Regulatory T cells: which role in the pathogenesis and treatment of allergic disorders?

Several recent data suggest the importance of different types of cells in the regulation of T‐cell effector‐mediated immune responses. However, a unique specific marker for these cells has not yet been identified. Moreover, in addition to a dedicated functional lineage, even a ‘plastic’ phenotype of regulatory T cells seems to exist. The lack of a unique specific marker for regulatory T cells, as well as their heterogeneity, make it difficult to determine whether a defect of regulatory T cells plays a role in the pathogenesis of common allergic disorders. Novel therapeutic strategies based on the induction or potentiation of regulatory T cells able to hamper allergic inflammatory reactions are desirable, but their possible efficacy and safety are not yet known. At present, therapeutic strategies able to induce an immune deviation of allergen‐specific type 2 T‐helper responses to a less polarized phenotype rather than a general immune suppression appear more realistic.

[1]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[2]  Lorian,et al.  ENVIRONMENTAL EXPOSURE TO ENDOTOXIN AND ITS RELATION TO ASTHMA IN SCHOOL-AGE CHILDREN , 2022 .

[3]  G. Trinchieri,et al.  Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells , 1993, The Journal of experimental medicine.

[4]  D. Klinman Immunotherapeutic uses of CpG oligodeoxynucleotides , 2004, Nature Reviews Immunology.

[5]  K. Asadullah,et al.  Interleukin-10 Therapy—Review of a New Approach , 2003, Pharmacological Reviews.

[6]  C. Hawrylowicz,et al.  Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma , 2005, Nature Reviews Immunology.

[7]  F. Annunziato,et al.  Polyinosinic acid: polycytidylic acid promotes T helper type 1‐specific immune responses by stimulating macrophage production of interferon‐α and interleukin‐12 , 1995, European journal of immunology.

[8]  M. Schilham,et al.  Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. , 2005, Human immunology.

[9]  E. Raz,et al.  Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. , 2000, The Journal of allergy and clinical immunology.

[10]  M. de Carli,et al.  IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. , 1992, Journal of immunology.

[11]  L. Cosmi,et al.  Phenotype, Localization, and Mechanism of Suppression of CD4+CD25+ Human Thymocytes , 2002, The Journal of experimental medicine.

[12]  C. Bécourt,et al.  Peripheral CD8+CD25+ T Lymphocytes from MHC Class II-Deficient Mice Exhibit Regulatory Activity1 , 2005, The Journal of Immunology.

[13]  S. Fu,et al.  TGF‐β Induces Foxp3 + T‐Regulatory Cells from CD4 + CD25 − Precursors , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  L. Adorini,et al.  Manipulating dendritic cells to induce regulatory T cells. , 2005, Microbes and infection.

[15]  L. Cosmi,et al.  The novel synthetic immune response modifier R-848 (Resiquimod) shifts human allergen-specific CD4+ TH2 lymphocytes into IFN-gamma-producing cells. , 2003, The Journal of allergy and clinical immunology.

[16]  K. Grzela,et al.  Immunostimulatory oligonucleotides in therapy of allergic diseases , 2005, Expert opinion on biological therapy.

[17]  C. Baecher-Allan,et al.  Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+CD25+ T cells. , 2005, Clinical immunology.

[18]  W. Strober,et al.  Cell Contact–Dependent Immunosuppression by Cd4+Cd25+Regulatory T Cells Is Mediated by Cell Surface–Bound Transforming Growth Factor β , 2001, The Journal of experimental medicine.

[19]  Ethan M. Shevach,et al.  CD4+CD25+ suppressor T cells: more questions than answers , 2002, Nature Reviews Immunology.

[20]  Y. Lei,et al.  Hyper Immunoglobulin E Response in Mice with Monoclonal Populations of B and T Lymphocytes 〉 , 2001, The Journal of experimental medicine.

[21]  Sergio Romagnani,et al.  The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? , 2004, Immunology.

[22]  P. Lipsky,et al.  Generation and Regulation of Human Th1-Biased Immune Responses In Vivo: A Critical Role for IL-4 and IL-10 1 , 2004, The Journal of Immunology.

[23]  Sergio Romagnani,et al.  Immunologic influences on allergy and the TH1/TH2 balance. , 2004, The Journal of allergy and clinical immunology.

[24]  M. de Carli,et al.  Reciprocal regulatory effects of IFN-gamma and IL-4 on the in vitro development of human Th1 and Th2 clones. , 1992, Journal of immunology.

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

[26]  Ethan M. Shevach,et al.  CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness , 2002, The Journal of experimental medicine.

[27]  A. Bowcock,et al.  JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. , 2000, The Journal of clinical investigation.

[28]  P. De Baetselier,et al.  Lipoprotein I, a TLR2/4 Ligand Modulates Th2-Driven Allergic Immune Responses , 2005, The Journal of Immunology.

[29]  A. Roberts The ever-increasing complexity of TGF-β signaling , 2002 .

[30]  R. Korpela,et al.  Lactobacillus GG effect in increasing IFN-gamma production in infants with cow's milk allergy. , 2004, The Journal of allergy and clinical immunology.

[31]  C. Riccardi,et al.  Frontline: GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations , 2004, European journal of immunology.

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

[33]  C. Nagler‐Anderson,et al.  Mucosal immunity and allergic responses: lack of regulation and/or lack of microbial stimulation? , 2005, Immunological reviews.

[34]  C. Hawrylowicz,et al.  Glucocorticoids drive human CD8+ T cell differentiation towards a phenotype with high IL‐10 and reduced IL‐4, IL‐5 and IL‐13 production , 2000, European journal of immunology.

[35]  H. Weiner,et al.  Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. , 1994, Science.

