Two famous ancient Greek mottos of Delphi are Gnothi Seauton, ‘know thyself’, and Meden Agan, ‘nothing in excess’. The former has been a favorite slogan of immunologists for decades in studying how self-and non-self-discrimination is achieved in the immune system, and in particular how T-cell selection by self-peptide/MHC complexes in the thymus purges hazardous self-reactive T cells, while at the same time allowing the production of protective T cells capable of responding to microbes. Although the other motto ‘(Let there be) nothing in excess’ has not attracted a great deal of attention from immunologists, it is not merely a recommendation of a modest life in an affluent society but is a vital principle by which the immune system sustains its homeostasis, i.e., inhibiting or suppressing aberrant or excessive immune responses to self-antigens and non-self-antigens. There is now considerable evidence that one aspect of immune homeostasis and self-tolerance is actively maintained by a population of T cells, once called ‘Suppressor T cells’ and now called ‘Regulatory T cells’ (Tregs). Although the existence of Tregs as a functionally definite cellular entity in the immune system was once doubted, an entire issue of Immunological Reviews in 2001 was devoted to Tregs with resurgent interest in this population at the time. The past 5 years have witnessed an explosive interest in Tregs in many fields of basic and clinical immunology. Accordingly, there has been a substantial advance in our understanding of the biology of Tregs and their roles in normal and disease states. This issue of Immunological Reviews brings together current efforts to understand how Tregs contribute to immune homeostasis and self-tolerance, and how they can be exploited to control physiological and pathological immune responses, including autoimmunity, tumor immunity, microbial immunity, allergy, transplantation, and feto-maternal tolerance.
If one defines Tregs simply as T cells with an immunosuppressive activity, there have been several different types of Tregs, including naturally arising CD25+CD4+ Tregs, IL-10-secreting Tr1 cells, TGF-β-secreting Th3 cells, Qa-1-restricted CD8+ T cells, CD8+CD28– T cells, CD8+CD122+ T cells, γ/δ T cells, and NKT cells (1–5). Some Treg populations are naturally produced in the immune system as functionally distinct populations, while others are adaptively induced from naïve T cells as a consequence of a particular mode of antigen exposure, especially in a particular cytokine milieu. This heterogeneity and apparent redundancy of Treg populations may not be surprising when one considers the vital importance of maintaining immune homeostasis and self-tolerance, as evidence by its derangement, such as in autoimmune disease. Indeed, several Treg populations, including CD25+CD4+ natural Tregs and Tr1 cells, are involved in suppressing autoimmune disease, in controlling microbial infection, allergy, and immunopathology, and in maintaining transplantation tolerance in animal models (6–12). Research has been conducted to delineate each Treg population in terms of cytokine dependency, the expression of particular molecular markers, the path of development, the mode of suppression, and the physiological roles in controlling immune responses.
Among the variety of Treg populations, naturally occurring CD25+CD4+ Tregs have been most intensively analyzed in humans and rodents (1–3, 13). Recent notable findings are that the transcription factor Foxp3 is a key control molecule for Treg development and function and that a genetic anomaly of Foxp3, and the resulting deficiency or dysfunction of natural CD25+CD4+ Tregs, is the primary cause of IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X–linked syndrome), a monogenic human disease manifesting as multiple autoimmune diseases, severe allergy, and inflammatory bowel disease (1, 13, 14). IPEX is thus far the clearest example that a deficiency or dysfunction of natural Tregs can be causative of human autoimmune disease (such as type 1 diabetes) and also allergy and immunopathology. Foxp3 therefore serves as a new clue to deciphering how Tregs develop and function at the molecular level (13, 14). Furthermore, Foxp3 is currently the most specific and reliable molecular marker for natural Tregs in rodents and humans (1, 13). Compared with previous studies of natural Tregs defined by other markers, the use of Foxp3 as a specific Treg marker has made it possible to conduct a more accurate and reliable analysis of the roles of natural Tregs, including CD25+ and CD25– Tregs, in both normal and disease states in rodents and humans (1, 3, 4, 13).
Efforts have also been made in these years to elucidate the mechanism of suppression exerted by CD25+CD4+ Tregs (2, 11, 15, 16). Numerous putative mechanisms of Treg-mediated suppression have been proposed in the literature. They include direct T cell – T cell interaction involving TGF-β, Lag3, or CTLA-4, perforin and/or granzyme B-dependent killing, IL-10-mediated suppression, modification of the function of dendritic cells, and IL-2 consumption by Tregs. In addition to these in vitro analyses of Treg functions, attempts have been made to visualize their in vivo behavior (15). It now appears that more than one mechanism of suppression is operative in vivo, and that one Treg may exert suppression by more than one mechanism depending on in vivo and in vitro situations.
How Tregs are generated in the thymus or the periphery and how they are activated and maintained in the immune system are other key foci of current research. Thymic development of natural Tregs appears to require a high avidity interaction between their TCRs and self-peptide/MHC ligands, and Tregs expand in the periphery by recognizing the selecting self-peptide/MHC ligands (17). Foxp3-expressing Tregs that are functionally and phenotypically akin to natural Tregs can also develop in vivo and in vitro from apparently naïve T cells under certain conditions, in particular in the presence of TGF-βin vitro (13, 16). Natural Tregs are highly dependent on exogenous IL-2 for their survival in the periphery (1, 13). IL-2 is also required for the de novo development of Tregs from naïve T cells in the periphery (18). Furthermore, local production of IL-2 by other lymphocytes at the site of inflammation may expand Tregs reactive with microbial antigens or self-antigens released from the damaged tissue, thus contributing to the suppression of excessive or misdirected immune responses to self-antigen and non-self-antigens (2). In addition to cytokines, such as IL-2, IL-10, and TGF-β, a variety of accessory molecules expressed by Tregs, including CD28 and CTLA-4, are involved in tuning the degree of Treg activation, expansion, and suppression (19). With evidence that Tregs engaging in the maintenance of self-tolerance are continuously primed with self-antigens in the regional lymph nodes, it is now an important theme of research how Tregs restrain self-reactive T cells from activation and expansion, while allowing microbe- or tumor-specific effector T cells to respond effectively to invading microbes or arising tumor cells (2, 7, 15, 20).
Occurring in parallel with the progress in our knowledge of basic Treg biology, studies of human Tregs are now elucidating the role of Tregs in human diseases, such as multiple sclerosis and type 1 diabetes (3, 8, 15). The strategic manipulation of either naturally occurring Tregs or adaptively induced Tregs with the intent of dampening or enhancing their functions may prove to have great clinical benefit. As discussed in several articles in this issue, adoptive transfer of antigen-stimulated Tregs has indeed provided encouraging results in various animal models for inhibiting autoimmune, allergic, or immunopathological responses and for maintaining allograft tolerance (4, 6, 15, 21, 22). It is also hoped that Treg manipulation will make the current methods of vaccination against microbes and tumor antigens more efficacious.
Tregs are now a focus of active research in basic and clinical immunology. The next 5 years will witness further progress in our understanding of Treg biology and pathology and in clinical applications of Tregs to treat and prevent immunological diseases and to control immune responses for the benefit of the host.