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*
Laboratory of Infectious Diseases, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; and
Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Structurally, the B. fragilis capsular polysaccharides exist in an ionic complex of molecules referred to as the capsular polysaccharide complex (CPC)6 8 . The CPC can be separated into two major high m.w. polysaccharides that are named, respectively, polysaccharide A (PS A) and polysaccharide B (PS B) 9, 10 . High resolution NMR spectra reveal that the PS A and PS B molecules are structurally dissimilar but are both comprised of repeating units that are substituted along their length with positively charged amino groups and negatively charged carboxyl groups 9, 10 . Structure-function studies have shown that PS A is significantly more potent in inducing abscesses than PS B. The distinctive zwitterionic chemical structures of these molecules are the basis of their unique immunological and pathobiological properties and are thought to mediate the stimulation of T lymphocytes in vivo 7, 11 .
Biologically, the PS A molecule induces separate and paradoxically opposing activities in vivo. Injection of purified or CPC-associated PS A i.p. into rodents along with barium sulfate adjuvant and sterile cecal contents of meat-fed rats induces prolonged inflammatory responses that promote cellular infiltration and subsequent abscess formation, while s.c. injection of PS A with no adjuvants induces systemic and protective immunity against abscess formation following i.p. challenge 7, 8 . Studies in T cell-depleted and T cell-reconstituted mice have shown that the formation of abscesses is a T cell-dependent process 6 . Although protection against B. fragilis bacteremia is conferred by serum Abs to the CPC Ags, previous work has demonstrated convincingly that immunity to B. fragilis-induced abscess formation in mice and rats is transferred to naive recipients only with immune donor T lymphocytes 4, 6, 12 . Thus, in addition to its distinctive biochemical structure, the ability of PS A to stimulate protective T cell-mediated immunity is a characteristic that further distinguishes this molecule from other bacterial capsular polysaccharide Ags.
Studies on the T cell stimulatory properties of PS A must also take into account the various immunological factors that contribute to the induction or suppression of T cell responses in vivo, and how these affect bacterial clearance or abscess formation during infection with B. fragilis. One way to investigate these factors is to develop in vitro analyses that can help define which types of accessory or APCs and cytokines are associated with the induction of T cell responses to PS A. To this end, we have investigated the cellular mitogenic properties of the B. fragilis PS A molecule on mouse and rat lymphocyte subsets in vitro. The results show the PS A molecule to be a potent lymphocyte mitogen that is distinguishable from the polyclonal B cell activator LPS, the T cell mitogen Con A, and the superantigen staphylococcal entertoxin A (SEA). Cellular depletion experiments demonstrated that the PS A molecule stimulated proliferation of mouse B lymphocytes and rat T lymphocytes differentially. The PS A-induced proliferation of mouse B cells did not require exogenous APC function, while rat T lymphocytes responded to the polysaccharide in a strictly APC-dependent fashion. The differential stimulatory effects of PS A on mouse and rat lymphocytes may reflect the ability of this capsular polysaccharide to stimulate different lymphocyte subsets in vivo that relate to the types and activities of receptor/counter-receptor pairs present on responder lymphocytes and cognate APC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6, C3H/FeJ, and C3H/HeJ (LPS nonresponder) male mice, aged 5–6 wk, were obtained from The Jackson Laboratory (Bar Harbor, ME), housed in our animal care facility at Dana-Farber Cancer Institute (Boston, MA), and given water and food ad libitum. Five- to 12-wk-old mice were used in all experiments. Male Wistar or Lewis rats were obtained from The Jackson Laboratory at 5–6 wk of age and were housed and fed at the animal care facility at Harvard Medical School (Boston, MA). Rats of various ages (from 6–16 wk) were used for cellular proliferation experiments.
