Role of regulatory T cells and FOXP 3 in human diseases

Immune regulation and tolerance are specific functions of the immune system, meaning at prevention or limitation of effector immune responses against inner and external insults. Regulatory T (Treg) cells are crucial players in this immune balance network. Research over the last 10 years has significantly contributed to characterizing Treg cell features, their mechanisms of function, and their role in human pathologies. The discovery of FOXP3 as an essential transcription factor not only for differentiation and function of naturally occurring Treg cells but also for regulation of intracellular molecules related to effector T-cell responses has provided new insights into the pathogenesis of immune-mediated diseases. Interestingly, there is increasing evidence that the individual signature of genes relevant for immune regulation definitely influences the final outcome of an immune response. (J Allergy Clin Immunol 2007;120:227-35.)

[1]  P. Rossini,et al.  Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. , 2007, Blood.

[2]  M. Battaglia,et al.  Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans , 2007, Nature Reviews Immunology.

[3]  Brigitta Stockinger,et al.  Differentiation and function of Th17 T cells. , 2007, Current opinion in immunology.

[4]  S. Ziegler,et al.  FOXP3 modifies the phenotypic and functional properties of regulatory T cells , 2007, Nature Reviews Immunology.

[5]  M. Roncarolo,et al.  Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. , 2007, International immunology.

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

[7]  S. Ziegler,et al.  Impaired T Cell Receptor Signaling in Foxp3+ CD4 T Cells , 2007, Annals of the New York Academy of Sciences.

[8]  V. Kuchroo,et al.  TH-17 cells in the circle of immunity and autoimmunity , 2007, Nature Immunology.

[9]  B. Chiang,et al.  The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma , 2007, Clinical and experimental immunology.

[10]  E. Shevach,et al.  Cutting Edge: IL-2 Is Essential for TGF-β-Mediated Induction of Foxp3+ T Regulatory Cells , 2007, The Journal of Immunology.

[11]  T. Nomura,et al.  Foxp3 and Aire in thymus-generated Treg cells: a link in self-tolerance , 2007, Nature Immunology.

[12]  B. Stockinger Good for Goose, but not for Gander: IL-2 interferes with Th17 differentiation. , 2007, Immunity.

[13]  L. Hennighausen,et al.  Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. , 2007, Immunity.

[14]  M. Levings,et al.  Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells. , 2007, Blood.

[15]  J. Bijlsma,et al.  Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. , 2007, Arthritis and rheumatism.

[16]  Shimon Sakaguchi,et al.  Natural regulatory T cells: mechanisms of suppression. , 2007, Trends in molecular medicine.

[17]  R. Lechler,et al.  Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. , 2007, Blood.

[18]  A. Rudensky,et al.  Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells , 2007, Nature.

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

[20]  K. Papadakis,et al.  Expression and functional characterization of FOXP3+CD4+ regulatory T cells in ulcerative colitis , 2007, Inflammatory bowel diseases.

[21]  A. Caudy,et al.  CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. , 2007, The Journal of allergy and clinical immunology.

[22]  T. Macdonald,et al.  IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes1 , 2007, The Journal of Immunology.

[23]  T. Huizinga,et al.  Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells , 2007, European journal of immunology.

[24]  D. Fitzpatrick,et al.  Expression of CD103 identifies human regulatory T-cell subsets. , 2006, The Journal of allergy and clinical immunology.

[25]  D. Wraith Anti‐cytokine vaccines and the immunotherapy of autoimmune diseases , 2006, European journal of immunology.

[26]  A. Banham,et al.  FOXP3+ regulatory T cells: Current controversies and future perspectives , 2006, European journal of immunology.

[27]  J. Ritz,et al.  IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. , 2006, Blood.

[28]  F. Sánchez‐Madrid,et al.  Regulatory T cells in human autoimmune thyroid disease. , 2006, The Journal of clinical endocrinology and metabolism.

[29]  M. Battaglia,et al.  Induction of transplantation tolerance via regulatory T cells. , 2006, Inflammation & allergy drug targets.

[30]  T. Torgerson Regulatory T cells in human autoimmune diseases , 2006, Springer Seminars in Immunopathology.

[31]  Kazuhiko Nakamura,et al.  Novel strategies for the treatment of inflammatory bowel disease: Selective inhibition of cytokines and adhesion molecules. , 2006, World journal of gastroenterology.

[32]  Katharina Fleischhauer,et al.  Interleukin‐10‐secreting type 1 regulatory T cells in rodents and humans , 2006, Immunological reviews.

[33]  A. Rudensky,et al.  The role of the transcription factor Foxp3 in the development of regulatory T cells , 2006, Immunological reviews.

[34]  E. Shevach From vanilla to 28 flavors: multiple varieties of T regulatory cells. , 2006, Immunity.

[35]  J. Bluestone,et al.  Regulatory T‐cell physiology and application to treat autoimmunity , 2006, Immunological reviews.

[36]  D. Umetsu,et al.  The regulation of allergy and asthma , 2006, Immunological reviews.

[37]  W. Selby,et al.  Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells , 2006, The Journal of experimental medicine.

[38]  T. Gingeras,et al.  CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells , 2006, The Journal of experimental medicine.

