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Bacterial toxin superantigens activate human T lymphocytes reactive with myelin autoantigens.

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Bacterial -1oxm buperantlgens
Activate Human T Lymphocytes Reactive
with Myelin Autoantigens
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James Burns, MD," Kim Littlefield, BS," Janice Gill, BS," and John L. Trotter, MDt
Some bacteria that are common human pathogens produce protein toxins that are potent activators of human T
lymphocytes expressing certain types of T-cell receptors. In this study we examined the ability of staphylococcal toxins
to stimulate human T lymphocytes that also recognized the myelin autoantigens myelin basic protein and proteolipid
protein. T-cell populations responding to myelin basic protein or proteolipid protein were isolated from 4 subjects
including 1 individual with multiple sclerosis. All myelin antigen-specific T cells responded in proliferation studies
to at least one of the nine superantigenic toxins used in this study. The superantigenic toxins were up to 7 x 105-fold
more potent in proliferation assays than the myelin antigens to which the T cells were initially sensitized. In addition,
cytotoxic, myelin basic protein-reactive T lymphocytes lysed antigen-presenting cells incubated with superantigenic
toxins. These findings demonstrate a mechanism by which some bacterial infections might produce activation of
myelin basic protein- and proteolipid protein-reactive T lymphocytes and perhaps contribute to demyelinating
disease in humans.
Burns J, Littlefield K, Gill J, Trotter JL. Bacterial toxin superantigens activate human T
lymphocytes reactive with myelin autoantigens. Ann Neurol 1992;32:352-357
Protein toxins produced by certain bacteria, including
Staphylococcus aureus and Streptococcus pyogenes, induce
massive, polyclonal activation of human T cells [l-5).
These superantigenic toxins induce proliferation by
specific interaction with the T-cell receptor variable
region of the p chain (TCR Vp) { 2 ) . Depending on
the particular toxin, the stimulation can be limited to
a small proportion of the total human T-cell repertoire
or can include more than 20% of all T cells [3). The
ability of superantigens to activate large numbers of T
cells without regard to antigenic specificity has generated speculation that autoantigen-reactive T cells may
be included in the activated populations [ 3 , 41. If this
occurs, the now activated and proliferating autoantigen-specific T cells might contribute to the induction
of autoimmune disease in susceptible individuals.
While the cause of multiple sclerosis (MS) remains
uncertain, there are numerous clinical and histological
similarities between MS and experimental autoimmune
diseases of central nervous system (CNS) myelin that
are mediated by T cells recognizing myelin basic protein (MBP) o r proteolipid protein (PLP) [b, 71.Human
T cells reactive with these myelin antigens can be isolated from subjects with MS as well as most neurologically intact individuals [S- 111. This report concerns
activation of MBP- and PLP-reactive human T cells
by superantigenic toxins produced by bacteria that are
common pathogens in humans. Many investigators
have suggested a role for viral infections in MS, possibly through molecular mimicry and activation of T cells
recognizing myelin antigens [12). The current report
concerns another mechanism by which bacterial infections might also contribute to demyelinating disease by
activating myelin antigen-reactive T cells.
Materials and Methods
Antigens
Human MBP was prepared by the method of Deibler and
associates [131. PLP was isolated as previously described I1 1,
14J. Staphylococcal toxins were purchased from Toxin Technology, Inc (Madison, WI). These included staphylococcal
enterotoxins A, B (SEB), C,, C,, D, and E. Toxic shock
syndrome toxin (TSST) and exfoliating toxin were also purchased from Toxin Technology, Inc. Mycoplasma arthritidis
mitogen was generously provided by Dr B. Cole and was
used at a dilution of 1/5,000 El5J.
Cell Lines and Clones
T-cell lines and clones specific for human MBP were isolated
from peripheral blood mononuclear cells (PBMCs) by the in
From the Veterans Administration Medical Center, Neurovirology
Research, University of Utah School of Medicine, Salt Lake City,
Received Aug 27,1991, and in revised form Feb 21, 1992. Accepted
for publication Feb 23, 1992.
and the
Of
School of Medicine, St Louis, MO.
Address correspondence to Dr Burns, Neurovirology Research151B, V.A. Medical Center, 500 Foothill Drive, Salt Lake City, UT
84148.
