Combined transplantation of solid organs and bone marrow or hematopoietic progenitor cells has resulted in successful achievement of tolerance in both laboratory animals and in humans. In the current study, the conditioning regimen of posttransplant total lymphoid irradiation (TLI) and anti-thymocyte serum (ATS) was used to prepare BALB/c mice for combined transplantation of bone marrow and heart grafts from MHC mismatched C57BL/6 donors. When wild type BALB/c mice were used, more than 90% of recipients became tolerant and accepted the heart grafts and developed stable mixed chimerism. When Batf3^-/-BALB/c mice that selectively lacked CD8⁺myeloid dendritic cells (DCs) were used, tolerance and chimerism were abrogated indicating that the CD8⁺DCs were required for tolerance induction. Further studies showed that the CD8⁺DCs obtained from BALB/c mice just after conditioning with TLI alone without transplantation developed changes in surface receptors and functions that were associated with tolerogenic DCs including down regulation of co-stimulatory receptors such as CD40, suppression of the MLR, and upregulation of IDO. The changes in the CD8⁺DCs after TLI and tolerance induction were dependent upon the presence of natural killer T (NKT) cells, since the DC changes and tolerance observed in wild type BALB/c mice were abrogated in Jα18^-/- BALB/c mice lacking invariant NKT cells. In addition, changes induced in the NKT cells after TLI alone including upregulation of the activation markers PD-1 and NKG2D were abrogated in the Batf3^-/- mice. Our previous studies showed that TLI conditioning upregulated the negative co-stimulatory receptor, PD-1, on conventional CD4⁺ and CD8⁺ T cells and on Treg cells in an NKT cell and IL-4 dependent manner. Interestingly, the changes in PD-1 expression were also abrogated in the Batf3^-/- mice suggesting that these NKT cell dependent changes were in turn dependent on CD8⁺DCs. In conclusion, the experimental data indicate that TLI conditioning induces interactive changes in CD8⁺DCs and NKT cells that promote tolerance.

CITATION INFORMATION: Hongo Apum D, Zhang X, Engleman E, Strober S. Tolerogenic Interactions Between Host CD8⁺Myeloid Dendritic Cells and Natural Killer T Cells Are Required for Acceptance of Combined Organ and Bone Marrow Transplants After TLI Conditioning. Am J Transplant. 2016;16 (suppl 3).

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