Microbial Lipopeptides Induce the Production of IL-17 in Th Cells

Naive Th cells can be directed in vitro to develop into Th1 or Th2 cells by IL-12 or IL-4, respectively. In vivo, chronic immune reactions lead to polarized Th cytokine patterns. We found earlier that Borrelia burgdorferi, the spirochaete that causes Lyme disease, induces Th1 development in alpha beta TCR-transgenic Th cells. Here, we used TCR-transgenic Th cells and oligonucleotide arrays to analyze the differences between Th1 cells induced by IL-12 vs those induced by B. burgdorferi. Transgenic Th cells primed with peptide in the presence of B. burgdorferi expressed several mRNAs, including the mRNA encoding IL-17, at significantly higher levels than Th cells primed with peptide and IL-12. Cytometric single-cell analysis of Th cell cytokine production revealed that IL-17 cannot be categorized as either Th1 or Th2 cytokine. Instead, almost all IL-17-producing Th cells simultaneously produced TNF-alpha and most IL-17(+) Th cells also produced GM-CSF. This pattern was also observed in humans. Th cells from synovial fluid of patients with Lyme arthritis coexpressed IL-17 and TNF-alpha upon polyclonal stimulation. The induction of IL-17 production in Th cells is not restricted to B. burgdorferi. Priming of TCR-transgenic Th cells in the presence of mycobacterial lysates also induced IL-17/TNF-alpha coproduction. The physiological stimulus for IL-17 production was hitherto unknown. We show here for the first time that microbial stimuli induce the expression of IL-17 together with TNF-alpha in both murine and human T cells. Chronic IL-17 expression induced by microbes could be an important mediator of infection-induced immunopathology.