Commitment of Individual Th1-Like Lymphocytes to Expression of IFN-γ Versus IL-4 and IL-10: Selective Induction of IL-10 by Sequential Stimulation of Naive Th Cells with IL-12 and IL-4

Abstract

Commitment of Th lymphocytes to the Th1 phenotype, as characterized by the expression of the major proinflammatory cytokine IFN-γ, may be critically involved in the establishment of chronic inflammation and inflammatory autoimmune disease. To date, it has been shown that in IL-12-stimulated murine Th cell lines containing a major fraction of Th1 cells, Th2 cells can be induced by IL-4 until about 2 wk after initial activation, but not later. Here we analyze, based on the magnetic isolation of viable Th1 cells according to their specific expression of IFN-γ, the cytokine commitment of individual Th1 cells. After activation of naive Th cells with Ag and IL-12 for up to 5 wk, isolated IFN-γ-producing cells were restimulated with Ag and IL-4. Within the first 3 to 4 wk of IL-12 stimulation, some IFN-γ+ cells stopped expression of IFN-γ when restimulated with IL-4. However, within only 1 to 2 wk of IL-12 stimulation, few IFN-γ+ cells could be converted to produce IL-4. Others continued to express IFN-γ and thus were already committed to a proinflammatory, Th1-like phenotype. Surprisingly, within 3 wk of IL-12 stimulation, many of the IFN-γ-producing cells responded to IL-4 restimulation by expression of IL-10, but neither IFN-γ nor IL-4, i.e., by conversion to a suppressive, anti-inflammatory phenotype.