin
receptor macrophages [142-145]
Hyaluronan
(HA)
ECM component;
secreted by astrocytes
and microglia
LMW HA inhibits OPC
maturation via TLR2 - CD44; TLR2 ODCs; T cells [146-148]

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS
214
Continued
Heparan sulfate
(proteoglycan)
ECM component
of basement
membrane
cleavage by heparanase
facilitates immune cell
migration through ECM
-
may act as a
chemokine
reservoir
N/A [149,150]
Laminin- and
collagen-derived
peptides
ECM components
of basement
membrane
cleavage by matrix
metalloproteinases
facilitates immune cell
migration through ECM
-
integrins (e.g.,
VLA-1,
VLA-2,
VLA-6)
lymphocytes
and monocytes [150,151]
Elastin-derived
peptides
component of the
dura mater;
degraded by
macrophage
metalloelastase
unknown - elastin recep-
tor
peripheral blood
lymphocytes [152-154]
Galectins
microglia and
macrophage,
astrocytes,
endothelial cells,
DCs
induction of tolerogenic
DCs; negative
regulation of effector T
cells
-
GM1
ganglioside;
glycoproteins
- [155-160]
[161]). These subsets can be distinguished by differences
in surface marker expression. mDCs are CD11c+ CD11b+.
In mice, pDCs are CD11clow CD11b− B220+ Ly6C+,
whereas in humans, pDCs are CD11c− CD4+ CD45RA+
IL-3R

+ ILT2+ ILT1− (reviewed in [162]). Additionally,
many more sub-subsets of mDCs have been found in
lymphoid and non-lymphoid tissues [161]. Distinct DC
subsets have been shown to accumulate in the CNS in
response to different environmental stimuli (bacterial,
viral, DAMP), and thereby promote the appropriate
adaptive immune response (reviewed in [163]). As we
will also discuss, pDCs may have a critical role in pro-
moting protection against CNS autoimmunity. It will
only be mentioned here in passing that mechanisms in-
ternal to the DC itself also contribute to immune regula-
tion by keeping the DC in an immature, non-stimulatory
state [164]. This was demonstrated recently, as DCs
lacking nuclear factor-  B1 (NF-  B1) were able to induce
autoimmune diabetes as a result of unchecked production
of TNF-  , which promoted cytotoxic CD8+ T cell pro-
duction of the apoptosis-inducing enzyme granzyme B
[164]. Finally, other cell types are involved in the sup-
pression of CNS autoimmune responses, such as regula-
tory T cells (Tregs) and myeloid-derived suppressor cells
(which are now beginning to be recognized for their con-
tribution to the resolution of CNS autoimmunity [103]),
but they will not be discussed further.
5.1. Environmental Imprinting of Myeloid DCs
Affects CNS Disease Outcome
5.1.1. Stimul a tory Roles for mDCs
DCs accumulate in the CNS when there is inflammation,
and so they are thought to be important for disease de-
velopment and maintenance. We have previously shown
that intracerebrally injected, antigen-loaded mDCs can
migrate to peripheral lymphoid tissues and induce the
homing of responder T cells to the CNS [26,100,165].
We found that intracerebral delivery of MOG35-55-pulsed
DCs lead to an increase in the frequency of activated
MOG35-55-specific (i.e., 2D2) effector T cells in the CNS,
which hastened the onset and increased the severity of
EAE [165]. Importantly, this effect was dependent upon
the functional status of the DCs. Mice intracerebrally
injected with stimulatory (i.e., LPS-stimulated) DCs had
more severe EAE and increased CNS accumulation of
pathogenic Th17 cells, whereas those that received
tolerogenic (i.e., TNF-
 -stimulated) DCs had a much
lower disease incidence, as well as delayed onset and
decreased severity; tolerogenic DCs promoted IL-10
production in the periphery and suppressed IL-17 pro-
duction in the CNS. Our work therefore demonstrates
that depending on the functional status of DCs, the dis-
ease outcome can be better or worse. This illustrates the
capacity of DC functional status/phenotype to determine
the resulting adaptive immune response. Similarly, the
disease environment within the CNS also determines the
functional state of DCs. Deshpande et al. showed that
CD11c+ mDCs isolated right after EAE onset were bet-
ter at promoting 2D2 T cell activation and were markedly
more mature (i.e., displaying increased levels of
costimulatory molecules and the lymphoid tissue homing
receptor CCR7) than those isolated right before disease
remission [166]. Interestingly, while the mDCs isolated
early in EAE supported differentiation of both Th1 and
Th17 T cells, they simultaneously also supported Treg

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS 215
suppression of 2D2 activation [166]. Collectively, these
studies show that, depending on how they are imprinted
in vitro or in vivo, mDCs may either facilitate or suppress
ongoing inflammation.
