Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells

Abstract

The fates of dendritic cells (DCs) after antigen presentation have been studied extensively, but the influence of lymphoid microenvironments on DCs is mostly unknown. Here, using splenic stromal cells to mimic the immune microenvironment, we show that contact with stromal cells promoted mature DCs to proliferate in a fibronectin-dependent way and that both stromal cell contact and stromal cell-derived transforming growth factor-beta induced their differentiation into a new regulatory DC subset. We have identified an in vivo counterpart in the spleen with similar phenotype and functions. These differentiated DCs secreted nitric oxide, which mediated the suppression of T cell proliferation in response to antigen presentation by mature DCs. Thus, our findings identify an important mechanism by which the microenvironment regulates immune responses.

TGF-β1 gene-modified, immature dendritic cells delay the development of inflammatory bowel disease by inducing CD4+Foxp3+ regulatory T cells

“…11 Briefly, bone marrow mononuclear cells were prepared from mouse (6-8 weeks old) tibia and femur suspensions by depletion of red cells and cultured at a density of 2310 6 cells/ml in six-well plates in RPMI 1640 medium supplemented with 10% fetal calf serum and 10 ng/ml recombinant murine granulocyte/macrophage colony-stimulating factor. Non-adherent cells were gently washed out after 48 h of culture; the remaining loosely adherent clusters were cultured for another 48 h and harvested for adenoviral (Ad) transduction.…”

Pulmonary stromal cells induce the generation of regulatory DC attenuating T‐cell‐mediated lung inflammation

“…Our data demonstrate that MPSC, which are mimics of the pulmonary stromal microenvironment, can drive imDC to proliferate and differentiate into DCreg suppressing T-cell proliferation and alleviating T-cell-mediated eosinophilic airway inflammation. Our results provide a new mechanistic explanation of the control of lung inflammation and immune response.Although the DCreg we identified in vitro and in the lung have similar phenotype and regulatory functions to the DCreg we previously generated from maDC under splenic stroma and naturally present in the spleen [7], these two kinds of DCreg exert their regulatory functions through different mechanisms. Splenic DCreg inhibit T-cell proliferation via NO, whereas pulmonary DCreg inhibit T-cell proliferation via PGE2.…”

“…These data indicate that the DCreg we identified are functionally different from imDC. By adding DCreg to an OVA 323-339 peptide-specific CD4 1 T-cell/mature DC/OVA 323-339 co-culture system as described previously [7], we investigated whether DCreg could regulate T-cell response. By detecting the absolute T-cell number (data not shown) and CFSE-labeled T-cell division (Fig.…”

“…More and more data show that the microenvironment in certain tissues has the ability to induce DC development [7][8][9][10] and also affects the function of DC; for example, DC in brain and kidney display regulatory functions but not T-cell-activating functions [11,12]. Our previous studies demonstrate that endothelial splenic stromal cells, which are used to mimic the in vivo splenic microenvironment, can promote the proliferation of mature DC (maDC) [7] and hematopoietic stem cells [8], driving them to à These authors contributed equally to this work. The lung is one of the organs connected with the outside environment of the organism and interfaces a vast quantity of environmental antigens, some of which are dangerous but some are innocent.…”

“…Up to now, regulatory DCreg were generated by culturing imDC in the presence of immunosuppressive cytokines such as IL-10 and TGF-b or immunomodulatory drugs [4][5][6], which does not represent the in vivo physiologic conditions of DCreg in the organ microenvironment. More and more data show that the microenvironment in certain tissues has the ability to induce DC development [7][8][9][10] and also affects the function of DC; for example, DC in brain and kidney display regulatory functions but not T-cell-activating functions [11,12]. Our previous studies demonstrate that endothelial splenic stromal cells, which are used to mimic the in vivo splenic microenvironment, can promote the proliferation of mature DC (maDC) [7] and hematopoietic stem cells [8], driving them to à These authors contributed equally to this work.…”