Preparation of purified PS A
PS A was extracted from pure cultures of B. fragilis grown under strict anaerobic conditions, purified biochemically as described previously, lyophilized, and stored desiccated at 4°C 10 . The purity of PS A was evaluated by high resolution NMR spectroscopy and immunoelectrophoresis, and determined to be free of contaminating bacterial LPS by the Limulus amebocyte lysate assay (Associates of Cape Cod, Falmouth, MA). Before analysis, lots of PS A were dissolved in sterile pyrogen-free water at a concentration of 500-1000 µg/ml and filter-sterilized. Lots prepared in this fashion and stored at 4°C maintained mitogenic activity for at least 3 mo.
Culture media and Abs
Single-cell suspensions of mouse and rat lymphocytes were prepared in RPMI medium (Mediatech, Herndon, VA) containing 10% heat-inactivated FBS (HyClone (Logan, UT) or BioWhittaker (Walkersville, MD)), 10 mM HEPES, 4 mM L-glutamine, 100 U/ml penicillin, and 0.1 mg/ml streptomycin (RPMI-C). Lymphocytes were cultivated for cellular proliferation assays in DMEM-C (Mediatech) containing 10% FBS, 4 mM L-glutamine, 4500 µg/ml L-glucose, 5 x 10-5 M 2-ME, 100 U/ml penicillin, and 0.1 mg/ml streptomycin. Anti-Thy-1.2 mAb (IgM ascites) was purchased from BioSource International (Camarillo, CA) and was clarified by centrifugation before storage at 4°C. Purified mouse mAbs against rat CD45R (clone HIS24, IgG2b), CD4 (clone OX-35, IgG2a), and CD8a (clone OX-8, IgG1) were purchased from PharMingen (San Diego, CA). Low-Tox M rabbit complement was purchased from Accurate Chemical (Westbury, NY). Goat anti-mouse IgG-conjugated and goat anti-rat IgG-conjugated Magnetobeads (heavy and light chain specific) were purchased from PerSeptive Biosystems (Cambridge, MA). LPS and Con A mitogens were purchased from Sigma (St. Louis, MO); SEA was a gift from Dr. Keith Solomon (Dana-Farber Cancer Institute).
Cells and cellular depletion
Single-cell suspensions of lymphocytes from mouse or rat spleens
and pooled inguinal, popliteal, and axillary lymph nodes (LN) of mice
(n 
2 animals) were obtained by pressing tissues
through flame-sterilized 200-mesh stainless steel screens (Small Parts,
Miami, FL) in the presence of RPMI-C. RBC in cell pellets were lysed
with aqueous ammonium chloride, and the lymphocytes were immediately
washed and resuspended in cultivation medium (DMEM-C) or medium used
for Ab depletion (RPMI-C). Bulk splenic lymphocytes and LN cell
preparations were enriched for T cells by passage through 1-g
quantities of sterile brushed nylon wool (Cellular Products, Buffalo,
NY), using a 45-min adsorption period at 37°C, followed by elution of
the nonadherent T cells with warm DMEM-C. Adherent macrophages and B
cells were also removed from mouse LN cell preparations directly by
treatment with goat anti-mouse IgG Magnetobeads for 30 min at
4°C, followed by separation over a strong magnetic source (Perseptive
Biosystems, Cambridge, MA). Rat splenic T lymphocytes were enriched by
nylon wool passage alone or by treatment of nylon wool nonadherent
cells with mouse anti-rat CD45R mAb and removal of Ab-coated cells
with goat anti-mouse Magnetobeads (30-min incubations each at
4°C). Rat CD4+ and CD8+ splenic lymphocytes
were removed from T cell-enriched cell suspensions by treatment with
mouse anti-rat CD4 or anti-rat CD8a mAbs, followed by
separation with goat anti-mouse IgG Magnetobeads. Mouse T cells
were removed by incubating bulk spleen or LN cells with 1/1000-diluted
anti-Thy-1.2 for 1 h at 4°C and then lysing Ab-coated cells
in 10% Low-Tox M rabbit complement at 37°C for 1 h according to
the manufacturer’s instructions. EBV-transformed human B
lymphoblastoid X50-7 cells (a gift from Dr. Joyce Fingeroth,
Dana-Farber Cancer Institute) were used as stimulator cells for rat T
cells in the indicated experiments and were cultivated continuously in
RPMI-C.
