Ly6C^hi monocytes are required for mesenchymal stem/stromal cell-induced immune tolerance in mice with experimental...

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 II^hiB220^hiCD11b^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^hiLy6C^hi monocytes are precursors to MHC II^hiB220^hiCD11b^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^hiB220^hiCD11b^mid macrophages in the lung with a concomitant decrease in CD11b^hiLy6C^hi monocytes. Selective depletion of circulating CD11b^hiLy6C^hi cells abrogated the effects of MSC in the induction of IL-10^hiMHC II^hiB220^hiCD11b^mid macrophages and immune tolerance in EAU mice. Similarly, an increase in CD4⁺CD25⁺Foxp3⁺ Tregs by MSCs was also reversed by CD11b^hiLy6C^hi cell depletion. These results suggest that CD11b^hiLy6C^hi monocytes are critical for MSC-induced immune tolerance.