Ly6Chi monocytes are required for mesenchymal stem/stromal cell-induced immune tolerance in mice with experimental autoimmune uveitis

The cells of the innate immune system, in addition to their capacity to elicit immunity, play a substantial role in immune tolerance induction. Our group has recently shown that a distinct subset of MHC IIhiB220hiCD11bmid suppressive macrophages is increased in the lung by intravenous (IV) administration of mesenchymal stem/stromal cells (MSC) and induces immune tolerance. Herein, we demonstrate that circulating CD11bhiLy6Chi monocytes are precursors to MHC IIhiB220hiCD11bmid macrophages in the lung and required for MSC-induced tolerance in a mouse model of experimental autoimmune uveitis (EAU). Analysis revealed that IV MSC induced an increase in IL-10-expressing MHC IIhiB220hiCD11bmid macrophages in the lung with a concomitant decrease in CD11bhiLy6Chi monocytes. Selective depletion of circulating CD11bhiLy6Chi cells abrogated the effects of MSC in the induction of IL-10hiMHC IIhiB220hiCD11bmid macrophages and immune tolerance in EAU mice. Similarly, an increase in CD4+CD25+Foxp3+ Tregs by MSCs was also reversed by CD11bhiLy6Chi cell depletion. These results suggest that CD11bhiLy6Chi monocytes are critical for MSC-induced immune tolerance.