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

• Published in: Journal of leukocyte biology Vol. 89; no. 2; pp. 235 - 249
• Main Authors: Bhattacharya, Palash, Gopisetty, Anupama, Ganesh, Balaji B., Sheng, Jian Rong, Prabhakar, Bellur S.
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.02.2011
• Subjects: Adaptive Immunity; Animals; autoimmunity; Bone Marrow Cells - cytology; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; Cell Development, Differentiation, & Trafficking; Cell Differentiation - immunology; Cell Proliferation; Cells, Cultured; Coculture Techniques; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Foxp3; Granulocyte-Macrophage Colony-Stimulating Factor - physiology; Immune Tolerance; Lymphocyte Count; Lymphoid Progenitor Cells - cytology; Lymphoid Progenitor Cells - immunology; Lymphoid Progenitor Cells - metabolism; Mice; Mice, Inbred CBA; Mice, Knockout; OX40‐OX40L; T cells; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; TGF‐β
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0310154

While expansion of natural Tregs requires OX40‐OX40L interaction, adaptive Treg induction requires TGF‐β and TCR signaling. 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+CD11bHiCD8α− 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.