(American Journal of Pathology. 1998;153:677-680.)
© 1998 American Society for Investigative Pathology
The Fate of T Cells in the Brain
Veni, Vidi, Vici and Veni, Mori
Paul V. Lehmann
From the Department of Pathology, Case Western Reserve University,
Cleveland, Ohio
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Introduction
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Since the dawn of modern immunology, immune responses within the
central nervous system (CNS) have puzzled immunologists. On one hand,
the immune-privileged status of the CNS has been known for a long time;
along with the eye, the gonads, and the placenta, the CNS is among the
few organs that accept grafted foreign cells more readily than the rest
of the body.1
On the other hand, the CNS has been
known to be particularly susceptible to autoimmune disease. The first
and best characterized autoimmune model, experimental allergic
encephalomyelitis (EAE), which resembles multiple sclerosis (MS), is
the result of an autoimmune attack by T lymphocytes on the
CNS.2
A report on EAE in this
issue3
by Bauer et al provides data of
exceptional clarity that should help in understanding this apparent
contradiction.
Neuroantigen-specific T cells, which can mount an autoimmune attack
against the CNS, are detectable in healthy individuals. This is
particularly well established for T cells that are specific for myelin
basic protein (MBP), the best-characterized target antigen in the CNS.
Studies using MBP-specific T cell receptor-transgenic mice suggested
that these T cells normally ignore the
autoantigen.4-6
Like lymphocytes that have not
encountered their antigen before, they retain a naive/resting
phenotype. Such T cells dramatically change their behavior as soon as
they become activated in the course of an immune response; they start
to infiltrate the CNS and cause inflammatory damage there. In
experimental models EAE is initiated either by immunization with a CNS
antigen (for active EAE) or by in vitro injection of
activated CNS antigen-specific T cells (for passive EAE, the model used
by Bauer et al). In MS, infections with crossreactive microorganisms
are thought to initiate the autoimmune attack. It remains unclear why
activated myelin-reactive T cells "see" and attack the autoantigen
that resting T cells with the same specificity had ignored. The
information needed to promote resolution of this question pertains to
the rules that govern the entry of lymphocytes into CNS tissue. This
issue was addressed by Bauer et al. They injected into rats congenic T
cells specific for either various CNS "self" antigens (Bauer et al,
Table 1) or for the irrelevant "foreign" antigen ovalbumin
(OVA). To distinguish clearly between injected T cells with a
defined specificity and activation state and recruited host-derived T
cells of unknown specificity and activation state, the authors took
advantage of a TK-tsa-transgenic model. The detection of the
TK-tsA transgene by in situ hybridization facilitated
reliable discrimination of the injected T cells from those of the
host.
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T Cells Entering the CNS
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Although OVA-specific T cells, irrespective of whether they were
freshly activated or in a resting state, were not detected in the CNS 4
days after the injection, MBP-reactive cells (Bauer et al, Table 5) and
T cells specific for three other CNS antigens (Bauer et al, Figure 2)
were found to infiltrate the CNS. At first glance these data might seem
to suggest that only autoreactive T cells can penetrate the blood-brain
barrier and that unlike most other organs the CNS is excluded from
general immune surveillance. Resting/naive T cells are known to
congregate in lymph nodes, where the first encounter with antigen
typically occurs, and to be sparse in nonlymphoid
organs.7,8
The degree to which these cells seek
lymph nodes is determined by the expression of the lymph node homing
receptor, L-selectin.9
Activated/memory cells
down-regulate L-selectin expression,10
lose their
lymph node-seeking tendency,11
and disseminate
throughout the organism,7,8
subjecting most
organs to a systematic search for their antigen. Is the CNS
exempt from this search? Earlier studies by Hickey et
al12
suggested that activated T cells of any
specificity can penetrate the uninflamed blood-brain barrier and that
the concentration of such T cells in the CNS peaks between 9 and 12
hours after injection. Strikingly, only recently activated T cell
blasts could enter the uninflamed CNS. These cells were found
predominantly in the mesenchymal compartment near blood vessels and the
meninges. Foreign antigen-reactive T cells, which were unable to
"find" their antigen in the CNS, returned to baseline levels 24 to
48 hours later. The autoreactive T cells that encountered their antigen
in the CNS stayed. According to these data12
the
CNS does not seem to be exempt from general immune surveillance.
The injection of preactivated CNS antigen-reactive cells results in
massive cellular infiltration of the CNS, a reaction that peaked around
day 6 in the case of the MBP-specific cells used by Bauer et al (Bauer
et al, Table 3). Although the specificity of the T cells that initiate
this infiltration is highly defined in this experimental setup, the
nature of the T cells that constitute the infiltrate had been a matter
of controversy before these experiments. It is, however, of particular
relevance for MS and other autoimmune diseases in which the target
antigens are not known. The study of T cells that infiltrate the target
organ is among the most promising approaches to identifying T cells
that mediate these diseases. It remained unclear whether the
infiltrating cells are the injected cells themselves or progenitors of
them that arose locally through antigen-driven proliferation.
