Cell-to-cell contact between activated CD4+ T lymphocytes and unprimed monocytes interferes with a TH1 response.

Abstract

The production of IL-12 by monocytes and dendritic cells is tightly regulated and critically dependent on signals from surrounding cells in the micromilieu. We studied the capacity of T cells to regulate directly the production of IL-12 by human monocytes. Human isolated CD4 + T cells from peripheral blood and T cells from acute patch test lesions were cocultured with autologous monocytes. IL-12 expression and production were measured, and intracellular signal transduction pathways were studied. Monocytes, which had been cocultured with activated T cells, were further investigated for their capacity to induce TH1-directed responses. A marked inhibition of IL-12 production was observable on coculture of monocytes with isolated CD4 + activated autologous T lymphocytes derived from blood or from acute eczematous skin lesions. The inhibiting effect of activated T lymphocytes on IL-12 production was dependent on cell-to-cell contact to monocytes but not on their ability to secrete soluble mediators. Experiments performed in the presence of mitogen-activated protein kinase kinase 1/2 inhibitors provided evidence that activation of the p44/42 pathway plays an important role for the inhibition of IL-12 production in monocytes (here referred to as IL-12 low monocytes). In addition, T cells cocultured with IL-12 low monocytes showed a markedly lower expression of the TH1 specific transcription factor T-bet, IFN-gamma, and IL-12Rbeta2 cell surface expression. Activated T lymphocytes may directly contribute to the TH2-like cytokine milieu found at sites of allergic inflammation (eg, in acute eczematous skin lesions) by inhibiting IL-12 production of unprimed antigen-presenting cells.