Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease

Alloantigen expression on host APCs is essential to initiate graft-vs-host disease (GVHD); however, critical APC subset remains to be elucidated. We compared the ability of dendritic cells (DCs) and B cells to initiate acute GVHD by an add-back study of MHC class II-expressing APCs (II^+/+) into MHC class II-defficient (II^-/-) mice that were resistant to CD4-dependent GVHD. Injection of host-derived, but not donor-derived, II ^+/+ DCs or host-derived II^+/+ B cells, was sufficient to break GVHD resistance of II^-/- mice and induced lethal acute GVHD. By contrast, host-derived II^+/+ B cells, both naive and LPS stimulated, failed to induce activation or tolerance of donor CD4⁺ T cells. Similarly, in a model of CD8-dependent GVHD across MHC class I mismatch injection of allogeneic DCs, but not B cells, induced robust proliferation of donor CD8⁺ T cells and broke GVHD resistance of chimeric recipients in which APCs were syngeneic to donors. These results demonstrate that host-derived DCs are critical in priming donor CD4⁺ and CD8 ⁺ T cells to cause GVHD, and selective targeting of host DCs may be a promising strategy to prevent GVHD.