Washington University
352 Copyright 0 1992 by the American Neurological Association
vitro sensitization method previously described (81.T cells
specific for PLP were isolated by the same technique, with
PLP used at a concentration of 25 Fglml in the initial culture
of freshly isolated PBMCs. T-cell lines and clones were maintained in culture by use of interleukin-2 and periodic restimulation at 1- to 2-week intervals by irradiated PBMCs (4,000
cGy) and the appropriate antigen. T cells were cloned by
limiting dilution in round-bottom microwells at 0.3 T cell
per well with 2.5 X lo4 irradiated PBMCs and phytohemagglutinin, 0.5 p,g/ml(16]. Cloning efficiency was usually 30 to
50%. T-cell phenotype was determined as previously described (161. Uncloned T-cell lines reactive with MBP and
PLP were more than 95% OKT3+ and OKT4+, with less
than 5% expressing OKT8. Cloned T cells were less than
1% OKT8 . B-cell lines were generated by transformation
of B cells in freshly isolated PBMCs by Epstein-Barr virus
(EBV).
polymerase chain reactions (PCRs) with primers specific for
20 TCR Vp region families and a common p chain constant
(Cp) region primer. A TCR Cm gene segment was also amplified as an internal control. The sequences of all primers and
the Cp region probe were generously provided by Drs J.
Oksenberg and L. Steinman (Stanford University Medical
Center). Oligonucleotide synthesis was performed at the
Peptide and Oligonucleotide Synthesis Facility, at the University of Utah. PCR products were electrophoresed and
Southern blots were prepared. Oligonucleotide base-pair size
markers were included to assess the size of the PCR products. An oligonucleotide probe for a common TCR Cp region was labeled and used to detect PCR products by autoradiography.
This study was approved by the University of Utah Institutional Review Board. Informed consent was obtained from
the donors whose T cells were used in this study.
Antigen-Induced Proliferation
Results
Preliminary dose-response studies were performed using freshly isolated PBMCs to determine the concentration of each superantigen that induced proliferation
of human T lymphocytes. At concentrations of 0.05
pglml, all superantigens generated brisk proliferation
of freshly isolated PBMCs from two different subjects
(not shown). This concentration was used in the initial
studies of MBP- and PLP-reactive T-cell lines. T-cell
lines and clones were studied from 4 subjects, including 3 neurologically intact control subjects and 1 subject with laboratory-supported definite MS.
Figure 1 shows the response of two, MBP-reactive
T-cell populations to the complete panel of nine superantigens as well as MBP. One clone, MBP Clone 1.3.3,
was isolated from the subject with MS and the other,
MBP Clone 7.11.1, from a neurologically intact control subject. Both T-cell clones were activated by at
least one bacterial superantigen as well as MBP. In
some instances, the level of proliferation induced by a
particular superantigen was at least as great as that induced by MBP. The results of a similar experiment
using a PLP-specific T-cell line isolated from a control
subject are shown in Figure 2. As with the MBPreactive T-cell clones, there is a brisk proliferation in
response to a number of superantigens by the PLPspecific T cells. All MBP- and PLP-reactive T-cell lines
and clones isolated from each of the 4 subjects responded to at least one of the superantigens.
Since superantigenic toxins are very potent T-cell
activators, we compared the proliferative response of
the MBP-reactive T-cell clone, 7.11.1 shown in Figure
1, to various concentrations of MBP or TSST. Figure
3 displays dose-response curves comparing the proliferation induced in parallel experiments by different
molar concentrations of MBP and TSST. As shown in
Figure 3A, 50% of the maximum response to MBP
occurs at a concentration of approximately 2.3 X lo-'
M, or 4 X
gm/ml of MBP. By contrast, as shown
+
Antigen-induced proliferation of the T-cell lines and clones
was measured by culture of T cells with irradiated autologous, antigen-presenting cells (APCs) plus antigen or superantigen without added interleukin-2. EBV-transformed Bcell lines were used as APCs for enterotoxin superantigens
to avoid high-background 3H-thymidine incorporation when
irradiated PBMCs were used as APCs. T cells reactive with
myelin antigens were removed from bulk culture and washed
in a balanced salt solution. MBP-reactive T cells (1.5 X lo4)
were incubated with 2.5 x lo4 irradiated autologous EBVtransformed B cells in 0.2 ml of medium. MBP or superantigen was added to cultures at the concentrations indicated and
proliferation was measured by 3H-thymidine incorporation
for the last 18 hours of a 72-hour culture. The response of
PLP-reactive T-cell lines to PLP or superantigens was measured in a similar manner. However, irradiated PBMCs were
used to present PLP to PLP-specific T cells since B-cell lines
were not effective in presenting PLP. However, the B-cell
lines were able to present superantigens to PLP-specific T
cells.
