Cell, Vol. 122, 107–118, July 15, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.cell.2005.05.007
An Immunomodulatory Molecule
of Symbiotic Bacteria Directs
Maturation of the Host Immune System
Sarkis K. Mazmanian,1,3,* Cui Hua Liu,1,2
Arthur O. Tzianabos,1,3and Dennis L. Kasper1,3,*
Department of Medicine
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts 02115
2Institute of Molecular Biology
Southern Medical University
3Department of Microbiology and Molecular Genetics
Harvard Medical School
Boston, Massachusetts 02115
2001). The magnitude of this interaction between com-
mensal bacteria and mammals must predictably exert
fundamental influences on the physiology of both. The
most impressive feature of this relationship may be that
the host not only tolerates but has evolved to require
colonization by commensal microorganisms for its own
development and health.
Autochthonous (indigenous) bacteria in the mamma-
lian gut have long been appreciated for potential bene-
fits to the host: provision of essential nutrients, me-
tabolism of indigestible compounds, defense against
colonization by opportunistic pathogens, and contribu-
tions to the development of the intestinal architecture
(Hooper et al., 2000; Hooper et al., 2002). How and, more
importantly, why does the immunocompetent gut envi-
ronment allow the presence of multitudinous foreign
organisms? Researchers have proposed that certain
commensal bacteria have evolved to aid in the host’s
health; several organisms are being studied for pro-
biotic (beneficial) potential (Guarner and Malagelada,
2003; Rastall, 2004). The “hygiene hypothesis” sug-
gests that the appropriate bacterial constitution of the
human microflora is a factor in protection from allergy
and asthma (Umetsu et al., 2002; Von Hertzen and
Haahtela, 2004). Investigations have shown that the in-
teractions of commensal bacteria with Toll-like recep-
tors are critical for intestinal homeostasis (Rakoff-
Nahoum et al., 2004). The intimate relationships between
commensal microorganisms and the host immune sys-
tem are increasingly evident (Macpherson and Harris,
2004; Noverr and Huffnagle, 2004).
The mammalian immune system is a dynamic and
remarkable organ. In recognizing, responding, and
adapting to countless foreign and self molecules, the
immune system is central to processes of health and
disease. CD4+T cells, a major component of the im-
mune system, are required for vital aspects of proper
immune function, from reactions to infectious agents to
control of autoimmune reactions and cancers (Janeway
et al., 2001). Effector CD4+T cells are of two general
subtypes, T helper 1 (TH1) and T helper 2 (TH2), each
carrying out distinct and opposing activities. The proper
balance between TH1 and TH2 immunologic responses
is critical to overall human and animal health (Neurath
et al., 2002; Sheikh and Strachan, 2004). A role for com-
mensal bacteria in establishing this equilibrium has
been postulated (Bowman and Holt, 2001; Rook and
Brunet, 2002). We investigated the molecular contribu-
tions of specific autochthonous organisms to the cellu-
lar development of the host immune system.
Bacteroides fragilis is a ubiquitous and important
Gram-negative anaerobe that colonizes the mammalian
lower gastrointestinal tract. Bacteroides species are
among the earliest-colonizing and most numerically
prominent constituents of the gut microflora (Kononen
et al., 1992). Although capsular polysaccharides are
common in many bacterial species, B. fragilis elabo-
rates an unprecedented eight distinct surface polysac-
charides (Krinos et al., 2001). Several of these polymers
have a novel zwitterionic structure, with both positive
The mammalian gastrointestinal tract harbors a com-
plex ecosystem consisting of countless bacteria in
homeostasis with the host immune system. Shaped
by evolution, this partnership has potential for symbi-
otic benefit. However, the identities of bacterial mole-
cules mediating symbiosis remain undefined. Here
we show that, during colonization of animals with the
ubiquitous gut microorganism Bacteroides fragilis, a
bacterial polysaccharide (PSA) directs the cellular
and physical maturation of the developing immune
system. Comparison with germ-free animals reveals
that the immunomodulatory activities of PSA during
B. fragilis colonization include correcting systemic T
cell deficiencies and TH1/TH2 imbalances and directing
lymphoid organogenesis. A PSA mutant of B. fragilis
does not restore these immunologic functions. PSA
presented by intestinal dendritic cells activates CD4+
T cells and elicits appropriate cytokine production.
These findings provide a molecular basis for host-
bacterial symbiosis and reveal the archetypal mole-
cule of commensal bacteria that mediates develop-
ment of the host immune system.
Immediately after a sterile birth, mammals are initiated
into an organized and lifelong process of colonization
by foreign organisms. Shaped by eons of evolution,
some host-bacterial associations have developed into
prosperous relationships creating diverse environments.
No better example exists in biology than the astound-
ing numbers of bacteria harbored by the lower gastroin-
testinal tract of mammals (Hooper et al., 1998). By
young adulthood, humans and other mammals are host
to w1012viable bacteria per gram of colonic content,
consisting of 500–1000 microbial species and outnum-
bering host cells by 100-fold (Hooper and Gordon,
and negative charges in each repeating unit (Tzianabos
et al., 1993). Zwitterionic polysaccharides (ZPSs) are
unique T cell-dependent antigens that specifically me-
diate the proliferation of CD4+T cells in vitro (Brubaker
et al., 1999; Tzianabos and Kasper, 2002). Adoptive
transfer experiments show that responses to polysac-
charide A (PSA), the most immunodominant ZPS of
B. fragilis, are conferred by CD4+T cells, not by B cells
or other T cells (Tzianabos et al., 1999). We have de-
scribed the novel internalization and processing of PSA
within endosomes of antigen-presenting cells (APCs)
(Cobb et al., 2004). Subsequent presentation of pro-
cessed polysaccharide by major histocompatibility com-
plex class II (MHC II) molecules activates CD4+T cells
and represents a previously undescribed pathway of
antigen presentation. Thus, ZPSs appear to have evolved
novel biological activities shaped by coevolution with
the host immune system.
