IL-4-PRODUCING NKT CELLS ARE BIASED TOWARDS IFN-GAMMA PRODUCTION BY IL-12 - INFLUENCE OF THE MICROENVIRONMENT ON THE FUNCTIONAL CAPACITIES OF NK T-CELLS

NK T cells are an unusual T lymphocyte subset capable of promptly prod ucing several cytokines after stimulation, in particular IL-4, thus su ggesting their influence in Th2 lineage commitment. In this study we d emonstrate that, according to the cytokines present in the microenviro nment, NK T lymphocytes can preferentially produce either IL-4 or IFN- gamma. In agreement with our previous reports showing that their IL-4- producing capacity is strikingly dependent on IL-7, CD4(-)CD8(-)TCR al pha beta(+) NK T lymphocytes, obtained after expansion with IL-1 plus granulocyte-macrophage colony-stimulating factor, produced almost unde tectable amounts of IL-4 or IFN-gamma in response to TCR/CD3 cross-lin king. However, the capacity of these T cells to produce IFN-gamma is s trikingly enhanced when IL-12 is added either during their expansion o r the anti-CD3 stimulation, while IL-4 secretion is always absent. A s imilar effect of IL-12 on IFN-gamma production was observed when NK T lymphocytes were obtained after expansion with IL-7. It is noteworthy that whatever cytokines are used for their expansion, IL-12 stimulatio n, in the absence of TCR/CD3 cross-linking, promotes consistent IFN-ga mma secretion by NK T cells without detectable IL-4 production. Experi ments in vivo demonstrated a significant upregulation of the capacity of NK T cells to produce IFN-gamma after anti-CD3 mAb injection when m ice were previously treated with IL-12. In conclusion, we provide evid ence that the functional capacities of NK T cells, which ultimately wi ll determine their physiological roles, are strikingly dependent on th e cytokines present in their microenvironment.