Cytotoxicity Assay
€3-cell lines were labeled with chromium 5 1 (51Cr)by incubation of 1 X lo6 cells in 0.2 ml of medium with 300 FCi of
"Cr for 1.5 hours at 37°C. Three aliquots were used with
one cell population incubated with 51Crplus MBP, the second with SICrplus superantigen, and the third cell population
in 51Crmedium alone. Each cell population was then washed
extensively before counting and use in the cytotoxicity assay.
Target cells (1 x lo4)were used with an effector-target ratio
of I0 : 1. Triplicate cultures were established in round-bottom
microwells and the supernatants were collected after 4 to 6
hours. Spontaneous release and maximal release were measured for all assays and used to determine the percentage
specific release. Spontaneous release was generally below
20% of the maximal release.
Determination of the T-cell Receptor Vp Usage
Messenger RNA (mRNA) was isolated from 3 x lo7cloned,
MBP-reactive T cells and complementary DNA (cDNA)
prepared. Equal amounts of cDNA were used in separate
Burns et al: Activation of T Cells by Superantigens
353
MBP Clone 1.3.3
-
MS
x
1
PLP Cell Line
- Control n 3
r
PLP
SEA
SEE
SEC,
SEC,
SED
SEE
Exfol
TSST
MAM
LA
D
10
20
L
,
C P M X 1,000 ('H-Thymidine
r
1
2
30
I
I
I
1
I
40
I
Incorporation)
Fig 2. Comparison of proliferation induced by proteolipid protein (PLP) and superantigenic toxins. A PLP-speczfic T-cell line
was isoiated from a control subject. Proliferation assays were
performed as described in Figure 1 except that irradiated peripheral blood mononuclear cells were used as antigen-presenting
cells for PLP, as described in the Methods section. Net count.,
per minute (CPM) are shown. Background CPM were less than
1,100. For abbreviation key, see Fixure 1 Legend.
MBP Clone 7.11.1 - Control # I
TCR V @ 2
MBP
SEA
SEE
SEC,
SEC,
SED
SEE
Exfol
t
I
TSST
u
0
10
CPM X 1,000 (3H-Thyrnidine
20
incorporation)
B
Fig 1. Comparison of proliferation induced by myelin basic protein (MBP) and superantigenic toxins. MBP-speci& T-cell
clones were isolated from (A) an individual with M S (Clone
1.3.3) and (8)a normal controlsubject (Clone 7.1 1.1). Prolif-
eration assays were perfrmed using Epstein-Barr virus-transf o m d B cells as antigen-presenting cells. MBP (50 &ml) or
superantigenic toxin (0.030 pglmi) was added and the proliferation was measured a f t r 72 hours. Net counts per minute
(CPM) are shwn and represent the mean 'H-thymidine incorporation in triplicate microwells minus the background CPM.
Background CPM were leu than 2,000for each assay shown.
SEA, SEB, SEC,, SEC2, SED, SEE = stapbylocoa-a1enterotoxins A . B. C,, C2, D,and E ; Exfol = exfoliating toxin; TSST
= toxic shock syndrome toxin; MAM = Mycoplasma arthritidis mitogen.
in Figure 3B, the bacterial toxin, TSST, induces 50%
maximum proliferation at approximately 3 x 1 0 - l ~
M, or 7.2 x
g d m l of TSST. In this particular
experiment the maximum proliferation induced by
MBP was approximately 15% greater than that induced by TSST. However, maximum proliferation was
induced by MBP at a concentration of 1.4 x 10 - " M
compared to a TSST concentration of 1.3 x lo-'' M.
