Lack of IL-12 signaling in human allergen-specific Th2 cells.
IL-12 is a powerful skewer of CD4+ T cell responses toward the Th1 phenotype by inducing IFN-gamma production in naive Th cells. In the present study we addressed the question of whether IL-12 can reverse established Th2 responses into Th1/Th0 responses by inducing IFN-gamma production in memory Th2 cells. To this aim, allergen-specific CD4+ T cell clones (TCC) were generated from the peripheral blood of three atopic patients, and their cytokine profiles were analyzed. The majority of these TCC exhibited a strongly polarized Th2 cytokine profile, and the production of IFN-gamma could not be induced by exogenous IL-12. Only those TCC with low IFN-gamma levels in the absence of IL-12 responded to IL-12 by additional enhancement of IFN-gamma production. The IL-12 nonresponsiveness of the Th2 clones was further evident by the total lack of IL-12-induced phosphorylation of STAT4 (signal transducer and activator of transcription-4), a transcription factor that is typically involved in IL-12 signaling. Consequently, IL-12 also failed to induce the DNA-binding activity of STAT4-containing complexes in the nuclei of these Th2 clones. All TCC expressed equal levels of the low-affinity IL-12R beta1 subunit. Our results indicate that human allergen-specific Th cells with strongly polarized Th2 cytokine profiles do not respond to IL-12 and, therefore, cannot be induced to produce IFN-gamma. The apparent high frequency of IL-12-nonresponsive Th cells within the allergen-specific populations in atopic patients predicts a limited skewing potential of IL-12 in the case of established Th2 responses, but only affecting newly recruited naive Th cells.
Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands.
C M
CM
Hilkens
G
G
Messer
K
K
Tesselaar
A G
AG
van Rietschoten
M L
ML
Kapsenberg
E A
EA
Wierenga
D000485:Allergens / Q000276:immunology*; D039741:Antigens, Dermatophagoides; D001483:Base Sequence / Q000235:genetics; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000819:agonists / Q000096:biosynthesis; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000819:agonists / Q000096:biosynthesis; D018664:Interleukin-12 / Q000172:deficiency* / Q000494:pharmacology*; D018123:Receptors, Interleukin / Q000032:analysis / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000819:agonists / Q000096:biosynthesis
D000485:Allergens; D039741:Antigens, Dermatophagoides; D004268:DNA-Binding Proteins; D006023:Glycoproteins; C508438:IL12RB1 protein, human; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma; C059296:Fel d 1 protein, Felis domesticus