Human Type 1 Conventional Dendritic Cells Contribute to Skin Transplant Rejection

Am J Transplant. 2025 Apr 24;S1600-6135(25)00221. Epub 2025 Apr 24

Authors:

Borges TJ, Lee CAA, Mucciarone K, Lima K, Lape IT, Lima-Filho M, Ayoama B, Kollar B, Gassen RB, Bonorino C, Talbot SG, Pomahac B, Lian CG, Murphy GF, Riella LV.

Abstract:

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.

Figure 1

(A) Gating strategy used for the characterization of circulating DC subsets: plasmacytoid DCs (pDCs: Lin2⁻HLA-DR⁺CD11c^low/−CD303⁺), conventional DCs type I (cDC1s: Lin2⁻HLA-DR⁺CD11c⁺CD141⁺CD1c⁻), conventional DCs type II (cDC2s: Lin2⁻HLA-DR⁺CD11c⁺CD141^low/−CD1c⁺), double-negative conventional DCs (DN: Lin2⁻HLA-DR⁺CD11c⁺CD141⁻CD1c⁻). Lin2: Lineage 2 (CD3, CD14, CD19, CD20, CD56). Percentages of (B) total DCs, (C) DC subsets, and (D) cDC1s from peripheral blood at rejection and nonrejection time points. Expression of (E) HLA-DR and (F) PD-L1 DC subsets from peripheral blood at rejection and non-rejection time points. (B-F) Statistical analysis was performed using a Wilcoxon test. Data from 12 time points pooled from 9 vascularized composite allotransplantation patients and represented as mean ± SD. Some stable time points and rejection episodes are from the same patient. n.s., not significant; ∗P < .05; ∗∗P < .01.