TSST is known to activate human T cells that utilize
TCR Vp2. Since Clone 7.11.1 responded predominantly to TSST, TCR Vp usage was assessed. As shown
in Figure 4 , TCR Vp2 utilization by this T-cell clone
was confirmed. Determinations of the TCR Vp usage
in other T-cell populations isolated from this control
subject indicate use of two additional TCR Vp families,
Vp5 and VplO (not shown). Characterization of TCR
Vp usage by MBP-reactive T-cell lines and clones from
the subject with MS revealed use of TCR Vp6.1, 7,
and 13.1.
A number of investigators have noted that MBPspecific T-cell populations may possess cytotoxic activity 110, 161. In additional studies, we determined
whether the superantigen SEB could also induce lysis
of APCs by MBP-specific T lymphocytes that recognized both MBP and SEB. As shown in the Table,
cytotoxic MBP-reactive T cells lysed antigen-present-
354 Annals of Neurology Vol 32 No 3 September 1902
L
0
Q
0
0
.C
0
0
I
X
J
I
a
0
/
0
1o
-~
Molar Concentration
15
1 o-6
- MBP
1
o-’
r
/-
/
I
F ig 4. Autoradiogram of T-cell receptor (TCR) V p transcripts
from myelin basic protein (MBP)-reactive Clone 7.11.1 amplified by polymerase chain reaction. Complementary D N A was
prepared and used to determine TCR Vp usage as described in
the Methods section. The approximate size of the polymerase
chain reaction product was 200 bp, as shown by the position of
the size marker on the left. The a lane on the right contains internal control TCR C a products that do not bind the TCR Cp
probe.
Myelin Basic Protein (MBP) and Staphylococcal Enterotoxin B
(SEB) as Target Antigens for Cytolytic, MBP-Specific T Cells”
/
Molar Concentration -Toxic Shock Syndrome Toxin
% Specific Lysis
Effector T Cells
Target
Cells
Alone
Target
Cells
Plus MBP
Target
Cells
Plus SEB
MBP Clone 3.3.2
MBP Clone 3.3.3
-0.2%
0.7%
35%
64%
48%
42%
aCytolytic assays were performed with 51Cr-labeled,autologous B
cells that were preincubated with MBP (100 CLg/ml),with SEB (0.05
kg/ml), or in culture medium alone. Spontaneous release was less
than 20% of the total release.
~
Fig 3. Magnitude of activation of myelin basic protein (MBP)speci$c T cells by various concentrations of MBP and toxic shock
syndrome toxin (TSST). Proliferation assays were performed as
described in Figure 1, with the molar concentrations of MBP
and TSST shown for each antigen. The molecular mass of
TSST is 24.0 kd and of MBP is 18.5 kd. Net counts per minute (CPM) are shwn; background CPM were 900.
ing B cells that presented either MBP or SEB to this
cytotoxic T-cell clone. In parallel experiments, this Bcell line was not lysed in the absence of SEB or MBP.
Similar results were noted with two other cytotoxic,
MBP-specific T-cell populations (not shown).
Discussion
The current study demonstrates that superantigenic
bacterial toxins can activate myelin autoantigen-specific human T cells. Four subjects were studied, includ-
ing 1 subject with MS. MBP-specific T cells were isolated from all subjects and PLP-specific T cells were
isolated from 1 control subject and the individual with
MS. All cell lines and clones recognizing myelin antigens also responded in vitro to at least one of the
superantigens, with most responding to multiple superantigens. The T-cell activation potency of MBP and
the superantigen TSST was compared by use of a T-cell
clone that responded to both MBP and TSST. The
activation potency of TSST greatly exceeded that of
MBP, with 50% maximum proliferation at a concentration of 3 x
M for TSST compared to 2.2 x
lo-’ M for MBP. Superantigens were also able to induce cytolytic activity with lysis of superantigen-presenting B cells by cytotoxic, MBP-reactive T lymphocytes.
Certain bacterial protein toxins are termed superantigens due to their ability to induce massive proliferation
Burns et aI: Activation of T Cells by Superantigens 355
of T lymphocytes through interaction with the TCR
Vp gene products El-51. Thus T cells recognizing entirely different antigens are susceptible to activation by
a superantigenic toxin if these T cells happen to have
a particular TCR Vp. In speculations concerning molecular mimicry, viral infections, and autoimmune disease, a viral antigen is postulated to closely match the
primary peptide structure of an autoantigen C12). Thus
infection by a particular virus might activate autoantigen-specific T cells and lead to overt disease. However,
superantigens appear to bind the TCR Vp outside of
the normal antigen-binding groove and thus are more
charlatan antigens than molecular mimics in their manner of lymphocyte activation C31.
