Use of gene-modified regulatory T-cells to control autoimmune and alloimmune pathology: Is now the right time?

• Genetically engineered T-cells are acquiring an increasing niche in cancer treatment.
• Antigen-specific regulatory T-cells achieve more potent immunosuppression.
• Gene transfer may be used to confer antigen specificity upon regulatory T-cells.
• Genotoxicity has not been observed as a result of retroviral T-cell engineering.
• Clinical evaluation in non-malignant immunopathologic states may now be warranted.

Adoptive immunotherapy using genetically targeted T-cells has recently begun to achieve impressive clinical impact in selected tumor types. Furthermore, long-term follow-up studies indicate thus far that integrating viral vectors do not elicit clinically evident genotoxicity in T-cells, unlike hematopoietic stem cells. The optimism engendered by this clinical experience provides a platform for consideration of the extended use of this technology in other disease types. One area of particular interest entails the harnessing of regulatory T-cells (Tregs) in order to down-regulate unwanted immune responses. Increasing evidence supports the efficacy of this approach in pre-clinical models of autoimmune disease and allograft rejection. Nonetheless, questions remain about optimal host cell, transgene cargo, phenotypic stability of engineered cells in vivo and potential for toxicity. Here, we review the evidence that genetically engineered Tregs can effectively dampen pathogenic immune responses and critically evaluate the prospects for clinical development of this approach.