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,¶
*
Department of Microbiology, Parasitology, and Immunology, University of Buenos Aires School of Medicine, Buenos Aires, Argentina;
Laboratorio de Inmunogenética and
Division of Dermatology, Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina;
Division of Dermatology and
¶ Department of Microbiology and Immunology, University of California, Los Angeles, Medical School, Los Angeles, CA 90095;
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Division of Dermatology, Leprosy Section, Hospital de Infecciosas F.J. Muñiz, Buenos Aires, Argentina; and
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Autoimmune Diseases Unit, Novartis Forschungsinstitut, Vienna, Austria
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production. The expression and role of SLAM in human infectious disease
were investigated using leprosy as a model. We found that SLAM mRNA and
protein were more strongly expressed in skin lesions of tuberculoid
patients, those with measurable CMI to the pathogen,
Mycobacterium leprae, compared with lepromatous
patients, who have weak CMI against M. leprae.
Peripheral blood T cells from tuberculoid patients showed a striking
increase in the level of SLAM expression after stimulation with
M. leprae, whereas the expression of SLAM on T cells
from lepromatous patients show little change by M.
leprae stimulation. Engagement of SLAM by an agonistic mAb
up-regulated IFN- production from tuberculoid patients and slightly
increased the levels of IFN- in lepromatous patients. In addition,
IFN- augmented SLAM expression on M.
leprae-stimulated peripheral blood T cells from leprosy
patients. Signaling through SLAM after IFN- treatment of
Ag-stimulated cells enhanced IFN- production in lepromatous patients
to the levels of tuberculoid patients. Our data suggest that the local
release of IFN- by M. leprae-activated T cells in
tuberculoid leprosy lesions leads to up-regulation of SLAM expression.
Ligation of SLAM augments IFN- production in the local
microenvironment, creating a positive feedback loop. Failure of T cells
from lepromatous leprosy patients to produce IFN- in response to
M. leprae contributes to reduced expression of SLAM.
Therefore, the activation of SLAM may promote the cell-mediated immune
response to intracellular bacterial pathogens. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(1), a macrophage-activating cytokine produced by T cells.
Leprosy is a dynamic infectious disease in which distinct
Mycobacterium leprae-responsive T cell subsets appear to
control the clinical and immunologic spectrum. For example, tuberculoid
leprosy patients, those able to restrict the growth of the pathogen and
mount strong T cell responses to M. leprae, locally produce
the Th1 cytokine pattern, including IFN- (2, 3). In
contrast, lepromatous patients manifest disseminated infection, their T
cells weakly respond to M. leprae, and their lesions express
the Th2 cytokines, typical of humoral responses and suppression of
cell-mediated immunity (CMI).3
Although Th cells go through a differentiation process that
"programs" their cytokine production upon TCR stimulation,
additional factors can influence the level and pattern of cytokines
produced by activated T cells. One of these factors is signaling
lymphocytic activation molecule (SLAM, CD150), a transmembrane type I
glycoprotein of the CD2 subfamily expressed on lymphocytes and immature
thymocytes that boosts IFN- production and proliferation
(4). The expression of SLAM is rapidly induced on naive T
cells after activation and ligation of SLAM redirects Th2 responses to
a Th1 or Th0 phenotype (5).
We wished to ascertain whether signaling through SLAM enhances T cell
production of IFN- in intracellular infection, therefore, we
investigated the role of SLAM in leprosy. We found that SLAM expression
in leprosy correlates with Th1 responses in vitro and in vivo. SLAM
ligation enhanced IFN- production and SLAM expression was
up-regulated by IFN-, suggesting that a positive feedback loop
exists whereby SLAM and IFN- promote CMI responses to mycobacterial
infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patients with leprosy were evaluated at the Hospital de Clínicas José de San Martín (University of Buenos Aires School of Medicine, Buenos Aires, Argentina) and at the Hospital de Infecciosas F.J. Muñiz (Buenos Aires, Argentina) and were classified according to the criteria of Ridley and Jopling (6). Peripheral blood was collected in heparinized tubes from patients with tuberculoid (T-Lep) and lepromatous (L-Lep) leprosy. After receiving informed consent, skin biopsies from leprosy patients were obtained, embedded in OCT medium (Ames, Elkhart, IN), snap frozen in liquid nitrogen, and stored at -70°C.
M. leprae
M. leprae was provided by Dr. P. Brennan (Colorado State University, Ft. Collins, CO, National Institutes of Health contract N01-AI-75320) and was prepared by probe sonication (7). A similar extract was prepared from the virulent M. tuberculosis strain H37Rv. In vitro stimulation of cells throughout the present study was performed with these sonicated preparations of mycobacteria.
