Proposed mechanisms of allogeneic tolerance induction after TLI/ATS/CTX-based conditioning and MHC-mismatched BMT. (Mechanism A) TLI/ATS/CTX conditioning is nonmyeloablative, allowing the maintenance and expansion of key recipient myeloid regulatory subsets, including MDSCs. MDSCs convert to regulatory PD-ligand expressing MDCs in the context of MHC-mismatched BMT, facilitating PD-1–dependent in vivo expansion of donor Treg. Donor Treg regulate donor Teffector (Teff) cell expansion and GVHD. (Mechanism B) Based upon robust data in TLI/ATS models,^15,17  we postulate that TLI/ATS/CTX may facilitate Th2 polarized iNKT-derived IL-4 secretion, which further drives recipient MDSC generation and/or conversion of MDSC to MDC in the setting of MHC-mismatched BMT. Mechanisms in B are currently being investigated using iNKT-deficient and STAT6-deficient models.