Autoimmune disease occurs when the mechanisms that control immunity break down, allowing T and B cells to respond to self antigens in a destructive manner (1). Treatments to combat the associated inflammation and tissue destruction have been limited to broad and nonspecific immune suppression. Moreover, little progress has been made in efforts to eliminate or inactivate selfreactive cells because of the diversity and breadth of the immune response. Recently, the field has undergone a paradigm shift wherein therapies seek to exploit the control mechanisms inherent within the immune system to create a durable state of immune tolerance (2). This momentum has been driven, in large part, by the discovery that regulatory T cells (Tregs) play an essential role in controlling immunity. The report by Wright et al.(3) in a recent issue of PNAS presents strategies for generating antigen-specific Tregs by using retroviruses to deliver TCR α-and ß-chains. This approach, pioneered as a means to augment responses in cancer and HIV immunotherapy, results in the expression of tissue-specific receptors on Tregs, leading to regulation at the site of inflammation. The approach is likely to be applicable to many autoimmune diseases and transplant settings. Tregs constitute 5–7% of peripheral CD4+ T cells, where they function to maintain homeostatic balance in the immune system (4). The loss of Tregs, as a result of failed development or experimental depletion, leads to multiorgan autoimmune disease (5). Conversely, augmenting Tregs has been shown to prevent, and in certain autoimmune settings, reverse ongoing disease (6). In these instances, the transferred antigenspecific Tregs are often more potent than polyclonal Tregs at abrogating disease (7). Expression of the key lineage transcription factor forkhead box P3 (FoxP3) is characteristic of Tregs and is required for their generation and maintenance (8). Tregs suppress immune responses through the expression of an array of contact-dependent negative regulators [ie, via cytotoxic T-lymphocyte antigen 4 (CTLA-4)], as well as through the production of the immunoregulatory cytokines IL-10 and TGF-ß (9). More recently, attention has been directed toward the capacity of Tregs to limit tissue inflammation directly by influencing biochemical pathways (10–12). The requirement for antigen recognition for T cell entry into tissues was recently demonstrated by Lennon et al.(13), who showed that autoreactive T cells entered the islets in a model of type 1 diabetes (T1D), whereas T cells expressing irrelevant TCRs did not. Thus, the effective application of Tregs relies on the capacity to direct these cells to the site of action [ie, the joints in rheumatoid arthritis (RA) or the pancreas in T1D], based on the specificity of the TCR.

Efforts to obtain antigen-specific Tregs have been limited by two major hurdles. First, the antigenic targets in tissue-specific autoimmune diseases may be poorly defined (this is particularly the case in RA). Second, when antigen targets are known, only a limited number of antigen-specific cells can be isolated from circulation, given the low percentage of Tregs coupled with the low frequency of autoreactive T cells. Furthermore, discriminating Tregs from potentially destructive effector T cells is challenging, given the potential for overlapping surface markers. This raises the question of how to isolate and expand a sufficient number of these cells from the peripheral blood of patients. Wright et al.(3) addressed these limitations through two alternative strategies. First,