Cell preparations and culture conditions
PBMCs were isolated from heparinized blood by density gradient
centrifugation on Ficoll-Paque (Amersham Pharmacia Biotech, Piscataway,
NJ) and were cultured (1 x 106/ml) with
sonicated M. leprae (10 µg/ml) in 24- or 96-well plates
with RPMI 1640 (Life Technologies, Grand Island, NY) supplemented with
glutamine (2 mM, Sigma-Aldrich, St. Louis, MO), streptomycin,
penicillin, and human serum (10%). After 5 days, cells were washed and
examined for SLAM expression by flow cytometry (below) or they were
cultured in the presence of anti-SLAM mAb (A12) and examined for
IFN- production by ELISA (Endogen, Woburn, MA). For studies
involving SLAM expression, neutralizing IFN- Abs or isotype control
Abs were added together with M. leprae in some cases. For
IFN- production studies, human rIL-12 (100 nM) or human rIFN-
(7.5 ng/ml; Endogen) were added to some cultures at final
concentrations. The anti-SLAM mAb A12 has previously been described
(4).
SLAM mRNA detection
RT-PCR for SLAM mRNA in leprosy lesions was performed using
specific primers, as described (4). Briefly, total RNA was
isolated using TRIzol reagent (Life Technologies). First-strand cDNA
was synthesized using Superscript reverse transcriptase (Life
Technologies, Rockville, MD) and oligo dT priming (Amersham Pharmacia
Biotech). cDNA samples were amplified with SLAM-specific PCR
primers and Taq polymerase (PerkinElmer/Cetus, Norwalk, CT)
in a DNA Thermocycler (PerkinElmer/Cetus). For comparison of SLAM mRNA
levels among different samples, cDNA concentrations were normalized to
yield equivalent 
-actin PCR products. PCR products were
electrophoresed on 1.5% agarose gels, transferred to nylon membranes
(Amersham, Arlington Heights, IL), probed with a
32P-labeled SLAM oligonucleotides internal to the
PCR primers, and visualized by autoradiography. The sequences of primer
pairs, 5' and 3', were as follows: 5'-ATCACTGGAGAACAGTGT, and
3'-CCCGTCACATACGACCC. The SLAM probe sequence was as follows:
5'-GACCTGCACCTTGATACTGG-3'.
PCR for IFN- mRNA was performed as described using specific primers
(3). The IFN- probe sequence was as follows:
5'-TGCAGAGCCAAATTGTCTCC-3'.
SLAM protein detection
SLAM expression in leprosy lesions was determined by immunoperoxidase labeling of cryostat sections of biopsy samples (8) using anti-SLAM mAb (IPO-3; Kamiya Biomedical, Seattle, WA) or an isotype-matched control mAb. Briefly, cryostat sections (3–4 µm) were acetone fixed and blocked with normal horse serum before incubation with the mAbs for 60 min, followed by biotinylated horse anti-mouse IgG for 30 min. Slides were washed with phosphate buffer between incubations. Primary Abs were visualized with the ABC Elite system (Vector Laboratories, Burlingame, CA), which uses avidin and biotin-peroxidase conjugate for signal amplification. ABC was incubated for 30 min, followed by the addition of substrate (3-amino-9-ethylcarbazole) for 10 min. Slides were counterstained with hematoxylin and were mounted in aqueous dry mounting medium (Crystal Mount; Biomeda, Foster City, CA). The level of SLAM-positive cells in dermal granulomas was quantitated by calculating the percentage of positive cells based on the total number of cells within the granuloma as described (8).
To determine the level of SLAM expression on T cells, PBMCs cultured with M. leprae were stained for surface expression with mAbs specific for CD3 (BD Biosciences, Mountain View, CA) and SLAM (A12) (4) before and after culture. Samples were analyzed on a FACScan flow cytometer (BD Biosciences). SLAM expression on cells cultured in media alone varied from patient to patient, but this variability was within the same range for both tuberculoid and lepromatous patients.
Intracellular analysis of IFN- production
Intracellular cytokine staining was used to determine the
IFN- production at the single-cell level as previously described
(9). Briefly, M. leprae-stimulated cells were
cultured with monensin (2 mM, Calbiochem, La Jolla, CA) for the final
2 h to induce the intracellular accumulation of newly synthesized
proteins. Cells were then harvested, stained for surface expression
with mAbs specific for CD3 (BD Biosciences) and SLAM (A12;
4), and washed with PBS-2% FCS. Intracellular IFN-
staining was performed with PE-conjugated anti-IFN- (BD
Biosciences), using the Fix & Perm kit (Caltag Laboratories, San
Francisco, CA) according to the manufacturer’s instructions. Samples
were analyzed on a FACScan flow cytometer (BD Biosciences). Negative
control samples were incubated with irrelevant, isotype-matched Abs in
parallel with all experimental samples.