Alternatively, the infiltrating cells might have originated in the host
and been recruited to the inflamed site, in which case recruitment
might be random or might primarily involve CNS antigen-specific cells.
Additionally, it has been unclear whether the rules that seem to govern
leukocyte entry into the noninflamed CNS also apply to the inflamed
organ, perhaps permitting the entry of naive T cells and resting memory
cells in addition to T cell blasts.
The experiments done by Bauer et al provide answers of exceptional
clarity to these questions. They showed that in the early stage (day 4)
of EAE caused by TK-tsA-transgenic, MBP-specific cells, up to
50% of the T cells in the CNS are transgene-positive and that their
frequency drops to approximately 25% at the peak of the disease on day
6 (Bauer et al, Table 3). These cells did not proliferate significantly
in the CNS, as the cell cycle marker "proliferating cell nuclear
antigen" was rarely detected in these T cells (Bauer et al, Figure 1). The remaining 50% to 70% of the T cells in the infiltrate
were clearly identified as host-derived. Of these, most must have been
bystander cells with irrelevant antigen specificity, because when
OVA-specific transgenic cells were coinjected, these were also detected
in high frequency in the cellular infiltrate (Bauer et al, Table 5).
When these OVA-specific cells were freshly activated, they were
recruited to the inflamed CNS more efficiently than when they were
resting (Bauer et al, Table 5). These data show clearly that acute
inflammatory T cell infiltrates in EAE are made up of a mixture of
autoantigen-reactive and irrelevant antigen-specific bystander cells. T
cell receptors in autoimmune lesions are therefore also likely to
consist of these two components. According to these data from Bauer et
al, prevalent V gene utilization in lesions can reflect peripheral
events not necessarily related to the autoimmune process. Were a
superantigen, for example, to activate and induce clonal expansion of
certain V gene-bearing cells that are not CNS antigen-specific, these
cells should still preferentially migrate and accumulate in the CNS, if
only because they are activated. Although the accumulation of V
gene-bearing cells may indicate superantigen-driven autoimmunity, it
alone does not provide clear evidence of it.
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T Cells Dying in the CNS
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Once T cells have been sensitized to an antigen they tend to
combat it until the antigen is cleared. Clinical examples are the
frequently therapy-resistant rejection of transplanted organs and the
inexorable progression of autoimmune diseases. In EAE one might also
expect the CNS antigen-reactive T cells to operate under this
"veni, vidi, vici" principle (Julius Caesar's famous
"I came, I saw, I conquered" message sent to Rome after
victory in battle) because there is abundant autoantigen available in
the CNS to "see" the CNS antigen-reactive T cells and stimulate
them to win. If this general response pattern characterized EAE, the
autoimmune attack would perpetuate itself and continue until the target
tissue was destroyed. Yet EAE comes to a spontaneous halt, typically in
less than a week. In most rodent models EAE is monophasic, recovery is
complete and permanent, and the animals even become resistant to the
re-induction of EAE. The rat model studied by Bauer et al falls
into this category. Why this autoimmune disease is self-limiting has
puzzled researchers since the model was introduced. In addition to
being a paradigm for autoimmune disease, monophasic EAE is a powerful
paradigm for peripheral tolerance mechanisms that rapidly correct the
mistake in self/non-self discrimination that causes the disease. Even
in murine models in which chronic EAE develops, there is frequently
complete recovery from the first episode of the disease before a
relapse occurs and subsequent disease episodes also tend to be
remitting.13
Why is this autoimmune disease
characterized by a self-limiting course, halting spontaneously and then
starting again? Counterregulatory immune mechanisms have been
implicated.14
Exhaustion of the T cell response
and apoptosis from "overwork" also seemed to be plausible
explanations.15
Alternatively, it is conceivable
that the T cells lose their function, becoming anergic and eventually
dying, when they encounter the antigen under suboptimal conditions of
antigen presentation; microglia and astrocytes, which can present
antigen but do not express appropriate costimulatory molecules, have
been implicated in the inactivation of the autoreactive T
cells.16,17
Similarly, the abundant apoptotic T
cells that can be detected in EAE lesions have been thought to
represent autoreactive T cells that die because of such unfavorable
antigen recognition or overwork.18,19
The
prevalent view was that T cells have to come and see before they die
(veni, vidi, mori). The data from Bauer et al
challenge this view.
