Summary of the cell interactions and molecular products that prevent rejection of combined donor hematopoietic cell and organ transplants by host Tcons, and prevent GVHD induced by donor Tcons after conditioning with TLI and ATG. Cell death in the lymphoid tissues induced by fractionated irradiation is sensed by host CD8⁺ DCs that become tolerogenic with IDO production, and then activate host iNKT cells to upregulate surface markers such as PD-1 and NKG2D, and polarize their cytokine production toward IL-4. The host NKT cells, in turn, activate host Tregs to upregulate PD-1 and polarize their cytokine production toward IL-10. The host NKT cells also activate host MDSCs to upregulate PD ligand 1 and IL-4Rα, and to secrete arginase-1. These activated innate and adaptive host immune cells suppress rejection by host Tcons, and promote chimerism and organ graft acceptance. In parallel, the activated host NKT cells also activate donor Tregs to expand, and polarize their cytokine production toward IL-10. The donor Tregs block GVHD. IDO, indoleamine 2, 3-dioxygenase; iNKT, invariant NKT; NKG2D, NK group 2, member D; Tcon, conventional T cells.