There is evidence that clinical infections caused by
bacteria-producing superantigenic toxins can lead to
massive activation of human T cells in vivo. Choi and
colleagues reported that during toxic shock syndrome,
the estimated percentage of peripheral blood T cells
utilizing TCR Vp2, and thus responding to TSST, increased in 5 of 8 patients from the normal value of
10% to as high as 30 to 70% E17). This suggests that
TSST generates a massive activation and proliferation
of T cells that utilize TCR Vp2 in vivo during this
infection. In the current study, an MBP-specific T-cell
clone isolated from a control subject utilized TCR Vp2
and responded to TSST. This MBP-reactive T-cell
clone was activated by concentrations of ‘CSST approximately 100,000-fold lower than required for activation
by MBP. The state of activation of MBP-specific T
cells is a critical factor in the induction of experimental
allergic encephalomyelitis. The factors responsible for
this are uncertain but may include activation-dependent adhesion molecule expression or lymphokine production. Vandenbark and colleagues noted that as few
as 0.1 x lo6 MBP-reactive T cells could induce experimental allergic encephalomyelitis if the cells had been
recently activated. However, as many as 7 x lo6 nonactivated MBP-specific T cells from the same cell line
did not induce disease [18). Thus the T-cell proliferation that can occur during some bacterial infections
might increase the number or activity of autoreactive
T cells beyond a threshold limit and contribute to overt
autoimmune disease in susceptible individuals.
A number of recent studies examined TCR Vp
usage by MBP-reactive T cells from subjects with
MS and control subjects [19-23). These studies were
prompted by findings that TCR Vp usage is very restricted in MBP-reactive T cells that induce experimental allergic encephalomyelitis E24, 251. TCR Vp usage
by MBP-specific T cells has been examined in relatively few MS subjects and control subjects. Thus there
is no consensus about whether the TCR Vp repertoire
is similarly restricted for the MBP-reactive T cells from
MS patients. Preliminary results suggest that some individuals use a restricted TCR Vp repertoire but that
different subjects may use different TCR Vp region
gene products for MBP-specific T cells 119-231. Since
the various superantigens activate T cells bearing different TCR Vp types, this implies that MBP-reactive
T cells from different individuals might be subject to
activation by different superantigens. Thus if bacterial
infections contribute to induction or exacerbation of
demyelinating disease, it is plausible that no single
pathogen is involved in all cases.
The current study demonstrates that human, myelin-reactive T lymphocytes may be activated by bacterial superantigenic toxins as well as the appropriate
autoantigen. There is speculation that viral or bacterial
infections perhaps influence the occurrence of autoimmune disease. For example, in subjects with rheumatoid arthritis, Paliard and colleagues noted an altered
T-cell repertoire in the peripheral blood and joint fluid,
suggesting possible effects of a Vp 14-specific superantigen 1261. In MS, epidemiological evidence and clinical observations suggest that environmental factors,
possibly infections, may contribute to MS induction
or exacerbation 17, 277. MS exacerbations sometimes
appear to be associated with infections; however, a
definite cause-and-effect relationship is difficult to establish {27]. Evidence linking MS and bacterial superantigenic toxins might include the association of MS
exacerbations with the selective expansion of peripheral blood T lymphocytes using particular TCR Vp
genes. If myelin-specific T cells used the same TCR
Vp genes, and a bacterial pathogen producing an appropriate superantigen toxin could be identified, then
the association would be strengthened. The current
study takes a first step in addressing these questions by
demonstrating that bacterial superantigenic toxins will
activate myelin antigen-specific T cells in vitro.
This work was supported by grants from the National Multiple Sclerosis Society (RG 1894-A to J. B. and PP 0137 to J. T.), the National
Institutes of Health (NS 275561, and by Veterans Administration
Research Funds.
We would like to thank Drs J. Rose and R. Fujinami for critical
review of the manuscript.
References
356 Annals of Neurology Vol 32 No 3 September 1992
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Burns et al: Activation of
T Cells by Superantigens 357
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