Statistical analysis
Statistical analysis was performed using nonparametric methods including the Wilcoxon signed rank test for paired samples or the Mann Whitney U rank sum test for independent samples. Values of p < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the role of SLAM in the Th1 response to M.
leprae infection, we examined the pattern of SLAM mRNA expression
in cells from leprosy lesions using RT-PCR. Our results showed that
SLAM mRNA was strongly expressed in cells from tuberculoid lesions,
whereas it was absent in most of the lepromatous patients (Fig. 1
A). Furthermore, we
determined the expression of IFN- mRNA in the same skin lesions. As
expected, IFN- mRNAs were markedly higher in tuberculoid lesions
than in lepromatous lesions (3). Interestingly, the only
lepromatous patient that expressed weak levels of SLAM mRNA also
expressed IFN- mRNA (Fig. 1A). The altered levels of SLAM
in cells from leprosy patients suggest that differential expression of
this activation molecule may contribute to the outcome of leprosy
infection.
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B shows numerous
SLAM-positive cells with strong staining in a tuberculoid granuloma. In
contrast, SLAM-positive cells were rare in lepromatous lesions.
Isotype-matched control mAb staining was negative (data not shown).
Quantification of SLAM-positive cells in leprosy lesions revealed that
tuberculoid lesions contained 12.3 ± 3.8% (mean ± SEM)
SLAM-positive cells, whereas lepromatous lesions contained 1.7 ±
0.8% (p < 0.001, rank sum test; Fig. 1C). These data indicate that local expression of SLAM is
greatest in the group of patients with effective CMI, suggesting that
the distribution of SLAM in leprosy parallels the level of CMI to
M. leprae.
In contrast to our findings in the active lesions of leprosy patients,
the levels of SLAM on resting peripheral blood T cells from tuberculoid
and lepromatous patients were similar (Fig. 1D), supporting
the hypothesis that the different T lymphocyte subsets in skin biopsies
from leprosy patients are more closely related to the immune status of
these individuals than those in peripheral blood (10).
However, we found higher SLAM expression on CD3+
T cells from leprosy patients compared with healthy donors (data not
shown), suggesting that, systemically, T cells in leprosy patients
exist in an activated state, although not necessarily responsive to the
pathogen.
T cells up-regulate SLAM after Ag stimulation in responsive, but not unresponsive, patients
Because SLAM was predominantly expressed in the lesions of
patients characterized by enhanced CMI against M. leprae, we
hypothesized that SLAM expression correlated with T cell activity
against the pathogen. To investigate this possibility, PBMCs from
leprosy patients were stimulated with M. leprae, and the
expression of SLAM was determined. Fig. 2A shows the increase in SLAM
expression in a tuberculoid patient after M. leprae
stimulation, whereas M. leprae did not modify the percentage
of SLAM-expressing T cells in a lepromatous patient (Fig. 2B). These results were confirmed in a large group of
leprosy patients. Fig. 2C illustrates that M.
leprae stimulation significantly increased the expression of SLAM
in tuberculoid patients (p < 0.001, signed
rank test), whereas the expression of the receptor was not modified by
specific M. leprae stimulation in lepromatous patients (Fig. 2D). Cells from healthy donors cultured with M.
leprae also up-regulated SLAM expression (data not shown). Healthy
donors likely responded to M. leprae because the donors were
bacillus Calmette-Guérin vaccinated and contained M.
tuberculosis-reactive T cells that cross-reacted with the leprosy
bacillus. Thus, SLAM expression correlates with T cell responsiveness
to M. leprae.
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E). In contrast, in lepromatous patients, M.
leprae did not modify the percentage of SLAM expression, whereas
M. tuberculosis strongly increased the levels of SLAM on
CD3+ T cells from these patients (Fig. 2F). Our results indicate that the lack of up-regulation of
SLAM after specific Ag stimulation in unresponsive lepromatous patients
is not related to a global defect in the expression of the protein, but
is associated with the specific unresponsiveness of T cells from these
individuals to M. leprae.
Regulation of SLAM expression by IFN-
Data from Fig. 1 demonstrate that SLAM expression in leprosy
lesions correlates with IFN- expression and that SLAM is expressed
in the group of patients who demonstrate CMI against the pathogen. To
further define the relationship between SLAM and IFN- production, we
measured SLAM expression and IFN- production by flow cytometry after
M. leprae stimulation. We found that virtually all (93%) of
the IFN--producing T cells expressed SLAM (Fig. 3A). T cells that expressed
SLAM but did not express IFN- may have taken up IFN- from
neighboring T cells. Together, these data suggested to us that SLAM
could be regulated by Th1 cytokines.
