Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells present in blood circulation. Their role in neo-vascularization and repairing damaged endothelial sites make them ideal for cell therapy and bio-artificial organ creation. Unfortunately, EPCs from patients with vascular disorders are often impaired, and transplanting allogeneic EPCs is complicated by T-cell-mediated immune rejection. Now, a new study has uncovered an important signaling pathway involved in protecting EPCs from T-cell activation and response. By co-culturing primary human EPCs and T cells, researchers discovered an immune checkpoint signaling pathway involved in blocking T cells’ response to EPCs. They found that EPCs suppress T-cell proliferation and direct them away from pro-inflammatory and activated phenotypes. Blocking TNFα/TNFR2 signaling prevented EPCs from having this immunomodulatory effect. These results provide evidence that EPCs use the TNFα/TNFR2 axis to prevent immune rejection by T cells and allow them to form new blood vessels. Future research will focus on in vivo evaluation of anti-TNFR2 treatment and how this pathway can be targeted for both immunosuppression and angiogenesis in cancer treatment, but the results suggest that this signaling pathway may be critical to the success of a variety of cell therapies.