Plasmacytoid Dendritic Cells and the Spontaneous Acceptance of Kidney Allografts

BACKGROUND: DBA/2J kidney allografts, but not heart allografts, are spontaneously accepted indefinitely in C57BL/6 (B6) mice, through regulatory tolerance mechanism dependent on Foxp3+ cells. In contrast, B6 kidneys are rejected within a week in DBA/2J recipients. We hypothesized that the tolerogenic difference of the kidneys might be due to differences in number or function of plasmacytoid dendritic cells (pDCs), since these cells are potent inducers of Foxp3+ cells. METHODS: pDCs from murine bone marrow, native kidneys, and spontaneously accepted kidney allografts were analyzed using flow cytometry and immunohistochemical staining. Naïve T cells were co-cultured with pDCs in specific strain combinations and analyzed for FoxP3 induction and functionality. MEK/ERK and NFκB inhibitors were used to assess the Treg induction pathways. pDCs and T cell cultures were adoptively transferred prior to heterotopic heart transplantation to assess allograft survival. RESULTS: DBA/2J pDCs were more potent in inducing Foxp3+ in B6 T cells than the reverse combination, correlating with survival of the kidney allografts. Foxp3 induction by pDCs in vitro was dependent on pDC viability, immaturity, and class II MHC mismatch, and blocked by MEK/ERK and NFκB inhibition. pDC-induced Foxp3+ T cells suppressed proliferation of B6 T cells in vitro, and adoptive transfer into B6 recipients two weeks prior to heterotopic DBA/2J heart transplantation resulted in prolonged allograft survival. CONCLUSIONS: These data suggest that pDC-induced Tregs are dependent on down-stream signaling effects and strain-dependent, MHC class II disparity with naïve T cells, which may explain organ and strain specific differences in spontaneous tolerance.