Donor skin dendritic cells (DCs) play a crucial role in providing allospecific signal to host T cells either by direct interaction of donor MHC with T-cell receptor or via release of exosomes that are uptaken by host DCs in a mechanism named cross-dressing. In both processes, donor DCs are major players in acute rejection initiation. Mouse skin contains three major migratory APCs: dermal DCs (dDCs), which include both CD11b⁺ and CD103⁺ DCs (dependent on the transcription factor Batf3), and epidermal Langerhan's cells. The precise role for each subset of dDCs in transplant rejection has not been fully determined. Identifying the different donor subsets involved in the skin alloimmune responses is crucial to yield new therapeutic approaches in VCA transplants.

Using a murine skin transplant model, we identified that CD103⁺ DCs are the main donor DC subset reaching the draining lymph nodes (dLNs). We analyzed the dLNs for donor and recipient MHC expression (I-A^b and H-2K^d, respectively) at multiple early time-points after transplantation. While 60% of donor CD103⁺ DCs solely expressed I-A^b antigens at 3 and 6h post-transplant, most I-A^b+ cells at 24h post-transplant were host DCs (H-2K^d+), that were cross withdonor antigens. To assess the importance of donor CD103⁺ DCs in the alloimmune response, we transplanted Batf3^-/- (lack CD103⁺ DCs) skins into BALB/c recipients, and noticed a significant improved survival (MST: 19 vs. 11 days; p=0.0019). We also observed reduced donor I-A^b expression in dLN of mice that received Batf3^-/- skins. This effect was due to a reduction in proliferating (Ki67⁺ cells), effector memory, and IFN-γ-producing CD8⁺ T cells. We next investigated donor CD141⁺ DCs (human counterpart of murine CD103⁺ DCs) on a cohort of full-face transplant recipients in our institution, before and 1 week post-transplant. In a preliminary result, we could observe the presence of DC-morphology CD141⁺ cells in the dermis prior the transplant. One week after the transplantation, virtually almost all CD141⁺ cells were gone, correlating with mice data.

In sum, we found that donor CD103⁺ DCs consist the major migrating cells to dLN and transferring donor antigens to host DCs. Also, Batf3-dependent DCs are crucial for initiation of skin acute rejection. Modulation of these cells could be a promising strategy to reduce early alloimmune activation, minimizing the need for stronger systemic induction immunosuppression.

CITATION INFORMATION: Borges T, Murakami N, Riella L. Donor Batf3-Dependent Dendritic Cells Initiate Acute Rejection in a Skin Transplantation Model. Am J Transplant. 2017;17 (suppl 3).

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