The mechanism(s) by which donor and recipient APC, in particular dendritic cells (DC), prime T cells with direct and indirect allo-specificities in lymphoid organs remains without confirmation in a transplantation model. The current “3-cell” model proposes that donor MHC molecules are transferred intact, from donor cells to recipient’s DC through what it has been dabbed the semi-direct pathway of allo-recognition. This concept is based on the findings that DC acquire intact MHC molecules from allogeneic cells in vitro and in traffic experiments. Aim: Here, we have addressed this fundamental question in a transplantation model, by analyzing the role of donor’s vs. recipient’s DC on elicitation of indirect and direct T-cell responses. Methods: wt B6 mice were Γ-irradiated and injected with wt or CD11c-diphteria toxin (DT) receptor (DTR)-B6 bone marrow to generate chimeras. The allo-response was measured by ELISPOT analysis. Results: To investigate the relative contribution of recipient’s vs. donor’s DC in elicitation of direct and indirect allo-recognition, we assessed rejection of BALB/c cardiac allografts in CD11c-DTR-B6 chimeras. Survival of the BALB/c grafts was significantly prolonged (p < 0.01) in CD11c-DTR-B6 chimeras depleted of recipient’s conventional DC (cDC) by repetitive DT-injection (MST=53 ± 13 d), compared to DT-injected control B6-B6 chimeras (MST=9±1 d). As expected, the frequency of splenic IFN-Γ-secreting T cells recognizing donor-Ag through the indirect pathway, and the titer of serum anti-donor Ab (another indicator of indirect allo-recognition) in CD11c-DTR-B6 chimeras depleted of cDC were both reduced drastically (p < 0.001), reaching levels similar to those found in naÏve animals. Interestingly, on POD 7, splenic T cells from recipient CD11c-DTR-B6 chimeras depleted of cDC were unable to respond to donor-Ag via the direct pathway. This was an unexpected result, considering that DT-injection does not ablate the donor’s DC present in the BALB/c grafts. Conclusions: our findings indicate that in our model, the donor DC mobilized from the cardiac allografts function as Ag-transporting cells for recipient’s cDC, instead of APC as it has been classically assumed.

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