Herein we show that monocolonization of germ-free
animals with B. fragilis is sufficient to correct several
immunologic defects found in the absence of a bacte-
rial microflora. The organism’s immunomodulatory ac-
tivity requires production of PSA, which mediates host
immune-system development through specific cellular
and molecular interactions. The significance of PSA’s
role in immune homeostasis lies in its ability to mediate
establishment of a proper TH1/TH2 balance for the host,
a fundamental aspect of healthy immunologic function.
B. fragilis PSA is the first identified member of a novel
class of molecules, referred to here as “symbiosis fac-
tors,” that mediate the beneficial relationship between
bacteria and mammalian hosts during mutualism.
colonization in animals with a naive immune system.
We chose the model microorganism B. fragilis because
of its prominence in the normal microbial gut flora and
its production of known immunomodulatory molecules
(Kononen et al., 1992; Tzianabos and Kasper, 2002). In
the absence of competing bacterial species, germ-free
mice monoassociated with B. fragilis strain NCTC 9343
are readily colonized to high levels (>1010cfu/g of fe-
ces; Figure 1B). Flow cytometry of splenic lymphocytes
from these mice shows a nearly complete restoration
of CD4+T cells to conventional proportions (Figures 1A
and 1C). Thus, B. fragilis monocolonization is sufficient
to correct CD4+T cell deficiency in spleens of germ-
free mice. No other bacterial species alone has been
shown to correct lymphoid defects in germ-free ani-
mals (Cash and Hooper, 2005).
The Immunomodulatory Effects of B. fragilis
Require Production of PSA
At least 2 of the 8 capsular polysaccharides of B. frag-
ilis are ZPSs, a unique class of bacterial molecules with
immunomodulatory properties (Tzianabos and Kasper,
2002). We wondered whether PSA, the most immuno-
dominant and highly conserved ZPS, plays a role in
splenic T cell expansion during B. fragilis commensal-
ism. We used PSA-deficient B. fragilis ?PSA to mono-
colonize germ-free mice (Coyne et al., 2001). The level
of intestinal colonization by the mutant is indistinguish-
able from that by the isogenic parent strain, as as-
sessed by fecal cfu counts (Figure 1B). Examination of
splenic lymphocyte populations from mice colonized
with B. fragilis lacking PSA but expressing all other an-
tigens produced by this organism reveals an inability to
correct CD4+T cell deficiencies in germ-free mice (Fig-
ure 1C). In pooled experiments (n = 4), the average pro-
portions of CD4+T cells were: conventional, 17.82% ±
2.1%; B. fragilis, 18.05% ± 1.9%; B. fragilis ?PSA,
10.95% ± 2.3%; and germ-free, 11.15% ± 1.5%. The
effects were specific to CD4+T cells, as the proportions
of CD8+T cells and CD19+B cells from splenic lympho-
cytes (Figure 1D) are indistinguishable between con-
ventional and either monocolonized or germ-free mice,
as previously observed (Pereira et al., 1986). Together,
these results show that B. fragilis colonizing the gut of
germ-free mice requires PSA production to correct host
systemic CD4+T cell deficiencies during commensalism.
Monocolonization of Germ-free Animals
with B. fragilis Results in CD4+T Cell Expansion
We investigated the effects of bacterial colonization on
immune maturation in animals, exploring the role of the
microbial flora in systemic T cell development. We used
germ-free mice: animals born and raised in sterile isola-
tors devoid of microbes. Initially, spleens were har-
vested from both conventionally colonized and germ-
free mice and were analyzed for total CD4+T cells by
flow cytometry (FC). All groups of mice had similar sple-
nic total lymphocyte counts (average: 1 × 108). Consis-
tent with seminal observations of a positive immuno-
logic role of autochthonous bacteria (Dobber et al.,
1992), the lymphocyte population purified from spleens
of conventional SPF (specific-pathogen-free) mice with
a diverse gut microflora contains a greater proportion
of CD4+T cells than that of germ-free mice (Figure
1A). Previous studies have documented the beneficial
role of commensal bacteria in intestinal development
(Hooper, 2004). The observed alteration in CD4+T cell
proportions of splenic lymphocytes highlights the pro-
found effects of bacterial colonization of the gut on the
systemic immune response.
SPF mice harbor a diverse and complex microbial
flora. To stringently investigate the influence of specific
bacterial constituents of the gut flora on the host im-
mune system, we needed to colonize germ-free mice
with a single bacterial species. This approach allows
“real-time” measurements of responses to bacterial
PSA Production by B. fragilis Directs
Commensal bacteria have long been appreciated for
their positive impact on development of gut-associated
lymphoid tissues (GALT, including Peyer’s patches) and
intraepithelial lymphocytes (IELs) and production of
mucosal IgA (Hooper, 2004). We studied whether cellu-
lar immune maturation after bacterial colonization was
also manifested in the morphological and ultrastruc-
tural development of peripheral lymphoid tissues. Germ-
free animals have recently been reported to display de-
fects in splenic structural development (Macpherson
and Harris, 2004). We examined histological sections of
spleens from germ-free mice colonized with wild-type
B. fragilis or B. fragilis ?PSA. Spleens from mice mono-
colonized with B. fragilis appear normal, with well-
formed lymphocyte zones appearing as defined folli-
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Postdoctoral Fellowship from the Helen Hay Whitney Foundation
to S.K.M. This work was supported by funding from the NIH (NIH/
NIAID R01AI039576) to D.L.K.
Received: January 12, 2005
Revised: February 28, 2005
Accepted: May 4, 2005
Published: July 14, 2005
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