[39]  S. Ziegler,et al.  Defective regulatory and effector T cell functions in patients with FOXP3 mutations. , 2006, The Journal of clinical investigation.

[40]  A. Rudensky,et al.  Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Ziegler FOXP3: of mice and men. , 2006, Annual review of immunology.

[42]  P. Debré,et al.  The immune paradox of sarcoidosis and regulatory T cells , 2006, The Journal of experimental medicine.

[43]  T. Merriman,et al.  Genetic progress towards the molecular basis of autoimmunity. , 2006, Trends in molecular medicine.

[44]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[45]  J. Isaacs,et al.  CD4+CD25+ T-regulatory cells are decreased in patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. , 2005, The Journal of allergy and clinical immunology.

[46]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[47]  M. Atkinson,et al.  Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. , 2005, Diabetes.

[48]  P. Isomäki,et al.  CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis , 2005, Clinical and experimental immunology.

[49]  C. Hölscher Targeting IL-23 in autoimmunity. , 2005, Current opinion in investigational drugs.

[50]  E. Bettelli,et al.  Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[51]  M. Kleinewietfeld,et al.  CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset. , 2005, Blood.

[52]  S. Ziegler,et al.  De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Shimon Sakaguchi,et al.  Homeostatic maintenance of natural Foxp3 + CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization , 2005, The Journal of experimental medicine.

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

[55]  P. Gottlieb,et al.  CD4+CD25high regulatory T cells in human autoimmune diabetes. , 2005, Journal of autoimmunity.

[56]  S. Ziegler,et al.  FOXP3 acts as a rheostat of the immune response , 2005, Immunological reviews.

[57]  M. Neurath,et al.  Cutting Edge: TGF-β Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells1 , 2004, The Journal of Immunology.

[58]  Shan Li,et al.  Regulatory CD4+CD25+ T lymphocytes in peripheral blood from patients with atopic asthma. , 2004, Clinical immunology.

[59]  T. Nomura,et al.  Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. , 2004, International immunology.

[60]  T. Ley,et al.  Human T regulatory cells can use the perforin pathway to cause autologous target cell death. , 2004, Immunity.

[61]  A. Rudin,et al.  Defective suppression of Th2 cytokines by CD4+CD25+ regulatory T cells in birch allergics during birch pollen season , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[62]  J. Bijlsma,et al.  CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. , 2004, Arthritis and rheumatism.

[63]  T. Malek,et al.  Tolerance, not immunity, crucially depends on IL-2 , 2004, Nature Reviews Immunology.

[64]  M. Karlsson,et al.  Allergen-responsive CD4+CD25+ Regulatory T Cells in Children who Have Outgrown Cow's Milk Allergy , 2004, The Journal of experimental medicine.

[65]  C. Akdis,et al.  Immune Responses in Healthy and Allergic Individuals Are Characterized by a Fine Balance between Allergen-specific T Regulatory 1 and T Helper 2 Cells , 2004, The Journal of experimental medicine.

[66]  H. Lorenz,et al.  Defective Suppressor Function of Human CD4+ CD25+ Regulatory T Cells in Autoimmune Polyglandular Syndrome Type II , 2004, The Journal of experimental medicine.

[67]  Clare Baecher-Allan,et al.  Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis , 2004, The Journal of experimental medicine.

[68]  H. Link,et al.  Circulating CD4+CD25+ T Regulatory Cells Are Not Altered in Multiple Sclerosis and Unaffected by Disease-Modulating Drugs , 2004, Journal of Clinical Immunology.

[69]  M. Dallman,et al.  Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease , 2004, The Lancet.

[70]  S. Ziegler,et al.  Transcription factors in autoimmunity. , 2003, Current opinion in immunology.

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

[72]  I. Bellinghausen,et al.  Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. , 2003, The Journal of allergy and clinical immunology.

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

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

[75]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[76]  C. Roifman,et al.  An interleukin-2 receptor gamma chain mutation with normal thymus morphology. , 1997, The Journal of clinical investigation.

[77]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[78]  Ann-Marie Lobo,et al.  Juvenile Idiopathic Arthritis , 2017 .

[79]  A. Rot,et al.  CCR 7 is required for the in vivo function of CD 4 + CD 25 + regulatory T cells , 2007 .

[80]  M. Battaglia,et al.  Diabetic Patients T Cells of Both Healthy Subjects and Type 1 Regulatory + FOXP 3 + CD 25 + Functional CD 4 Rapamycin Promotes Expansion of Roncarolo , 2006 .

[81]  D. Littman,et al.  The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. , 2006, Cell.

[82]  A. Rudensky,et al.  Single-cell analysis of normal and FOXP 3-mutant human T cells : FOXP 3 expression without regulatory T cell development , 2006 .

[83]  F. Por Adaptive human regulatory T cells: myth or reality? , 2006 .

[84]  A. Akbar,et al.  Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. , 2006, The Journal of clinical investigation.

[85]  M. Peakman,et al.  Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. , 2005, Diabetes.

[86]  M. Noris,et al.  Natural versus adaptive regulatory T cells. , 2005, Contributions to nephrology.

[87]  Svetlana Ten,et al.  Multiple immuno-regulatory defects in type-1 diabetes. , 2002, The Journal of clinical investigation.

[88]  R. Coffman,et al.  TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. , 1989, Annual review of immunology.