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.