Bauer et al clearly show that not only the T cells reactive to various
CNS antigens (Bauer et al, Figure 2) but also those reactive to the
foreign antigen OVA (Bauer et al, Table 5) undergo apoptosis in CNS
lesions and that the host-derived T cells, in addition to the injected
MBP-specific cells, die (Bauer et al, Table 4). Because the CNS
antigen-specific T cells induced EAE they must have recognized
autoantigen in the CNS and must have secreted cytokines there.
Apparently, though, they did not proliferate before they died, as very
few of them expressed the cell cycle marker `proliferating cell
nuclear antigen'. Antigen recognition on resident antigen-presenting
cells (astrocytes and microglia, which deliver costimulatory signals
deficiently and are therefore implicated in the induction of anergy and
apoptosis)16,17
did not augment the rate of
apoptosis in MBP-specific T cells, a fact that was elegantly shown with
major histocompatibility complex-mismatched chimeras. Overall it
seems as if the mere entry of a T cell into the neurodermal parenchyma
would suffice to eventually activate the apoptosis program in a T cell;
in the parenchyma of the inflamed CNS, veni, mori seems to
apply for T cells. By showing that all T cells, not only the
antigen-specific ones, die, these data substantiate that the CNS is an
immune-privileged organ and suggest a mechanism for it. Fas-FasL
interactions have been shown to mediate the immune privilege of the
eye.20
While it is tempting to implicate the same
molecular mechanism for the CNS, the rate of T cell apoptosis in the
CNS was not found to be reduced in mice that are genetically deficient
for Fas or FasL.21
Several other apoptosis
pathways are discussed in Bauer and colleagues' paper.
In light of all these findings, the immune privilege of the CNS could
be defined as follows. The CNS does not prevent peripherally activated
memory cells, T cell blasts in particular, from entering and surveying
it. Naive T cells and resting memory cells might not be able to
penetrate the noninflamed blood-brain barrier. If the peripherally
preactivated T cell blasts encounter "their" antigen ("foreign"
or "self") in the CNS, they can induce a vigorous inflammatory
response: T cell blasts, macrophages, and, to a lesser extent, resting
T cells (Bauer et al, Table 5) are now recruited through the inflamed
blood-brain barrier and engage in a delayed type hypersensitivity (DTH)
reaction. The duration of this T cell-mediated DTH reaction is
stringently controlled, however, by the indiscriminate killing of all
infiltrating cells after a couple of days. In this way the immune
surveillance and protection of the CNS is warranted yet chronic
inflammatory reactions that could cause permanent damage to the CNS are
prevented. This precaution might be seen as an understandable
requirement because CNS functions are more sensitive to cellular injury
than are those of most other organs.
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T Cells Surviving Entry into the CNS
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There is a further striking and novel observation reported in the
paper by Bauer et al, namely that apoptosis of T cells in the CNS is
confined to the neuroectodermal parenchyma and is not seen in the
connective tissue compartment of this organ, the perivascular space and
the meninges. The latter is where T cell blasts preferentially enter
for immune surveillance and where they leave if they do not encounter
antigen.12
The autoimmune lesions in MS and in
chronic EAE are usually perivascular. It is tempting to speculate,
therefore, that this connective tissue compartment represents the
germinal center for chronic immune and autoimmune processes. For
example, whereas the majority of the autoreactive T cells die in the
neuroectodermal parenchyma, which leads to recovery from the
initial EAE attack, the autoreactive T cells in the perivascular
compartment might become stimulated to engage in clonal expansion by
the endogenous antigen, giving rise to a new generation of effector
cells. Determinant spreading, a process during which
target-organ-specific autoreactive T cells with different specificities
become activated,21-25
also might occur in the
connective tissue compartment. Should the effector cell mass generated
during the second wave response suffice to cause disease (induction of
EAE is strictly dependent on the injection of a minimal number of CNS
antigen-reactive T cells), a relapse would occur. As in the primary
episode of the disease, the cells that enter the neuroectodermal
parenchyma will die and the second episode of EAE will also become
self-limiting. In this manner relapses and remissions of the disease
could be caused by the fluctuation of new waves of T cell responses
generated in the CNS mesenchyma followed by their decimation in the
parenchyma. It is tempting to speculate that chronic autoimmune disease
of the CNS will occur only in those individuals in whom, for various
genetic and somatic reasons, the amplifying mesenchymal reaction
prevails or in whom the counter-regulatory apoptosis in the parenchyma
is defective. However, the apoptosis pathway might be the more common
one. Only a few rodent strains are sensitive to induction of even
monophasic EAE and it took decades to identify the select strains and
protocol combinations that permit induction of chronic relapsing EAE.
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Footnotes
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Address reprint requests to Dr. Paul V. Lehmann, Department of Pathology, Biomedical Research Building, 9th Floor, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106. E-mail:pvl2{at}po.cwru.edu
Accepted for publication July 21, 1998.
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Introduction
T Cells Entering the...
