Editorial [Hot Topic: CD4+ Regulatory T Cells: Do They Treat Mucosal and Systemic Allergy and Inflammation? (Guest Editor: Noriko M. Tsuji)]

There is accumulating evidence that CD4+ regulatory T cells (TREG) play a pivotal role in the maintenance of peripheral tolerance, thus preventing immune disorders such as allergy, autoimmune diseases and inflammation caused by transplantation. CD4+ TREG are divided in two major groups: thymus-derived naturally occurring CD25+Foxp3+ suppressor cells (nTREG) that govern self-tolerance, and CD25-/CD25+ immunoregulatory cells (iTREG), induced in the periphery during the immune response, which are related to IL-10 and /or TGF-β . Both nTREG and iTREG suppress inflammation and detrimental immune responses, and ameliorate disease symptoms in experimental models. Therefore, therapeutic application of TREG to immunological intervention seems to be ever promising. Several aspects of these two groups of TREG remain rather unclear, however. For example, how are TREG generated and maintained in vivo over a lifetime? Do TREG share any biological and/or biochemical characteristics despite differences in their origin and activation route? Are they able to cooperate to prevent and cure immunological disorders? Can we induce and maintain these cells more efficiently (in vitro and in vivo) by use of immunomodifiers. In this special issue of Inflammation & Allergy - Drug Targets, several leading investigators review recent findings in this inspiring research area. The perspective of each author will help readers to understand the challenge of yet unsolved problems and will provide insights into the possibility for clinical use of TREG as well as the development of drugs to counteract immunerelated conditions. Dr. K.S. Nicolson and Dr. D.C. Wraith provide an overview of nTREG and iTREG and how different subsets of CD4+ T cells mediate immune suppression; these authors also discuss prospective therapeutic uses of peptide antigens for selective immune regulation. Antigen-specific TREG indeed have an advantage over nonspecific immunosuppression methods. In this regard, Dr. L.S. Taams, Dr. A.N. Akbar and colleagues discuss the nature of antigen-specific CD4+CD25+ TREG and how those cell populations are maintained among circulating human T cells. There also have been great advances in methods to enhance therapeutic TREG in vivo and in vitro. Thus, Dr. M. Battaglia and Dr. M.G. Roncarolo describe how immunosuppressive drugs are used to induce and expand TREG; they also discuss clinical applications. Natural immunosuppressive cytokines also create favorable conditions for TREG proliferation and maturation. To address this issue, Dr. M. Pyzik and Dr. C.A. Piccirillo consider in depth the impact of the immunoregulatory cytokine TGF-β on nTREG. Indeed, TGF-β seems to be a key player that connects nTREG and iTREG. In light of this fact, Dr. A.M.C. Faria and Dr. H. Weiner describe the history of oral tolerance, the principal mechanism of tolerance induction against external antigens, and provide evidence that TGF-β plays a pivotal role in mucosal immunity, through which iTREG are most efficiently generated. I will further discuss the nature and significance of intestinal microenvironments, including those involving TGF-β and IL-10, for the induction of antigen-specific CD4+ TREG. Close investigation of mucosal iTreg and their microenvironments will not only facilitate novel interventions of mucosal immunity but will also help to best utilize iTREG and nTREG in an integrated way. I am very grateful to all the authors and colleagues for their time and effort spent on this project; their scientific communication and considerable advice has been invaluable. I wish to thank colleagues in our lab for facilitating the editorial process. Finally, I would like to extend my appreciation to Bentham Science Publishers, especially Senior Manager Samina Khan for the continuous and kind support.