Figure 1.

Expansion of donor-specific T_REG following pre-transplant MSC infusion. (1) MSC infused before transplant induce T_REG from conventional T cells and promote a polyclonal, antigen-independent expansion; at the same time, (2) MSC inhibit dendritic cell maturation increasing the frequency of protolerogenic DCs, and (3) reprogram macrophages toward an M₂ phenotype. (4) Allogeneic transplantation causes migration of donor DCs from the graft to lymphoid organs and provides alloantigen for recipient DC uptake (other antigen presenting cells can act the same way). (5) Direct and indirect antigen presentation provide the survival stimuli necessary for donor-specific T_REG proliferation, while the non-alloreactive T_REG pool is progressively lost over time. Protolerogenic DCs can also induce T_REG from conventional alloreactive T cells, while alternatively-activated macrophage TGFβ secretion promotes T_REG expansion. MSC, mesenchymal stromal cell; T_CONV, conventional T cell; T_REG, regulatory T cell; mDC, mature dendritic cell; tDC, tolerogenic dendritic cell; M₁ϕ, classically-activated macrophage; M₂ϕ, alternatively-activated macrophage; PGE2, prostaglandin-E₂; IDO, indoleamine 2,3-dioxygenase; TGFβ, transforming growth factor β; HLA-G5, human leukocyte antigen G5; IL-6, interleukin 6; TSG6, tumor necrosis factor-inducible gene 6 protein.