Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival

Dendritic cell (DC) precursors were propagated from C57BL/10 (B10; H2(b)) mouse bone marrow in fms-like tyrosine kinase 3 ligand. Cosignaling molecule (B7-1/B7-2 and B7-H1) expression and stimulatory capacity of precursor (pre)-plasmacytoid (p)DC (CD11c(+)B220(+)CD11b(-)CD19(-)) and classic myeloid DC (MDC) for allogeneic (C3H; H2(k)) T cells were compared. Unstimulated pre-pDC exhibited very low levels of surface MHC class II and classic costimulatory molecules (B7-1/B7-2), whereas a minor population expressed B7-H1 at levels higher than on MDC. The pre-pDC were ineffective T-cell stimulators and induced nonspecific hyporesponsiveness to rechallenge with donor alloantigens in vitro and in vivo. Following stimulation with CpG-oligonucleotide (CpG-ODN), B7 molecule expression was upregulated on pre-pDC, however the ratio between coinhibitory (B7-H1) and costimulatory (B7-1/B7-2) signals was much higher (five- to six-fold) on pre-pDC than MDC. Blockade of B7-H1 expression on pDC increased their T-cell allostimulatory capacity significantly. A single preoperative infusion of C3H hosts with pre-pDC prolonged B10 heart graft survival significantly but nonspecifically compared with untreated mice (median survival times 22 vs. 9 days, respectively). Thus, pre-pDC of donor origin have potential to regulate T-cell responses to alloantigens and can prolong organ graft survival.