Human type 1 conventional dendritic cells contribute to skin transplant rejection

The skin is the most immunogenic tissue in transplantation and the most difficult tissue in which to induce immune modulation. Batf3-dependent type 1 conventional dendritic cells (cDC1s) are important in initiating rejection in murine skin transplantation. In humans, the CD141⁺ cDC1 subset is the functional counterpart of the murine Batf3-dependent cDC1s. However, their contribution to the rejection of human skin allografts remains unknown. Using samples from human face and upper extremity transplant recipients, we demonstrated that CD141⁺ cDC1s are increased and more activated in human skin grafts than native skin tissue from the same individual. Moreover, circulating and tissue CD141⁺ cDC1s were elevated at rejection time points. Local modulation of graft CD141⁺ cDC1s decreased HLA-DR expression and increased regulatory T cells, which correlated with a decreased presence of skin allogeneic T cells in a humanized transplantation model. Thus, CD141⁺ cDC1s play an important role in rejecting human skin allografts, and their local modulation is a promising therapeutic approach.