Graft rejection results from the immune system recognizing and damaging the transplanted organ, a process that involves lymphocyte extravasation into target organs. Because the inciting T cells recognize the transplant as foreign, once at the site (e.g. kidney, pancreatic islets), they inflict damage and release cytokines that recruit other leukocytes, ultimately resulting in graft rejection. In contrast, regulatory T cells (Treg) can prevent immune-mediated damage and thereby control chronic graft rejection. Therefore, isolated Treg have great therapeutic potential in prevention or reversal in a number of clinical situations, including organ transplantation and autoimmune disease. Thus far, efforts to use them have been hampered by small numbers, inability to select those most relevant to an immunological process, such as transplant rejection, and only a limited understanding of how they are distinct from effector T cells. We have focused on the role of a form of the lymphocyte adhesion receptor (CD44^act) expressed on only a small fraction of activated T cells and used to adhere to endothelial surfaces. We have shown that CD44^act is preferentially expressed on Treg and that Treg expressing CD44^act are much more effective in controlling damaging immune responses than Treg not expressing it. Our data in mice indicate that CD44^act identifies T cells with a superior regulatory function that can prevent autoimmunity and allogeneic responses. We have also shown relevance of CD44^act-bearing T cells in human autoimmune disease, including Type 1 Diabetes. In renal transplant patients, we will explore whether peripheral blood Treg express this marker post-transplantation and whether it can be used to identify highly effective Treg specifically protective for the transplanted organ. This may aid in therapies that lead to augmentation of the preventative regulatory T cell response in a variety of transplant situations.