Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells

• Published in: Blood 2011-06, Vol.117 (24), p.6532-6541
• Main Authors: Hoechst, Bastian, Gamrekelashvili, Jaba, Manns, Michael P., Greten, Tim F., Korangy, Firouzeh
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - physiology; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Differentiation - physiology; Cells, Cultured; Gene Expression Profiling; Hematologic and hematopoietic diseases; Humans; Interleukin-17 - metabolism; Lipopolysaccharide Receptors - metabolism; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocyte Activation - physiology; Medical sciences; Microarray Analysis; Myeloid Cells - classification; Myeloid Cells - immunology; Myeloid Cells - metabolism; Myeloid Cells - physiology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - physiology; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - physiology; Transforming Growth Factor beta1 - metabolism; Tretinoin - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-11-317321

CD4+ T helper cell differentiation is essential for mounting robust immune responses without compromising unresponsiveness toward self-tissue. Here, we show that different subsets of myeloid cells isolated from human peripheral blood modulate TGF-β–dependent CD4+ T-cell developmental programs ex vivo. Human CD14+HLA-DR−/low myeloid-derived suppressor cells (MDSCs) induce Foxp3+ regulatory T cells, whereas CD14+HLA-DR+ monocytes promote generation of IL-17–secreting RORc+ Th17 cells when cocultured with naive CD4+ T cells. More importantly, not only do these 2 subsets modulate the de novo induction of Tregs and Th17 cells from CD4+ T cells, but MDSCs also catalyze the transdifferentiation of Foxp3+ regulatory T cells from monocyte-induced Th17 cells. The mechanism of such Th17 plasticity is dependent on MDSC-derived TGF-β and retinoic acid. Our results identify a previously unknown feature of the different subsets of CD14+ myeloid cells namely their pivotal role in immune response regulation and plasticity of CD4+ T helper cells. We propose that different subsets of myeloid cells in humans can orchestrate the differentiation of naive CD4+ T cells into effector/regulatory T-cell subsets. The balance between these 2 subsets can impact the outcome of immune reaction from inflammation to tolerance.