Reviews and feature articleTherapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion
Section snippets
Basic immunologic properties of natural Treg cells and the molecular basis of Treg cell–mediated suppression
FoxP3+CD25+CD4+ natural Treg cells are characterized by several immunologic properties pertinent to their crucial role in the maintenance of self-tolerance and immune homeostasis. Most, if not all, of them are produced in the thymus as a functionally distinct and mature T-cell subpopulation with suppressive function before antigen encounter.12, 13 Therefore thymus-derived FoxP3+ natural Treg cells are distinct from other adaptive/induced Treg cells that convert from naive T cells after they
In vivo antigen-specific activation and expansion of Treg cells
Because FoxP3+ natural Treg cells are present in the immune system as a functionally distinct and mature population with a diverse TCR repertoire, mere clonal expansion of Treg cells through appropriate pathways of antigenic stimulation leads to induction of antigen-specific immunosuppression. For example, Treg cells specific for islet antigen were shown to be more potent in suppressing diabetes in NOD mice than polyclonally activated Treg cells.26, 27 Also, allergen-specific immunotherapy
In vitro activation and expansion of natural Treg cells
Another possible strategy for separating in vivo Treg cell dominance over effector T cells is to expand antigen-specific Treg cells in vitro and transfer them back to the host. As previously discussed, an important precaution to take in Treg cell–based therapy is to avoid possible activation of pathogenic effector T cells that might contaminate Treg cell inocula. It should be emphasized that Treg cells are poorly proliferative in vitro on TCR stimulation,55, 56, 57, 58, 59, 60 and in the
Problems and prospects of Treg cell–based immunotherapy of immunologic disease
The ultimate goal of Treg cell–based immunotherapy is to tip the balance between Treg cells and effector T cells toward dominance of the former and to stably sustain the balance, even if effector T cells are not completely eliminated.
Several issues need to be resolved to make Treg cell–based immunotherapy a clinical reality. First, we need to know more precisely the molecular basis of Treg cell activation, proliferation, and survival to differentially control Treg cells and effector T cells
Conclusion
Recent advances in our understanding of the roles of natural or induced Treg cells for the maintenance of self-tolerance and immune homeostasis support the notion that a Treg cell–targeted strategy is a promising modality for the treatment of autoimmune disease and allergy. Judging from our current knowledge on the functional stability of Treg cells, thymus-derived FoxP3+ Treg cells might be the best target for such Treg cell–based immunotherapy because of their functional stability and their
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(Supported by an educational grant from Merck & Co., Inc.)
Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD
Supported by a grant-in-aid from the Ministry of Education, Sports, and Culture of Japan, Japan Science and Technology Agency. M. Miyara was a Japan Society for the Promotion of Science Fellow.
Terms in boldface and italics are defined in the glossary on page 750.
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M. Miyara is currently affiliated with the Internal Medicine Department and Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 945, Laboratoire d'immunologie tissulaire et cellulaire, AP-HP Hôpital Pitié-Salpêtrière, Paris, France.
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K. Wing is currently affiliated with the Department of Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.