Lymphocyte proliferation
Cellular proliferative responses were measured by incubating 2.0–2.5 x 105 unfractionated or fractionated splenic lymphocytes or LN cells in 200 µl of medium containing optimal concentrations of PS A, LPS, SEA, or Con A for 5 days or over a range of time periods at 37°C in a 10% CO2 atmosphere. Samples were cultured in triplicate or quadruplicate wells of 96-well U-bottom plates (Costar, Cambridge, MA). In certain experiments, mouse lymphocyte responses to LPS and PS A were tested in the presence of 10 µg/ml of the lipid A antagonist polymyxin B (Sigma). The proliferative responses of purified rat splenic T cells were measured in the presence of an equal or twofold increased number of unfractionated irradiated (6000 rad) rat spleen feeder cells, irradiated EBV-transformed human B lymphoblastoid (X50-7) cells 13, 14 , or irradiated and paraformaldehyde-fixed X50-7 cells. Cells were then labeled for 5–6 h with 1 µCi/well of tritiated thymidine ([3H]TdR; New England Nuclear, Boston, MA), harvested in an automated plate harvester (TomTech, Orange, CT), and counted in a Wallac 5000 scintillation spectrometer (Wallac, Gaithersburg, MD). Data are expressed as the arithmetic mean counts per minute ± SEM.
FACS analysis
Mouse lymphocytes were stained for FACS analysis with the
FITC-conjugated mAbs, hamster anti-mouse CD3
(clone 145-2C11,
IgG, Boehringer Mannheim, Indianapolis, IN), rat anti-mouse CD45R
(clone RA3-6B2, IgG2a, PharMingen, San Diego, CA), or rat
anti-mouse CD4 (clone H129.19, IgG2a, Sigma). Rat lymphocytes were
stained for FACS with FITC-conjugated anti-rat CD45R, CD4, and CD8
mAbs (mAbs listed in Culture media and Abs above) and with
anti-rat CD3 mAb (clone G4.18, IgG3, PharMingen). Irrelevant Abs
used as controls for FACS included affinity-purified, FITC-labeled goat
anti-rabbit IgG and FITC-labeled mouse anti-human CD4 (clone
Q4120, IgG1), both purchased from Sigma. At least 100,000 lymphocytes
contained in 25 µl of medium were stained with 10–20 µg/ml of
FITC-conjugated mAbs in RPMI-C for 30 min on ice, washed once in 1-ml
volumes of cold medium, and fixed in 1 ml of cold 1% buffered
paraformaldehyde before analysis in a Becton Dickinson flow cytometer
(Mountain View, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preliminary experiments showed that purified PS A stimulated proliferation of bulk spleen cells from uninoculated syngeneic mice of the H-2d, H-2b, and H-2k haplotypes, with maximal proliferation noted between 3 and 5 days of incubation in vitro. We considered the cellular activating property of PS A to be mitogen-like, since this activity did not require prior immunization or MHC restriction. We subsequently studied the mitogenic potential of PS A on pooled lymphocytes from inguinal, popliteal, and axillary LN and spleens of C57BL/6 (B6) mice, and performed a series of cellular depletion experiments to determine whether mouse T or B lymphocytes were the predominant responder cells to PS A in vitro.