The precise mechanisms by which DCs regulate CNS
disease processes are beginning to be unraveled. While
DCs are known for their unique ability to determine the
lineage commitment, and thus effector function, of naïve
T cells, effector T cells may also participate in perpetu-
ating their own lineage by directing monocytes to differ-
entiate into particular lineage-promoting DC subtypes
[167]. Particular attention has been paid to the differen-
tiation of Th17 cells, which are regarded as one of the
main pathogenic subsets involved in MS and EAE dis-
ease initiation. A recent study showed that Th17 produc-
tion of GM-CSF drove mDC production of IL-23, which,
in turn, had a positive feedback on Th17 lineage com-
mitment [168]. Thus, by assisting with the differentiation
of this pathogenic population, mDCs play a critical role
in stimulating ongoing inflammation and autoimmunity.
It has been shown that the ability of DCs to produce
IL-23 in response to GM-CSF depends on their expres-
sion of CC chemokine receptor 4 (CCR4), which is re-
quired for EAE initiation [169]. Finally, it was also
demonstrated that, mDCs, compared to pDCs and CNS
macrophages, induce Th17 polarization of naïve CD4+ T
cells specific for non-EAE-inducing epitope in the R-
EAE mouse model, thereby facilitating epitope spreading
[112]. Thus, there is strong evidence that mDCs contrib-
ute to CNS autoimmune disease initiation and relapse by
regulating the development of pathogenic Th17 cells.
5.1.2. Tolerogenic Roles for mDCs
There are many soluble factors that can promote the
tolerogenic phenotype of mDCs within the CNS and con-
tribute to the prevention and/or resolution of CNS auto-
immunity, including anti-inflammatory cytokines (e.g.,
IL-10; TGF-
 ), neuropeptides and hormones (e.g.,
vasoactive intestinal peptide, VIP;  -melanocyte-stimu-
lating hormone,  -MSH), as well as new molecular can-
didates that need to be considered (e.g., galectins).
However, we will only discuss a few examples here. For
a more thorough review of tolerogenic DCs, see [170].
Anti-inflammatory cytokines are well known for their
ability to promote tolerogenic immune responses by
competing effectively with pro-inflammatory cytokines
in an inflammatory setting; generally, they are thought to
activate Th2 and Treg cells and/or suppress Th1 cells and
inhibit pro-inflammatory cytokine synthesis (reviewed in
[171]). However, as recent evidence indicates, anti-in-
flammatory cytokines may also contribute to tolerance in
normal settings by preventing self-reactive T cell active-
tion [172]. Laouar et al. sought a mechanistic explana-
tion for the protective effect of TGF-  against EAE. Us-
ing a specialized set of bone marrow chimeric mice, they
were able to demonstrate that inhibiting TGF-
 -mediated
signaling specifically in DCs could promote the devel-
opment of spontaneous and severe EAE that was accom-
panied by general features of inflammation (e.g., micro-
glia activation and increased levels of mRNA for pro-
inflammatory cytokines), as well as CD4+ T cell accu-
mulation in the CNS [172]. Interestingly, the majority of
MHC class II+ cells observed in the spinal cord were
CD45low, indicating that they were microglia. This sug-
gests that DCs exert their tolerogenic influence outside
the CNS. These results indicate that intact TGF-
 R sig-
naling in DCs promotes suppression of autoimmunity,
perhaps by keeping resting DCs in an immature state.
Apart from cytokines, VIP, as mentioned above, is a
neuropeptide that induces tolerogenic function in mDCs
[173]. Lentiviral vectors were recently used to engineer
DCs to express VIP [174]. In this study, mice that re-
ceived a single injection of VIP-expressing DCs were
protected against disease development in both relapsing
and primary progressive models of EAE. Interestingly,
the VIP-expressing DCs were found to accumulate in
non-lymphoid peripheral tissues (e.g., liver and lung) in
higher numbers than in lymphoid tissues, a migration
pattern somewhat unexpected in the acute phase of EAE.
