to c-PGA. Our results also suggest that a putative receptor
for c-PGA mi ght be expressed by CD 4
T cel ls, which can
directly trigger APC-independent pathways of adaptive im-
Molecules regulating T
2 polarization pathways have
been implicated in therapeutic intervention in many immune
diseases. A well-established example comes from bacterial
CpG DNA. The therapeutic effects of CpG on allergies have
been demonstrated by the selective down-regulation of T
type responses in murine models of asthma and in human
PBMC from atopic patients (31–33). The effects of c-PGA on
selective up-regulation of T
1 responses and down-regula-
tion of T
2 responses might have the therapeutic potential
to treat diseases whose pathogenesis largely relies on anti-
2 responses, such as asthma and atopic der-
matitis. One issue with which to be concerned is that, in
addition to T
2 regulation, c-PGA favors the polarization
T cells toward T
17 cells. It was shown recently that
although IL-17 was essential during antigen sensitization to
establish allergic asthma, in sensitized mice it attenuated
the allergic response by inhibiting DC and chemokine syn-
thesis (34). In this context, the characteristic of c-PGA on
17 cell promotion could be beneﬁcial in treating estab-
lished allergic asthma.
Our results suggest the potential of c-PGA reacting as an
adjuvant for T
1 and T
17 response augmentation. On the
other hand, we found that the ability of c-PGA to activate
DC seemed to be less potent than LPS and CpG. In fact,
many potent adjuvants including CFA and LPS induce se-
vere local reactions and were excluded from clinical use for
humans, despite a potent activity of immune modulation.
Aluminum phosphate or hydroxide are relatively safe and
currently used as predominant adjuvants in humans. These
compounds are able to induce T
2 responses, yet they have
little capacity to stimulate T
1 responses. Therefore, it
appears mandator y to develop new adjuvants that are less
toxic and more effective in T
1 response induction. In this re-
spect, despite less potent activity, edible and non-toxic fea-
tures of c-PGA could contribute to the usefulness of c-PGA
as an immunomodulatory agent retaining minimized side
Previously, fermented soyb eans have been shown to
possess anti -tumor a nd i mmunomod ulator y ac tivitie s (35,
36). In particular, among products from the soybean fer-
mentation process, a fructose polymer named levan was
found to be a potent induc er of I L-12p40 and TNF- a pro-
duction by macrophages in vitro via TLR-4 (37). Moreover,
levan suppressed allergic inﬂammation with IgE produc-
tion, thus offering a n approach for the prevention of al ler-
gic diso rders. The latter paper reporte d that c-PGA did
not mediate such effects, whic h conﬂicts with our results.
This discrepancy may arise from differences of experi men-
tal systems including dose and molecular weight of
In summary, we demonstrated for the ﬁrst time that c-PGA
is a novel regulator of selective development pathways of T
subsets through APC-dependent and -independent mecha-
nisms. Our ﬁndings suggest that this aspect of c-PGA may
be applicable to preventing or treating T
Seoul R&BD Program (10580).
We thank Dr Moon Hee Sung for p roviding c-PGA, Dr Chul Hoon
Lee for valuable discussion and Ms Jocelyn Graf for editorial
APC antigen-presenting cells
BMDC bone marrow-derived dendritic cells
DC dendritic cells
Flt3L FMS-like tyrosine kinase 3 ligand
GM-CSF granulocyte–macrophage colony-stimulating factor
PAMP pathogen-associated molecular patterns
c-PGA poly-c-glutamic acid
PRR pattern recognition receptors
TGF transforming growth factor
17 IL-17-producing T
TLR Toll-like receptor
TNF tumor necrosis factor
Treg regulatory T
YFP yellow ﬂuorescence protein
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c-PGA effects on T
cell differentiation 989
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