The two graphs in Fig. 1
show the
proliferative responses of unfractionated and T cell-depleted B6 LN and
spleen cells after 5-day incubation with previously optimized
concentrations of PS A, LPS, SEA, or Con A. Both unfractionated and T
cell-depleted lymphocytes proliferated well in the presence of PS A,
and these responses were comparable to those to LPS. However,
variability in the responses to PS A and LPS between experiments did
not permit comparison of the relative potencies of the two stimuli at
fixed incubation periods or kinetically. Depletion of T cells with
anti-Thy-1.2 and complement effectively eliminated cellular
responses to SEA (Fig. 1A) and Con A (Fig. 1B),
but did not affect responses to LPS and PS A. Flow cytometric analysis
(Fig. 2) illustrates the fact that
antibody plus complement treatment removed the majority of T cells from
bulk spleen lymphocyte suspensions, but may have left a small number of
CD3+ T cells behind (<5% of the control T cell number).
This same depletion method also removed the majority of T cells from
mouse LN cell suspensions (data not shown). Thus, similar to LPS, mouse
LN or spleen lymphocyte responses to PS A were not T cell associated.
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). The observation that B cell depletion
did not actually increase SEA responses suggested that limiting numbers
of APC in these preparations dampened the resulting enriched T cell
responses to SEA. Mouse lymphocyte responses to PS A were consistently
similar to the pattern observed with the B cell mitogen LPS; namely,
that T cell depletion had no effect on cellular responses to either PS
A or LPS, while B cell depletion eliminated cellular responses.
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) indicated that B lymphocytes from naive mice were the
predominant responder cells to PS A in vitro. However, these data could
not rule out the possible contribution of even small numbers of T cells
to the overall proliferative responses to PS A by mouse lymphocytes.
Our attempts to measure mouse T cell responses to PS A by repletion
with irradiated syngeneic feeder spleen cells were not successful (data
not shown). The mitogenic activity of PS A is distinguishable from that of LPS
Experiments were performed to provide immunological evidence that
PS A and LPS were qualitatively different and to corroborate
biochemical and immunochemical data on the purity of the PS A
preparations made in our laboratories. Two lines of evidence
demonstrated that the PS A and LPS mitogens were distinguishable from
each other. First, the PS A-driven proliferative response of whole LN
cells from B6 mice was not affected by the lipid A antagonist polymyxin
B, which effectively inhibited the response to LPS (Fig. 4). Secondly, PS A stimulated the
proliferation of spleen cells obtained from LPS-nonresponder C3H/HeJ
mice to a level equalling 75% of the response obtained with cells from
LPS responder C3H/FeJ control mice (Fig. 5). As expected, spleen cells from HeJ
mice responded poorly to LPS, reaching only 24% of the LPS-driven
response achieved by control FeJ spleen cells (Fig. 5).
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A model for abscess induction in the rat has demonstrated a role
for rat T cells 7, 11, 12 . The T cell-mediated protective immunity
elicited by this polysaccharide in vivo led us to investigate the in
vitro stimulatory effect of PS A on rat lymphocytes. In contrast to
mouse lymphocytes, the proliferative responses of B cell-depleted (T
cell-enriched) rat lymphocytes to PS A could be restored with
autologous irradiated splenic feeder cells (Table I), thus rendering our assay system
useful for studying the potential T cell stimulatory effects of PS A on
murine lymphocytes. The pattern of repletion in several experiments
with rat spleen cells suggested that rat B cells may also respond to PS
A, since addition of irradiated feeder cells to B cell-depleted
responder lymphocytes did not completely restore cellular proliferation
to the level seen in unfractionated cells (Table I). Of interest,
however, was the fact that any response could be obtained from a T
cell. B cells are known to respond to polysaccharide Ags 15 . We
therefore used our assay system for identifying the subclass(es) of rat
T cells that respond to PS A using the cellular depletion strategy.
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T cell-enriched rat spleen cells (B cell-depleted group) proliferated
in response to PS A in a time-dependent manner, with the maximum
response occurring after 7 days of incubation. This response was
comparable to the 7-day response of unfractionated spleen cells but, in
this and other experiments, demonstrated slower response kinetics to PS
A than did unfractionated spleen cells. Depletion of the
CD4+ population of cells resulted in nearly complete
elimination of the proliferative response to PS A (Fig. 6). In two
other time-course experiments, the proliferative responses of purified
rat spleen T cells to PS A in the presence of feeder cells remained at
maximal levels through 9 days of incubation and declined by 12 days in
culture (data not shown).
