Inflammation & Allergy-Drug Targets (Discontinued) - Volume 5, Issue 3, 2006

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.

Recent advances in immunology have greatly increased our understanding of immunological tolerance. In particular, there has been a resurgence of interest in mechanisms of immune regulation. Immune regulation refers to the phenomenon, previously known as immune suppression, by which excessive responses to infectious agents and hypersensitivities to otherwise innocuous antigens such as self antigens and allergens are avoided. We now appreciate that various distinct cell types mediate immune suppression and that some of these may be induced by appropriate administration of antigens, synthetic peptides and drugs of various types. The induction of antigen specific immunotherapy for treatment of autoimmune and allergic diseases remains the 'holy grail' for treatment of these diseases. This goal comes ever closer as understanding of the mechanisms of immune suppression and in particular antigen specific immunotherapy increases. Here we review evidence that immune suppression is mediated by various different subsets of CD4 T cells.

CD4+CD25+ regulatory T cells are essential components of the immune system. They help to maintain immune tolerance by exerting suppressive effects on cells of the adaptive and innate immune system. In the last few years there has been an abundance of papers addressing the suppressive effects of CD4+CD25+ regulatory T cells and their putative role in various experimental disease models and human diseases. Despite the enormous amounts of data on these cells a number of controversial issues still exists. CD4+CD25+ regulatory T cells were originally described as thymusderived anergic/suppressive T cells. Recent papers however indicate that these cells might also be generated in the periphery. Due to the thymic development of CD4+CD25+ regulatory T cells it was thought that these cells were specific for self-antigens. Indeed it was shown that CD4+CD25+ regulatory T cells could be positively selected upon high affinity interaction with self-antigens. However, evidence is accumulating that these cells might also interact with non-self antigens. Finally, in the literature there is conflicting evidence regarding the role of soluble factors versus cell-contact in the mechanism of suppression. The aim of this review is to summarize the evidence supporting these opposing viewpoints and to combine them into a general model for the origin, function and antigen-specificity of CD4+CD25+ regulatory T cells.

In the last two decades, graft survival has been greatly improved by the introduction of efficient immunosuppressive drugs. On the other hand, late graft loss caused by chronic rejection together with the side effects of long-term immunosuppression, remain major obstacles for successful transplantation. Operational tolerance, which is defined by the lack of acute and chronic rejection and indefinite graft survival with normal graft function in the absence of chronic immunosuppression, represents an attractive alternative. Several approaches have been explored to achieve transplantational tolerance, which is considered the “Holy Grail” of transplantation, including induction of central tolerance by establishing mixed chimerism through hematopoietic stem cell transplantation or induction of peripheral tolerance through modulation of allogeneic immune responses. Graft-specific alloreactive T cells, which largely mediate graft rejection, can be silenced through different mechanisms, including deletion, which may occur within the thymus or in the lymphoid organs; anergy, in which alloreactive T cells cannot adequately respond following restimulation with the specific antigen; and suppression, which may be mediated by direct interactions with regulatory T cells (Tregs) or by soluble factors produced by Tregs. This review attempts to summarize the most novel and successful strategies to achieve operational tolerance via induction of Tregs.

CD4+ regulatory T cells (TREG) are important contributors to the induction and maintenance of peripheral tolerance. It is now becoming evident that this heterogeneous population consists of naturally occurring and induced CD4+ TREG cells that share between themselves key immunoregulatory characteristics. Their phenotype and function often relies on the expression of Foxp3 transcription factor (TF) and the presence of the immunomodulating cytokine TGF-β 1. The interdependence of TGF-β 1 and Foxp3 in the induction and maintenance of regulatory T cell networks is gradually being elucidated, shedding new light on peripheral tolerance. Thus, comprehension and delimitation of those processes predict the development of novel therapies for the treatment of infectious and autoimmune diseases, cancer and graft rejection.

Multiple mechanisms have been proposed to explain the immune hyporesponsiveness to fed antigens, a phenomenon named oral tolerance. Low doses of orally administered antigen are reported to favor active suppression with the generation of regulatory cells, whereas high doses would favor clonal anergy/deletion. A major conceptual advance in oral tolerance has been the demonstration that TGF-β plays a central role in oral tolerance as a mediator secreted by Th3 cells. In addition, recent pieces of evidence suggest that TGF-β may be a primary link between distinct populations of regulatory T cells that are induced by feeding. Conversion of CD4+CD25- into CD4+CD25+ T cells by the expression of FoxP3 involves TGF-β . A membrane-bound form of TGF-β (containing latency-associated peptide - LAP) has also been described and LAP+ CD4+ T cells mediate suppression in the gut by a TGF- -dependent mechanism. Most of these regulatory T cells are anergic cells indicating that anergy may be also related to Treg induction. Moreover, deletional events taking place in the gut mucosa induce TGF-β production by either macrophages that phagocyte apoptotic cells or by the dying T cells. Thus, it appears that TGF-β -producing cells are not only crucial for oral tolerance, but they may be master regulators of most of the mechanisms triggered by antigen feeding.

Mucosal surfaces, especially the gastrointestinal (GI) tract, are obligatory sites for tolerance induction against numerous exogenous antigens. Therefore, the mucosal surface seems to provide a microenvironment conductive to the induction of antigen-specific regulatory T cells. The cytokine milieu, which includes IL-10 and TGF-β , affects effector function of local dendritic cells and induces regulatory T cells (iTREG). During immune homeostasis (steady state) in the GI tract, noninflammatory innate immune signals provided by innocuous or commensal bacteria seem to play important roles in the induction of regulatory cytokines that enable the establishment of tolerance, which involves iTREG function. In accordance with this viewpoint, utilizing physiological means such as probiotics and TLR ligands may improve the homeostatic conditions of immune-mediated diseases and inflammation. Antigen-specific iTREG is a great counterpart of thymus-derived CD25+CD4+Foxp3+ TREG (nTREG), and therefore clinical applications of TREG should be developed that integrate the advantages of both of these cell populations. Close investigation of mucosal iTREG and related microenvironments not only will facilitate novel interventions of mucosal immunity but also will help to best utilize iTREG and iTREG in an integrated way.