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, we studied
the effect of neutralizing anti-IFN- mAb on M.
leprae-induced SLAM expression. PBMCs from responder tuberculoid
patients were stimulated with M. leprae Ag in the presence
or absence of neutralizing anti-IFN- mAb or an isotype control
mAb, and the expression of SLAM was determined after five days. As
shown in Fig. 3, B (one donor) and C (multiple
donors), the levels of SLAM induced in response to Ag were markedly
inhibited by anti-IFN-, suggesting that M.
leprae-induced IFN- participates in the up-regulation of SLAM
expression. Up-regulation of SLAM in healthy donors after stimulation
with M. leprae was also IFN- dependent (data not
shown).
We next examined whether SLAM expression could be enhanced in M.
leprae-unresponsive patients through the addition of
proinflammatory cytokines. PBMCs from leprosy patients were stimulated
with M. leprae in the presence or absence of IFN- or
IL-12, and after 5 days the cells were stained for SLAM expression.
When added alone, cytokines did not alter the expression of SLAM (data
not shown). However, when the cells were stimulated with M.
leprae, IFN- significantly increased the expression of SLAM on
T cells from lepromatous patients when compared with cells stimulated
with M. leprae alone (Fig. 3D). As expected,
IFN- treatment also increased SLAM expression on M.
leprae- stimulated T cells from tuberculoid patients (Fig. 3D). Enhancement of M. leprae-activated SLAM
expression by rIFN- appears modest relative to the ability of
IFN- Abs to reduce SLAM expression. Neutralization of IFN- by Ab
reduces the ability of M. leprae-triggered IFN- as
well as endogenous IFN- to enhance SLAM expression, thus the effect
of the Ab can be expected to be more striking. rIL-12 enhanced the
expression of SLAM on M. leprae-stimulated T cells,
however, this effect was not as striking as the effect of IFN- (data
not shown). These results, together with our observation that
anti-IFN- mAb blocked the ability of Ag to up-regulate SLAM,
indicate that the up-regulation of SLAM expression in tuberculoid
patients in response to M. leprae is mediated by
IFN-.
Effect of SLAM ligation on Th1 responses to M. leprae
Because specific unresponsiveness of T cells to M.
leprae is the primary immunologic characteristic of lepromatous
leprosy patients and because engagement of SLAM was demonstrated to
induce up-regulation of IFN- production by T cell clones
(13), even Th2 clones, we investigated whether ligation of
SLAM could enhance M. leprae-induced Th1 responses in
leprosy. To address this question, PBMCs from a large group of
tuberculoid and lepromatous patients were stimulated for 5 days with
M. leprae and then with an agonistic anti-SLAM mAb. Fig. 4A shows that engagement
through SLAM significantly increased IFN- production from
tuberculoid patients (p < 0.01, signed rank
test). No effect of anti-SLAM mAb on IFN- production was
observed if cells were cultured in the absence of M. leprae.
We also investigated whether engagement through SLAM could enhance
M. leprae-induced T cell responses in unresponsive
lepromatous patients. Although stimulation with anti-SLAM mAb
slightly augmented the levels of Ag-induced IFN- produced by L-Lep
patients (Fig. 4B), the levels of IFN- produced by
lepromatous patients did not reach those produced by tuberculoid
patients after ligation through SLAM (Fig. 4A), likely
because SLAM is not induced dramatically on the T cells of lepromatous
patients in response to M. leprae (Fig. 2). Addition of
anti-SLAM mAb had no effect on IL-4 production, either from
tuberculoid or from lepromatous patients.
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production to M.
leprae after treatment with proinflammatory cytokines
We wished to determine whether IFN- production from
unresponsive patients could be enhanced by ligation of SLAM. To
investigate this possibility, we stimulated PBMCs from lepromatous
patients with M. leprae in the presence or absence of
IFN- or IL-12. After 5 days, stimulated cells were washed to remove
exogenously added cytokines and were cultured in the presence or
absence of anti-SLAM mAb. In tuberculoid patients, culture with
M. leprae alone caused T cells to be responsive to SLAM
ligation as measured by IFN- production (Fig. 4A). In
contrast, when lepromatous patient PBMCs were cultured with M.
