Abbreviations
BMDCs, bone marrow-derived dendritic cells; DClps, LPS-activated BMDCs;
tolDCs, tolerogenic dendritic cells; Tregs, regulatory T cells; DCia,
immature DCs; DC10, IL-10-induced DCs; TCM cells,
central memory T cells; TEM cells, effector memory T
cells.
DCs are considered essential for regulating CD4 T cell immunity,
controlling Th1 and Th2 differentiation, inducing Tregs, and mediating
tolerance1. Physiologically, immature DCs are
distributed in peripheral tissues; upon stimulation by proinflammatory
factors (LPS or CD40 ligand), immature DCs can further differentiate
into mature DCs that express high levels of CD80 and CD86 and migrate to
secondary lymphoid organs to elicit adaptive immune
responses2. Nevertheless, DCs may present distinct
phenotypic and functional characteristics according to the stimulus that
they received. Ample evidence has demonstrated that DCs differentiated
under certain conditions are capable of inducing immune tolerance in
multiple disease models ranging from autoimmune to allergic
diseases3-7. These specific tolDCs are distinguished
by the decreased expression of costimulatory molecules and
proinflammatory cytokines along with enhancement of
anti-inflammatory
cytokines, thus leading to T cell anergy and Treg
activation8.
A large number of in vitro protocols have been established to generate
tolDCs that exert prophylactic impacts on Th1-mediated
immunopathogenesis, whereas how Th2-mediated allergic reactions are
modulated remain obscure9, 10. IL-10, an
anti-inflammatory and immunoregulatory cytokine, was confirmed to be a
more potent inducer of tolDCs than vitamin D(3), dexamethasone, TGFβ,
and rapamycin11. IL-10 can suppress the expression of
MHCII and certain costimulatory molecules on DCs; furthermore,
IL-10-induced DCs (DC10) can secrete IL-10, leading to Treg
activation12, 13. Koya et al. proved that DC10 can
dramatically attenuate lung allergic responses, with high IL-10
production and low T cell activation14. In contrast,
the role of DC10 in the Th2-mediated inflammation has been indicated to
skew the Th1/Th2 balance to Th2 in vivo via selectively preventing IL-12
synthesis15.
While IL-10/TGFβ-activated DCs can abrogate experimental asthma, several
research groups have already demonstrated that LPS, which is most
frequently used to stimulate DC maturation in vitro to initiate
inflammatory responses, can also cause DCs to produce sufficient IL-10
and exert immunosuppressive effects5, 16. For example,
Zhou et al. revealed that LPS pretreatment modified the phenotype of
DCs, thus blocking experimental autoimmune encephalomyelitis (EAE)
development by suppressing effector CD4+ T cells5.
Additionally, Kushwah et al. proved that although LPS-activated DC
maturation may lead to DC apoptosis, immature DCs can immediately take
up apoptotic DCs and then convert into tolDCs that induce augmented TGFβ
secretion and Foxp3+ Treg differentiation17. In
contrast, BMDCs were found to upregulate expression of CD80 and CD86
following LPS treatment3. Taken together, these
findings suggest that LPS might play different roles in modulating
phenotypes and functions of DCs under various conditions. Moreover,
asthma is a disease with complex immune microenvironment. Whether LPS
confers tolerogenic capabilities in BMDCs and the potential mechanisms
warrant further investigation.
Herein, we critically evaluated the impact of the intraperitoneal
adoptive transfer of LPS-treated BMDCs on airway inflammation and
pulmonary memory CD4+ T cells, Tregs, and signal transcription molecules
expression in asthmatic models.