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To extend our observations, we measured the 8-day proliferation of
CD4-depleted and CD8-depleted splenic rat lymphocytes in response to PS
A (see Fig. 7 for the phenotypic profiles
of depleted cell preparations). The results of this experiment, shown
in Fig. 8, revealed that depletion of
CD4+ cells, but not of CD8+ T cells, eliminated
PS A-driven cellular proliferation, thereby identifying
CD4+ rat lymphocytes as the PS A-responsive cell type in
vitro.
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).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data indicate that PS A is not a classical T cell mitogen, because
of its ability to stimulate both B and T cells. However, it can be
classified as a cellular mitogen by virtue of its ability to stimulate
nonimmune lymphocytes with no apparent restriction for MHC
determinants. Initially, we eliminated the possibility that LPS
contaminated our preparations of PS A by several sensitive criteria,
including immunoelectrophoresis, NMR spectroscopy, and
Limulus amoebocyte lysate assay. The experiments presented
in this report showed clearly that the mitogenic activity of PS A could
be distinguished from that of LPS by its ability to stimulate cellular
proliferation in LPS-nonresponder mice and its insensitivity to the
inhibitory effects of polymyxin B. PS A could also be distinguished
from SEA by several criteria including 1) its ability to stimulate both
B (mouse) and T (rat) cells, 2) the differential effect of T cell
depletion on mouse lymphocyte responses to the two agents (Fig. 1), and
3) the differential effects of paraformaldehyde fixation of requisite
APC on rat T cell responses to the two agents (Fig. 9).
The mechanism(s) of rat T cell activation by PS A remain unknown, as does the lack of T cell responses to PS A in mice. Because mouse T cell responses to PS A could not be restored with irradiated feeder cells, we could not pursue the study of mouse T cells in our assay system. Thus, we could not correlate the cellular stimulatory properties of PS A on mouse lymphocytes in vitro with the immunostimulatory properties of PS A in vivo 3, 4 . Conceivably, our techniques may have eliminated those APC functions required for T cell responses in mouse lymphocytes (e.g., B cells vs macrophages as APC). Indeed, the much greater responses to PS A observed for unfractionated mouse lymphocytes than rat lymphocytes may reflect a proportionately greater non-T cell component to PS A responses in mice. In any case, our in vitro assay may actually measure cellular responses that differ significantly from cellular immune responses in vivo, because no prior immunization is required for the rapid responses of naive lymphocytes to PS A in vitro, while repeated immunization with either complex capsular polysaccharide from B. fragilis or purified PS A is required to elicit immune T cell responses to PS A in rodents 4, 7 .
These experiments did not address the influence of TCR structures on T cell responses to PS A. Studies with congenic and TCR transgenic mice might reveal important associations between MHC and TCR usage in the cellular responses to PS A. Human T cells do respond to PS A, and this is a current topic of investigation. The in vitro mitogenic activity of PS A may be one manifestation of a virulence mechanism that B. fragilis uses to interact with the host in vivo. The proposed tendency of ionically charged PS A to form Schiff bases with functional groups on proteins may promote homotypic and/or heterotypic cellular interactions, similar to other substances that cross-link receptors on cell surfaces 11, 16, 17, 18, 19 . A chemically reactive polysaccharide such as PS A, which does not degrade quickly in tissues, would be expected to promote the proinflammatory responses that are associated with the selective activation of certain T cell subsets and their associated cytokines, abscess formation, and possibly the global production of Abs, including polyclonal IgM and nonspecific IgG 17, 20, 21 .
