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 IlluB220(hi)CD1lb(mid) 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 CD11b(hi)Ly6C(hi) monocytes are precursors to MHC II(hi)B220(hi)CD11b(mid) 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 II(hi)B220(hi)CD11b(mid) macrophages in the lung with a concomitant decrease in CD11b(hi)Ly6C(hi) monocytes. Selective depletion of circulating CD11b(hi)Ly6C(hi) cells abrogated the effects of MSC in the induction of IL-10(hi)MHC II(hi)B220(hi)CD11b(mid) macrophages and immune tolerance in EAU mice. Similarly, an increase in CD4(+)CD25(+)Foxp3(+) Tregs.by MSCs was also reversed by CD11b(hi)Ly6C(hi) cell depletion. These results suggest that CD11b(hi)Ly6C(hi) monocytes are critical for MSC-induced immune tolerance. (C) 2017 Elsevier Inc. All rights reserved.