Reviews and feature article
Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion

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Forkhead box protein 3–positive regulatory T (Treg) cells are indispensable for the maintenance of self-tolerance and immune homeostasis. They can also be exploited for the treatment of immunologic diseases, including autoimmune diseases and allergy, by way of activating and expanding antigen-specific Treg cells in vivo. Cell therapy with in vitro activated and expanded Treg cells can be another therapeutic modality. The feasibility of such Treg cell–based therapeutic strategies is discussed based on recent advances in our understanding of the molecular and cellular basis of Treg cell development and function.

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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

References (77)

  • M. Battaglia et al.

    Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells

    Blood

    (2005)
  • H.J. Koenen et al.

    Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells

    Blood

    (2008)
  • T. Yamaguchi et al.

    Regulatory T cells in immune surveillance and treatment of cancer

    Semin Cancer Biol

    (2006)
  • M.E. Brunkow et al.

    Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse

    Nat Genet

    (2001)
  • J.D. Fontenot et al.

    Foxp3 programs the development and function of CD4+CD25+ regulatory T cells

    Nat Immunol

    (2003)
  • S. Hori et al.

    Control of regulatory T cell development by the transcription factor Foxp3

    Science

    (2003)
  • R. Khattri et al.

    An essential role for Scurfin in CD4+CD25+ T regulatory cells

    Nat Immunol

    (2003)
  • C.L. Bennett et al.

    The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3

    Nat Genet

    (2001)
  • R.S. Wildin et al.

    X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy

    Nat Genet

    (2001)
  • W. Chen et al.

    Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3

    J Exp Med

    (2003)
  • M.G. Roncarolo et al.

    Interleukin-10-secreting type 1 regulatory T cells in rodents and humans

    Immunol Rev

    (2006)
  • H.L. Weiner

    Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells

    Immunol Rev

    (2001)
  • M. Itoh et al.

    Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance

    J Immunol

    (1999)
  • I. Apostolou et al.

    In vivo instruction of suppressor commitment in naive T cells

    J Exp Med

    (2004)
  • M.S. Jordan et al.

    Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide

    Nat Immunol

    (2001)
  • C.S. Hsieh et al.

    An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires

    Nat Immunol

    (2006)
  • S. Sakaguchi et al.

    Thymic generation and selection of CD25+CD4+ regulatory T cells: implications of their broad repertoire and high self-reactivity for the maintenance of immunological self-tolerance

    Novartis Found Symp

    (2003)
  • S. Fisson et al.

    Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state

    J Exp Med

    (2003)
  • T. Takahashi et al.

    Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state

    Int Immunol

    (1998)
  • A.M. Thornton et al.

    CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

    J Exp Med

    (1998)
  • K. Wing et al.

    CTLA-4 control over Foxp3+ regulatory T cell function

    Science

    (2008)
  • Y. Onishi et al.

    Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation

    Proc Natl Acad Sci U S A

    (2008)
  • P. Pandiyan et al.

    CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells

    Nat Immunol

    (2007)
  • D. Vignali

    How many mechanisms do regulatory T cells need?

    Eur J Immunol

    (2008)
  • Q. Tang et al.

    In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes

    J Exp Med

    (2004)
  • E.L. Masteller et al.

    Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice

    J Immunol

    (2005)
  • S.R. Durham et al.

    Long-term clinical efficacy of grass-pollen immunotherapy

    N Engl J Med

    (1999)
  • M. Larche et al.

    Immunological mechanisms of allergen-specific immunotherapy

    Nat Rev Immunol

    (2006)
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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.

    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.

    K. Wing is currently affiliated with the Department of Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.

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