Differences in the responses of mouse vs rat lymphocytes to PS A in vitro may be related to the polysaccharide’s affinity for different receptors on selected lymphocyte subsets in these two species or its ability to induce binding of certain receptor/counter-receptor pairs involved in cellular activation or regulation of inflammatory responses 22, 23 . To explain the different responses to PS A, one must seek obvious differences in the identities, abundance, and/or activities of T and B cell receptors in mice, rat, and human lymphocytes or APC. For example, recent studies have shown that a high percentage of bone marrow-derived, nonimmune rat B lymphocytes are rapidly dividing, short-lived cells that possess the Thy-1+ phenotype 24 . These Thy-1+ rat B cells, like CD5- human tonsillar B cells, do not express a significant amount of the CD5 Ag that is associated with mitogen-induced cell activation or proliferative responses to thymus-independent Ags and may therefore not respond well to the B cell-activating properties of PS A 25, 26, 27, 28 .
The mitogenic, and presumably proinflammatory, properties of PS A on rat T cells may derive from its ability to stimulate and/or up-regulate costimulatory molecules such as CD40L, which, when engaged, can directly activate T cells in the absence of TCR/MHC binding events and alter surface receptor expression (e.g., increased CD5 expression) in follicular B cells 29, 30, 31 . Because CD40/CD40L and the B7/CD28-CTLA-4 receptor/counterreceptor pairs are expressed on both T cells and APC, the ability of PS A to activate T or B cells preferentially is probably dependent on the activation kinetics, magnitude of surface expression, and cellular distribution of these costimulatory molecules on various cell types in tissues of different species 30, 32, 33, 34, 35, 36, 37, 38 . The ability of EBV-transformed human X50-7 cells to provide APC function for rat T cell responses to PS A supports the idea that induction of cellular proliferation by PS A is a cell contact-dependent phenomenon that can be induced by efficient binding of costimulatory receptor/ligand pairs, such as CD40/CD40L, CD5/CD72, or B7-1 and B7-2/CD28 or CTLA-4, that can operate across species barriers 39, 40, 41 . In mouse lymphocytes, PS A might operate as a T-independent Ag by cross-linking CD40 and CD40L molecules, by cross-linking surface Ig on B cells in a manner similar to the proposed actions of other bacterial polysaccharides, or by the T-independent stimulatory mechanisms of other bacterial cell wall or cell membrane components 15, 17, 42, 43, 44 .
The differential cellular stimulatory activities of PS A in vitro permits further experimentation into the mechanisms by which this molecule induces T and B cell activation by direct engagement of cell surface receptors or through contact- or cytokine-dependent mechanisms. Theoretically, the assay systems described in this report can also be used to study the innate and acquired cellular immune functions that are involved in the proinflammatory properties of PS A. These in vitro cellular responses to PS A may have relevance to certain aspects of the in vivo pathogenesis of PS A and B. fragilis in host animals and humans.
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Footnotes |
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2 J.O.B. and Q.L. contributed equally to this work.
3 Current address: Division of Immunologic and Infectious Diseases, Abramson Pediatric Research Building, Children’s Hospital of Philadelphia, Philadelphia, PA 19104.
4 Current address: Department of Surgery, Section of General Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109.
5 Address correspondence and reprint requests to Dr. Robert Finberg, Laboratory of Infectious Diseases, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. E-mail address:
6 Abbreviations used in this paper: CPC, capsular polysaccharide complex; PS A, polysaccharide A; PS B, polysaccharide B; NMR, nuclear magnetic resonance; SEA, staphylococcal entertoxin A; LN, lymph node; CD40L, CD40 ligand.
Received for publication June 5, 1998. Accepted for publication November 4, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(1–3) dextran elicits proliferation of precursors for specific IgM antibody-producing cells (memory cells), which are revealed by LPS stimulation in soft agar cultures and detected by immunoblot. Eur. J. Immunol. 23:2959.[Medline]
interferon in ß and 
T-cell subpopulations in response to peritonitis. Infect. Immune. 63:4957.[Abstract]
production. Eur. J. Immunol. 26:1430.[Medline]
production. Eur. J. Immunol. 26:1621.[Medline]
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