GM-CSF-induced, bone-marrow-derived dendritic cells can expand natural Tregs and induce adaptive Tregs by different mechanisms

Abstract

In our earlier work, we had shown that GM-CSF treatment of CBA/J mice can suppress ongoing thyroiditis by inducing tolerogenic CD8α(-) DCs, which helped expand and/or induce CD4(+)Foxp3(+) Tregs. To identify the primary cell type that was affected by the GM-CSF treatment and understand the mechanism by which Tregs were induced, we compared the effect of GM-CSF on matured spDCs and BMDC precursors in vitro. Matured spDCs exposed to GM-CSF ex vivo induced only a modest increase in the percentage of Foxp3-expressing T cells in cocultures. In contrast, BM cells, when cultured in the presence of GM-CSF, gave rise to a population of CD11c(+)CD11b(Hi)CD8α(-) DCs (BMDCs), which were able to expand Foxp3(+) Tregs upon coculture with CD4(+) T cells. This contact-dependent expansion occurred in the absence of TCR stimulation and was abrogated by OX40L blockage. Additionally, the BMDCs secreted high levels of TGF-β, which was required and sufficient for adaptive differentiation of T cells to Foxp3(+) Tregs, only upon TCR stimulation. These results strongly suggest that the BMDCs differentiated by GM-CSF can expand nTregs and induce adaptive Tregs through different mechanisms.

Alteration of early dendritic cell activation by cancer cell lines predispose immunosuppression, which cannot be reversed by TLR4 stimulation

“…While it has not been tested if RMA cells or RMA SN increase any of the inhibitory marker expression, these GM-CSF-derived early DCs induce robust T-cell proliferation after LPS stimulation in spite of the pre-existing PD-L1 expression, suggesting that these DCs can induce a strong immune response when given a proper stimulation. This was in line with a study done by Bhattacharya et al [29] where they demonstrated that BM-derived DCs selectively expand regulatory T-cells in the presence of OX40L but not PD-L1. Furthermore, blockade of CD80 on BM-derived DCs has also been shown to discourage regulatory T-cell expansion.…”

Properties of bcr-abl-transformed mouse 12B1 cells secreting interleukin-2 and granulocyte-macrophage colony stimulating factor (GM-CSF): II. Adverse effects of GM-CSF

“…On the other hand, no marked difference was observed in the relative contents of Treg cells. This seems to be at variance with some earlier observations which have indicated that GM-CSF can support the expansion of Treg cells (22,23), though our present observation may be obscured to a certain degree by the different sizes of the spleens. Other organs displaying pathological changes in the 12B1/GM-CSF/ cl-5-inoculated animals were the livers and the kidneys.…”

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…ICOS is necessary for the development of experimental MG [67], and its inhibition can ameliorate autoimmunity, including in diseases in which autoantibodies are produced [68], suggesting that this may be a useful strategy in MG. Another co-stimulatory molecule induced upon T-cell activation is OX40, which binds to OX40L on the APC and enhances cytokine production, proliferation, and survival of T cells [69]. There is also accumulating evidence that the OX40-OX40L pathway controls the suppressive ability of Tregs [70], and that OX40L expressed on dendritic cells can selectively expand Tregs [71]. Thus, targeting the OX40-OX40L pathway could be further investigated in MG.…”