title: IL-12-induced reversal of human Th2 cells is accompanied by full restoration of IL-12 responsiveness and loss of GATA-3 expression.
abstract: IL-12 is a potent inducer of IFN-gamma production and drives the development of Th1 cells. Human polarized Th2 cells do not express the signaling beta2-subunit of the IL-12R and, therefore, do not signal in response to IL-12. The question was raised as to what extent the loss of the IL-12Rbeta2 chain in Th2 cells has bearing on the stability of the human Th2 phenotype. In the present report, we show that restimulation of human fully polarized Th2 cells in the presence of IL-12 primes for a shift towards Th0/Th1 phenotypes, accompanied by suppression of GATA-3 expression and induction of T-bet expression. These reversed cells are further characterized by a marked IL-12Rbeta2 chain expression and fully restored IL-12-inducible STAT4 activation. The IL-12-induced phenotypic shift proved to be stable as a subsequent restimulation in the presence of IL-4 and in the absence of IL-12 could not undo the accomplished changes. Identical results were obtained with cells from atopic patients, both with polyclonal Th2 cell lines and allergen-specific Th2 cell clones. These findings suggest the possibility of restoring IL-12 responsiveness in established Th2 cells of atopic patients by stimulation in the presence of IL-12, and that IL-12-promoting immunotherapy can be beneficial for Th2-mediated immune disorders, targeting both naive and memory effector T cells.
authors: Academic Medical Centre, University of Amsterdam, Department of Cell Biology and Histology, Amsterdam, The Netherlands.
authors: H H
authors: HH
authors: Smits
authors: J G
authors: JG
authors: van Rietschoten
authors: C M
authors: CM
authors: Hilkens
authors: R
authors: R
authors: Sayilir
authors: F
authors: F
authors: Stiekema
authors: M L
authors: ML
authors: Kapsenberg
authors: E A
authors: EA
authors: Wierenga
mesh_terms: D000485:Allergens / Q000276:immunology; D000911:Antibodies, Monoclonal; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007150:Immunohistochemistry; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D000098815:T-bet Transcription Factor
chemical_list: D000485:Allergens; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C508439:IL12RB2 protein, human; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma