Graft rejection results from immune system recognition of the transplanted organ, a process involving lymphocyte movement into tissue. Because the inciting T cells recognize the transplant as foreign, once at the site (e.g., kidney, pancreatic islets) they inflict damage and release compounds that recruit other white blood cells, ultimately resulting in graft rejection. In contrast, regulatory T cells (Treg) can prevent immunemediated damage and thereby prevent rejection. Thus, Treg have great therapeutic potential in prevention or reversal of 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 immunologic process, and only a limited understanding of how they are distinct from the effector T cells that cause rejection. We have shown that a form of the lymphocyte adhesion receptor (CD44^act) is preferentially expressed on Treg and identifies Treg that are much more effective in controlling damaging immune responses than Treg not expressing it. Our data indicate that CD44^act identifies T cells with superior regulatory function that can prevent autoimmunity and responses to transplanted tissues. We have also shown relevance of CD44^act-bearing T cells in human autoimmune disease, including Type 1 Diabetes (T1D). In renal transplant patients, we have recently shown that T cells in blood express this marker post transplant. We now wish to determine if it can be used to identify highly effective Treg, that are specifically protective of the transplanted organ and that are tailored individually for each patient. In addition this approach may prevent damage to islets in T1D while simultaneously preventing rejection of islets in patients undergoing islet transplantation. Our studies may form the basis for a general approach to aid in therapies that lead to augmentation of the preventative regulatory T cell response in a variety of transplant and autoimmune situations.