Monocyte-derived human macrophages mediate anergy in allogeneic T cells and induce regulatory T cells

Activation of alloreactive T cells by APCs such as dendritic cells (DC) has been implicated as crucial step in transplant rejection. In contrast, it has been proposed that macrophages (M phi) maintain tolerance toward alloantigens. It was therefore the aim of this study to further analyze the T cell-stimulatory capacity of mature DC and M phi in vitro using the model of allogeneic MLR. There was a strong proliferative response in T cells cocultured with DC, which was further increased upon restimulation in a secondary MLR. In contrast, T cells did not proliferate in cocultures with M phi despite costimulation with anti-CD28 and IL-2. Cytokine analysis revealed considerable levels of IL-10 in cocultures of T cells with M phi, whereas high amounts of IL-2 and IFN-gamma were present in cocultures with DC. There was only minimal T cell proliferation in a secondary MLR when T cells were rescued from primary MLR with M phi and restimulated with DC of the same donor, or DC of an unrelated donor (third party), whereas a strong primary proliferative response was observed in resting T cells, demonstrating induction of T cell anergy by M phi. Functional analysis of T cells rescued from cocultures with M phi demonstrated that anergy was at least partly mediated by IL-10-producing regulatory T cells induced by M phi. These results demonstrate that M phi drive the differentiation of regulatory T cells and mediate anergy in allogeneic T cells, supporting the concept that M phi maintain peripheral tolerance in vivo.