Developmental plasticity of Foxp3+ regulatory T cells.

Foxp3(+) regulatory T (Treg) cells constitute a distinct lineage of T lymphocytes committed to suppressive functions, thereby ensuring the robustness of self-tolerance and immune homeostasis in a changing environment. Recent studies have challenged this notion by suggesting that they retain developmental plasticity to convert to Foxp3(-) helper T (Th) cells in response to environmental perturbations such as inflammation and lymphopenia. However, this issue of Treg cell plasticity remains controversial because unequivocal evidence for lineage reprogramming is lacking. Instead, available evidence supports an alternative view of plasticity based on pre-existing heterogeneity of Foxp3(+) T cells. Recent studies of Foxp3 gene regulation have provided a framework to dissect the molecular mechanisms underlying Treg cell lineage commitment and plasticity.

[1]  Edgar Schmitt,et al.  Epigenetic Control of the foxp3 Locus in Regulatory T Cells , 2007, PLoS biology.

[2]  Y. Wan,et al.  Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression , 2007, Nature.

[3]  Keiichiro Suzuki,et al.  Preferential Generation of Follicular B Helper T Cells from Foxp3+ T Cells in Gut Peyer's Patches , 2009, Science.

[4]  Yuelei Shen,et al.  TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function , 2008, Nature.

[5]  A. Coutinho,et al.  Evidence for a Thymus‐Dependent Form of Tolerance that is Not Based on Elimination or Anergy of Reactive T cells , 1996, Immunological reviews.

[6]  I. Türbachova,et al.  DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells , 2007, European journal of immunology.

[7]  M. A. Curotto de Lafaille,et al.  Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? , 2009, Immunity.

[8]  Y. Belkaid,et al.  Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid , 2007, The Journal of experimental medicine.

[9]  Christophe Benoist,et al.  Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. , 2007, Immunity.

[10]  A. Rudensky,et al.  TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells , 2005, The Journal of experimental medicine.

[11]  A. Coutinho,et al.  Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection. , 2005, Current topics in microbiology and immunology.

[12]  Gisen Kim,et al.  Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis , 2009, Nature Immunology.

[13]  A. Rudensky,et al.  CD4+ Regulatory T Cells Control TH17 Responses in a Stat3-Dependent Manner , 2009, Science.

[14]  James L Riley,et al.  Human T regulatory cell therapy: take a billion or so and call me in the morning. , 2009, Immunity.

[15]  Daniel J. Campbell,et al.  T-bet controls regulatory T cell homeostasis and function during type-1 inflammation , 2009, Nature Immunology.

[16]  A. Rudensky,et al.  A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3 , 2005, Nature Immunology.

[17]  Jing Ma,et al.  T cell receptor CDR3 sequence but not recognition characteristics distinguish autoreactive effector and Foxp3(+) regulatory T cells. , 2009, Immunity.

[18]  F. Powrie,et al.  Cutting Edge: Cure of Colitis by CD4+CD25+ Regulatory T Cells1 , 2003, The Journal of Immunology.

[19]  J. Bluestone,et al.  Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo , 2009, Nature Immunology.

[20]  Shimon Sakaguchi,et al.  Foxp3: a critical regulator of the development and function of regulatory T cells. , 2004, Microbes and infection.

[21]  C. Loddenkemper,et al.  Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease , 2007, The Journal of experimental medicine.

[22]  Y. Wan,et al.  Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. Rudensky,et al.  Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3 , 2007, Nature Immunology.

[24]  S. Hori.  Rethinking the molecular definition of regulatory T cells , 2008, European journal of immunology.

[25]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[26]  M. Merkenschlager,et al.  PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factors , 2010, The Journal of experimental medicine.

[27]  B. Malissen,et al.  Heterogeneity of natural Foxp3+ T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity , 2009, Proceedings of the National Academy of Sciences.

[28]  K. Kretschmer,et al.  DNA methylation controls Foxp3 gene expression , 2008, European journal of immunology.

[29]  Chen Dong,et al.  Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. , 2008, Immunity.

