Lack of IL-12 signaling in human allergen-specific Th2 cells.

Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.

Lack of IL-12 signaling in human allergen-specific Th2 cells.

J Immunol. 1996 Nov 15;157(10):4316-21. Unique Identifier : AIDSLINE MED/97064186
Hilkens CM; Messer G; Tesselaar K; van Rietschoten AG; Kapsenberg ML; Wierenga EA; Department of Cell Biology and Histology, Academic Medical; Center, University of Amsterdam, The Netherlands.

Abstract: 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.

Keywords: Allergens/*IMMUNOLOGY Base Sequence/GENETICS Clone Cells DNA-Binding Proteins/AGONISTS/BIOSYNTHESIS Glycoproteins/IMMUNOLOGY Human Interferon Type II/AGONISTS/BIOSYNTHESIS Interleukin-12/*DEFICIENCY/*PHARMACOLOGY Receptors, Interleukin/ANALYSIS/BIOSYNTHESIS Signal Transduction/*IMMUNOLOGY Support, Non-U.S. Gov't T-Lymphocytes, Helper-Inducer/DRUG EFFECTS/IMMUNOLOGY/METABOLISM Th2 Cells/*DRUG EFFECTS/IMMUNOLOGY/*METABOLISM Trans-Activators/AGONISTS/BIOSYNTHESIS JOURNAL ARTICLE
970228
M9721863

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