[36]  M. Roncarolo,et al.  Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. , 2005, Blood.

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

[38]  Fiona Powrie,et al.  Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25+Cd4+ Regulatory Cells That Control Intestinal Inflammation , 2000, The Journal of experimental medicine.

[39]  C. Akdis,et al.  Role of interleukin 10 in specific immunotherapy. , 1998, The Journal of clinical investigation.

[40]  Maria Yazdanbakhsh,et al.  Allergy, parasites, and the hygiene hypothesis. , 2002, Science.

[41]  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.

[42]  Brigitta Stockinger,et al.  T cell regulation: a special job or everyone's responsibility? , 2001, Nature Immunology.

[43]  M. Sporn,et al.  Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth , 1986, The Journal of experimental medicine.

[44]  G. Pawelec Extrathymic T-cell differentiation in vitro , 2004, Nature Reviews Immunology.

[45]  S. Maleki,et al.  Characterization of lymphocyte responses to peanuts in normal children, peanut-allergic children, and allergic children who acquired tolerance to peanuts. , 2003, The Journal of clinical investigation.

[46]  S. Durham,et al.  Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. , 2003, The Journal of allergy and clinical immunology.

[47]  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.

[48]  A. Kay,et al.  Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial , 2002, The Lancet.

[49]  S. Wahl,et al.  TGF-β: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression , 2003 .

[50]  D. P. Strachan,et al.  Hay fever, hygiene, and household size. , 1989, BMJ.

[51]  V. Godfrey,et al.  Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes , 1996, European journal of immunology.

[52]  F. Simons,et al.  Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. , 2004, The Journal of allergy and clinical immunology.

[53]  F. Annunziato,et al.  Phosphorothioate oligodeoxynucleotides promote the in vitro development of human allergen-specific CD4+ T cells into Th1 effectors. , 1999, Journal of immunology.

[54]  Irah L. King,et al.  Cutting Edge: IL-12 Induces CD4+CD25− T Cell Activation in the Presence of T Regulatory Cells1 , 2005, The Journal of Immunology.

[55]  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.

[56]  H. Lodish,et al.  Role of transforming growth factor beta in human disease. , 2000, The New England journal of medicine.

[57]  S. Durham,et al.  Mechanisms of immunotherapy. , 2004, The Journal of allergy and clinical immunology.

[58]  M. Roncarolo,et al.  Type 1 T regulatory cells , 2001, Immunological reviews.

[59]  R. Homer,et al.  Airway remodeling in asthma. , 1999, The Journal of clinical investigation.

[60]  J. Massagué TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[61]  M. Probst-Kepper,et al.  Frontline: Neuropilin‐1: a surface marker of regulatory T cells , 2004, European journal of immunology.

[62]  Anna Chodos,et al.  Antigen-dependent Proliferation of CD4+ CD25+ Regulatory T Cells In Vivo , 2003, The Journal of experimental medicine.

[63]  R. Geha,et al.  IL-10 is critical for Th2 responses in a murine model of allergic dermatitis. , 2003, The Journal of clinical investigation.

[64]  Q. Hamid,et al.  Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. , 2004, The Journal of allergy and clinical immunology.

[65]  V. Godfrey,et al.  X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. , 1991, The American journal of pathology.

[66]  H. Stein,et al.  Analysis of FOXP3 protein expression in human CD4(+)CD25(+) regulatory T cells at the single-cell level. , 2006, European journal of immunology.

[67]  C. Page,et al.  Airway remodelling in asthma , 2002 .

[68]  S. Mazmanian,et al.  An Immunomodulatory Molecule of Symbiotic Bacteria Directs Maturation of the Host Immune System , 2005, Cell.

[69]  L. Cosmi,et al.  Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. , 2003, Blood.

[70]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[71]  G. Rook,et al.  Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells , 2002, Nature Medicine.

[72]  G. Berry,et al.  Induction of T helper type 1–like regulatory cells that express Foxp3 and protect against airway hyper-reactivity , 2004, Nature Immunology.

[73]  Airway Remodelling in Asthma , 2006, Archivos de bronconeumologia.

[74]  L. Cosmi,et al.  Reversal of human allergen-specific CRTH2+ T(H)2 cells by IL-12 or the PS-DSP30 oligodeoxynucleotide. , 2001, The Journal of allergy and clinical immunology.

[75]  C. Drake,et al.  Role of LAG-3 in regulatory T cells. , 2004, Immunity.

[76]  C. Riccardi,et al.  GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily , 2005, European journal of immunology.

[77]  S. Salminen,et al.  Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial , 2003, The Lancet.

[78]  L. Cosmi,et al.  Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines. , 2004, Blood.

[79]  J. Bach,et al.  The effect of infections on susceptibility to autoimmune and allergic diseases. , 2002, The New England journal of medicine.

[80]  Jeffrey A. Bluestone,et al.  Opinion-regulatory lymphocytes: Natural versus adaptive regulatory T cells , 2003, Nature Reviews Immunology.

[81]  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.

[82]  R. Coffman,et al.  T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells , 2005, The Journal of experimental medicine.

[83]  A. Kagey‐Sobotka,et al.  Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes T(H)1 cytokine expression while downregulating T(H)2 cytokine expression in PBMCs from human patients with ragweed allergy. , 2001, The Journal of allergy and clinical immunology.

[84]  P. Matricardi,et al.  Parasites and the hygiene hypothesis , 2004, Clinical reviews in allergy & immunology.

[85]  H. Ochs,et al.  The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 , 2001, Nature Genetics.

[86]  D. Wraith,et al.  Peptide-based therapeutic vaccines for allergic and autoimmune diseases , 2005, Nature Medicine.

[87]  S. Zheng,et al.  Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-101 , 2004, The Journal of Immunology.