[30]  P. Chambon,et al.  Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. , 2008, Immunity.

[31]  Y. Belkaid,et al.  Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. , 2009, Immunity.

[32]  R. Noelle,et al.  All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation , 2007, The Journal of experimental medicine.

[33]  Gisen Kim,et al.  Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells. , 2009, Immunity.

[34]  H. Boehmer.  Central tolerance: essential for preventing autoimmune disease? , 2009 .

[35]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[36]  D. Littman,et al.  Identification of IL-17-producing FOXP3+ regulatory T cells in humans , 2009, Proceedings of the National Academy of Sciences.

[37]  Vincent C. Manganiello,et al.  Foxp3-dependent programme of regulatory T-cell differentiation , 2007, Nature.

[38]  W. Strober,et al.  Cutting Edge: Regulatory T Cells Induce CD4+CD25−Foxp3− T Cells or Are Self-Induced to Become Th17 Cells in the Absence of Exogenous TGF-β , 2007, The Journal of Immunology.

[39]  H. Waldmann,et al.  Infectious tolerance and the long‐term acceptance of transplanted tissue , 2006, Immunological reviews.

[40]  S. Ziegler.  FOXP3: Not just for regulatory T cells anymore , 2007, European journal of immunology.

[41]  Yuka Kanno,et al.  Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. , 2009, Immunity.

[42]  A. Rudensky,et al.  Foxp3 in control of the regulatory T cell lineage , 2007, Nature Immunology.

[43]  V. Oliveira,et al.  IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo , 2005, The Journal of experimental medicine.

[44]  K. Kretschmer,et al.  Peripherally Induced Treg: Mode, Stability, and Role in Specific Tolerance , 2008, Journal of Clinical Immunology.

[45]  Alf Hamann,et al.  Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? , 2009, Nature Reviews Immunology.

[46]  C. Benoist,et al.  Foxp3+ regulatory T cells: differentiation, specification, subphenotypes , 2009, Nature Immunology.

[47]  Y. Belkaid,et al.  A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism , 2007, The Journal of experimental medicine.

[48]  A. Rudensky,et al.  Control of regulatory T cell lineage commitment and maintenance. , 2009, Immunity.

[49]  A. Rudensky,et al.  Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses , 2009, Nature.

[50]  F. Powrie,et al.  Regulatory T cells in the control of immune pathology , 2001, Nature Immunology.

[51]  G. Eberl,et al.  DC activated via dectin-1 convert Treg into IL-17 producers , 2008, European journal of immunology.

[52]  A. Rudensky,et al.  Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate , 2010, Nature.

[53]  Takako Kato,et al.  Critical role of IFN-gamma in CFA-mediated protection of NOD mice from diabetes development. , 2009, International immunology.

[54]  S. Zelenay,et al.  Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions , 2009, European journal of immunology.

[55]  C. Baecher-Allan,et al.  IL-17-producing human peripheral regulatory T cells retain suppressive function. , 2009, Blood.

[56]  S. Sakaguchi.  Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. , 2004, Annual review of immunology.

[57]  A. Coutinho,et al.  Regulatory T cells in microbial infection , 2006, Springer Seminars in Immunopathology.

[58]  A. Rudensky,et al.  Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice , 2007, Nature Immunology.

[59]  F. Ramsdell,et al.  An essential role for Scurfin in CD4+CD25+ T regulatory cells , 2003, Nature Immunology.

[60]  A. Rudensky,et al.  Control of immune homeostasis by naturally arising regulatory CD4+ T cells. , 2003, Current opinion in immunology.

[61]  A. Rudensky,et al.  Regulatory T cell lineage specification by the forkhead transcription factor foxp3. , 2005, Immunity.

[62]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[63]  T. Chatila,et al.  Regulatory T cell development in the absence of functional Foxp3 , 2007, Nature Immunology.

[64]  A. Coutinho,et al.  A Model for Developmentally Acquired Thymus‐Dependent Tolerance to Central and Peripheral Antigens , 1996, Immunological reviews.