Programmed death-1 signaling is essential for the skin allograft protection by alternatively activated dendritic cell...

Alternatively activated dendritic cell (aaDC) can prolong allograft survival in the mouse model. However, the molecular mechanism(s) by which these DCs function to regulate alloreactive T-cell responses remains to be clearly defined.

Bone marrow-derived DCs were incubated in the presence of interleukin (IL)-10 (immature DC), stimulated with lipopolysaccharide only (mature DC), or pretreated with IL-10 and then activated with lipopolysaccharide (aaDC). These cells were compared for their phenotypes and regulatory capacities both in vitro and in vivo. In addition, programmed death-1 (PD-1)/PD-L pathway was blocked to test its contribution to the regulatory function of aaDC.

The expression of surface major histocompatibility complex class II, CD80, and CD86 on aaDC was lower than that on mDC, whereas aaDC had a higher expression of PD-L1 and PD-L2 compared with immature DC or untreated DC. In vitro co-culture of aaDC with allogeneic T cells led to a significant decrease in the T-cell response as well as a reduction of interferon-gamma secretion and an enhanced IL-10 production while CD4 CD25 Foxp3 T cells were expanded. Interestingly, these regulatory effects of aaDC were partially abolished when PD-1/PD-L pathway was blocked using anti-PD-1 blocking antibody. Infusion of BALB/c donor-derived aaDC into naive C57BL/6 recipients resulted in a significantly prolonged skin allograft survival, which was, at least in part, PD-1/PD-L pathway dependent.

Our data indicate that the PD-1/PD-L pathway plays an important role in aaDC-mediated prolongation of skin allograft survival.