It would be interesting to see whether the anti-inflam-
matory cytokine profile observed in total RNA isolated
from the spinal cord at the peak of disease was due to
VIP-expressing DCs exerting their tolerogenic effects
systemically or within the CNS. However, the clear sup-
pression of EAE observed in two disease models illus-
trates that DCs may be used to deliver anti-inflammatory
agents for use in the treatment of CNS inflammatory
diseases.
As a final example, another soluble factor that works
as an anti-inflammatory cytokine in the traditional sense
is galectin-1 (Gal1), a glycoprotein that is a member of a
family of lectins. It promotes a tolerogenic phenotype in
DCs during their differentiation process. DCs differenti-
ated in presence of Gal1 or that express Gal1 endoge-
nously were shown to suppress the chronic phase of
MOG35-55-induced EAE, inhibit T cell proliferation and
pro-inflammatory cytokine production, and increase
IL-10 production via an IL-27-dependent pathway [102].
They also found that Gal1 levels were the highest at peak
and chronic phases of EAE. Additionally, immature, but
not mature, mDCs produced high levels of Gal1. When
subsequently cultured with tolerogenic stimuli (such as
VIP, IL-10, vitamin D3, and also apoptotic cells) these
immature mDCs significantly increased Gal1 expression,
whereas pro-inflammatory stimuli had the opposite effect.
This study is interesting because it shows that as the in-
flammatory milieu changes within the CNS, the matura-
tion status of DCs may render them more or less suscep-

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS
216
tible to tolerogenic environmental factors, thereby influ-
encing their contribution to disease resolution.
5.2. Plasmacytoid DCs and Their Contribution
to Regulation of CNS Autoimmunity
While pDCs from the inflamed CNS are not as efficient
as mDCs at priming naïve or effector PLP peptide-spe-
cific T cells [175], they seem to play a crucial role in
negatively regulating EAE [175-177]. However, the
mechanisms by which they do this are only beginning to
be elucidated. In order to directly address the question of
whether protection against severe EAE was the result of
T cell priming by pDCs, Irla et al. used mutant chimeric
mice lacking MHC class II only in pDCs to show that
pDCs facilitated Treg priming and expansion in the
draining lymph nodes of mice with EAE in an anti-
gen-specific fashion [177]. A different mechanism was
proposed by Bailey-Bucktrout et al. [176], who found
that pDCs exerted their immunoregulatory effects by
suppressing mDC-induced CD4+ T cell production of
IFN-
 , IL-17, and IL-10 cytokines, and not through
IDO-mediated inhibition of T cells. However, they did
observe that blocking IDO resulted in slightly increased
levels of IFN-
 and IL-17 when CD4+ T cells were
stimulated with mDCs. This could be due to the inhibi-
tion of the natural Treg subpopulation [178], and would
also support that CNS mDCs might promote Treg prolif-
eration in the CNS, which was not found to be impaired
in the CNS of mutant chimeric mice in the Irla et al.
study [177].
6. Conclusion
The CNS is a precious tissue in which there must be a
fine balance between immune surveillance (i.e., immune
cell admittance) and privilege (i.e., immune cell exclu-
sion). We have discussed that while routine surveillance
of the subarachnoid space by T cells does occur in the
healthy CNS, increased surveillance results in autoim-
munity. While EAE initiation has been shown to be de-
pendent on DCs, it is still unknown where initial T cell
priming occurs. Based on our discussion, disease initia-
tion likely involves antigen drainage and priming of na-
ïve T cells in the CLNs, but disease progression likely
involves local restimulation by DCs and (to a lesser ex-
tent) perivascular macrophages within the PVS and ec-
topic lymphoid structures in the SAS. This is an ongoing
field of investigation. Several theories of CNS autoim-
mune disease initiation in humans have been presented,
including whether primary death of myelin-producing
cells in the CNS stimulates autoimmunity, which remains
controversial. Whether cell death induces immunity, tol-
erance, or ignorance is determined by the entire micro-
environmental context, which induces different func-
tional phenotypes of DCs. Therefore, DCs are probably
master regulators of the autoimmune disease process in
CNS.
7. Acknowledgements
The authors would like to thank Benjamin D. Clarkson
for critically reviewing this manuscript. This work was
funded by NIH/NIGMS grant T32-GM007507 (Neuro-
science Training Program) and NIH grant R01-NS37570
(Z. Fabry).
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