Identification of a Novel OX40L+ Dendritic Cell Subset That Selectively Expands Regulatory T-Cells

Granulocyte macrophage-colony stimulating factor (GM-CSF) has been demonstrated to play a protective role in autoimmune disease through the dendritic cell-mediated expansion of regulatory T-cells (Tregs). We have previously shown that GM-CSF derived bone-marrow dendritic cells (G-BMDCs) can induce expansion of Tregs through the surface-bound molecule OX40L; however, the physiological relevance of this ex vivo derived DC subset remained to be elucidated. We determined OX40L+G-BMDCs, and not OX40L-G-BMDCs, were responsible for the selective expansion of Tregs expressing functionally suppressive markers. Phenotypic characterization of OX40L+G-BMDCs revealed higher expression levels of co-stimulatory/co-inhibitory molecules, CD80, CD86, and PDL2. Furthermore, OX40L+CD11c+ cells, phenotypically and functionally similar to OX40L+G-BMDCs, were identified in the spleen, brachial lymph nodes and liver of GM-CSF treated mice, but absent in the thymus. Concordantly, the percentage of functionally suppressive Tregs was increased in the spleen, brachial lymph nodes, and liver, of GM-CSF treated mice, but not the thymus, implying a role for OX40L+ DCs in peripheral Treg expansion. Microarray analysis of OX40L+G-BMDCs and OX40L-G-BMDCs revealed significant differences in the expression of PDL2, IL33, CCL17, and CCL22 molecules which could play important roles in the tolerogenic function of OX40L+CD11c+ DCs. Comparing the transcriptome data from OX40L+ G-BMDCs to that of all immune cell types from the ImmGen database revealed OX40L+ G-BMDCs to be distinct from steady-state immune cells. These findings suggest that OX40L+CD11c+ DCs represent a unique tolerogenic DC subset which may play an essential role in maintaining Treg homeostasis and suppressing autoimmunity.