In the setting of transplantation, T cells are deliberately depleted to prevent allograft rejection. However, this IL-7 activates the accelerated proliferation of effector memory T cells, which are the predominant mediators of graft rejection. Multipotent adult progenitor cells (MAPC) have been previously shown to modulate the response of T cells to IL-7, in vitro but not in vivo. Here, for the first time, we demonstrate that MAPC suppress IL-7 and anti-thymocyte (ATG) driven pro-inflammatory cytokine production by both CD4 + and CD8 + T cells in the spleen. While, MAPC significantly suppressed T cell proliferation in the IL-7 driven model, MAPC did not suppress T cell proliferation in the ATG model when administered on day 4. The effects of routes of administration on the bio-distribution of MAPC in our model of homeostatic proliferation was further clarified using novel 3D whole animal Cryo-imaging technology. MAPC administered i.v. were observed in the spleen 48 hours post injection. However, following i.p. administration, MAPC do not gain access to the spleen but reside in the omentum tissue suggesting that MAPC mediate their effects in the spleen through trophic signalling. Importantly, we demonstrate that MAPC mediate their suppression of pro-inflammatory cytokine production in a PGE-2 dependent manner. Given the importance of successful reconstitution of the immune cell compartment to provide a functional immune system, the fact that MAPC do not suppress this reconstitution but dampen pathogenic cytokine production is a very positive finding. Together this data supports the idea that MAPC may be useful in controlling immune dysregulation via suppression of T cell cytokine production while sparing T cell reconstitution in lymphodepleted patients.