leprae alone, SLAM ligation induced IFN- only slightly above
that of cells cultured without Ag. However, signaling through SLAM
after treatment with rIFN- plus M. leprae enhanced
IFN- production in unresponsive lepromatous patients up to the
levels of responsive tuberculoid patients (Fig. 4, A and
B). Treatment with rIL-12 plus M. leprae caused a
small increase in the levels of IFN- produced by L-Lep patients
after SLAM ligation (Fig. 4B). Our data indicate that the
ability of T cells to respond to SLAM ligation can be enhanced by
culture with IFN-.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production from tuberculoid patients, but only slightly
increased the levels of IFN- in lepromatous patients. However,
rIFN- increased the expression of SLAM on T cells from lepromatous
patients, and subsequent SLAM ligation enhanced IFN- production in
lepromatous patients comparable with those of tuberculoid patients.
Together, these data suggest that SLAM may contribute to the generation
of Th1 responses to M. leprae.
An important aspect of our study was the ability to investigate
the expression of SLAM at the site of a human infection. We found that
SLAM mRNA and protein expression correlated with the self-limiting form
of leprosy and with IFN- expression in vivo, providing evidence that
SLAM signaling promotes Th1 responses at the site of infection. The
activation of SLAM on T cells not only promotes Th1 responses in human
disease, but also has the capacity to reverse existing Th2 responses
toward the Th1 pole in HIV disease (14) and allergy
(13). Further evidence implicating SLAM in directing Th1
cytokine responses in human disease has recently emerged from the study
of X-linked lymphoproliferative disease, a disease resulting from a
deficiency in a protein termed SLAM-associated protein
(15), resulting in disregulated SLAM signaling. These
patients are characterized by T cells that, in response to virus,
produce high levels of IFN- (16), an inability to
differentiate into Th2 cells (16), and deficient T and B
cell interactions (15).
Differences in SLAM expression in the polar forms of leprosy led us to
examine the regulation of SLAM expression in vitro. Our data suggest
that two factors may be involved in regulating SLAM expression: TCR
activation and IFN- production. Tuberculoid leprosy patients, whose
T cells proliferate (10) and make IFN-
(17) in response to M. leprae, up-regulated
SLAM in response to the pathogen; in contrast, lepromatous patients,
whose T cells show only weak proliferative and Th1 responses to
M. leprae (10, 17), did not up-regulate SLAM
under the same conditions. However, coculture of PBMCs with IFN- and
M. leprae did up-regulate SLAM expression in lepromatous
patients to the level of tuberculoid patients, suggesting that IFN-
production is critical to induction of SLAM expression. Our finding
that neutralizing IFN- strongly inhibited the M.
leprae-stimulated up-regulation of SLAM in tuberculoid patients
further supported this hypothesis. Furthermore, murine studies indicate
that Th1 cells up-regulated SLAM when stimulated through the TCR,
whereas Th2 cells did not (5). We found that IFN- alone
did not up-regulate SLAM, indicating that at least two signals are
required for the up-regulation of SLAM. Therefore, the polar lesions of
leprosy patients are a snapshot of the extremes of SLAM expression.
Tuberculoid lesions contain Ag-responsive, IFN--producing T cells
resulting in SLAM expression; in contrast, lepromatous lesions contain
M. leprae-unresponsive T cells and lack IFN- production,
but express Th2 cytokines, including IL-10 (3), a cytokine
shown to inhibit SLAM expression (18).
Our study suggests that SLAM might be a focal point for therapeutic
modulation of T cell cytokine responses in diseases characterized by
dysfunctional Th2 responses, as has been suggested in allergy
(13) and HIV disease (14). However, caution
must be used in designing ways to manipulate SLAM to promote Th1
responses because inappropriate expression of SLAM can result in
overproduction of IFN- and autoimmune pathology. For example, when T
cells recognize self-Ag such as in rheumatoid arthritis and multiple
sclerosis, SLAM expression and IFN- production are up-regulated
(5, 19). Thus, through the induction of IFN-, SLAM can
either enhance antimicrobial immunity or promote autoimmunity,
depending on the context of the immune response, making it critical to
understand the regulation of SLAM expression and function in greater
detail.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Peter A. Sieling, Division of Dermatology 52-121 CHS, University of California, Los Angeles, Medical School, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail address: psieling{at}mednet.ucla.edu
3 Abbreviations used in this paper: CMI, cell-mediated immunity; SLAM, signaling lymphocytic activation molecule; T-Lep, tuberculoid leprosy; L-Lep, lepromatous leprosy.
Received for publication June 7, 2001. Accepted for publication September 17, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene-disrupted mice. J. Exp. Med. 178:2243.
T cell responses to nonpeptide mycobacterial antigens. J. Immunol. 159:1328.[Abstract]
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