IL-17-secreting CD4 T cells play an important role in several physiologic and pathologic processes. In mice TGF-b and IL-6 have been shown to trigger Th17 differentiation of naive CD4 T cells, but their or other cytokines? role in human Th17 commitment has not been evaluated.
To investigate the signals driving Th17 differentiation in humans, we sorted naïve CD4 T cells from peripheral blood mononuclear cells and stimulated them with immobilized CD3 antibodies in the presence of different cytokine combinations and neutralizing antibodies to IL-4 and IFN-g. We found that TGF-b alone or in combination with IL-6 failed to induce and in fact inhibited differentiation of naive T cells to Th17. Interestingly, IL-1b alone was able to induce differentiation of IL-17-secreting cells and, in combination with IL-6 led to the highest percentage of IL-17 secreting cells obtained. Accordingly, IL-1b upregulated in activated T cells mRNA for RORgt, the transcription factor involved in Th17 commitment, and in combination with IL-6 ensured its sustained expression.
We next evaluated the ability of different types of antigen presenting cells (APC) to prime Th17 cells. For this, we stimulated human naïve CD4 T cells with CD3 antibodies in the presence of different LPS-activated APC. We observed that monocyte-derived dendritic cells (DC), that secreted low levels of IL-1b and high levels of IL-6 and IL12p70 upon LPS stimulation, were poor inducers of Th17 differentiation and mainly induced Th1 differentiation. Circulating CD1c+ DC, that secreted low levels of IL1-b, IL-6 and IL-12p70, induced low amounts of both Th17 and Th1 cells. Importantly, circulating CD14+ monocytes, that produced high levels of IL1b and IL-6 and low or no IL12p70 upon LPS stimulation, were very effective in inducing Th17 differentiation. This induction was abrogated by blockade of IL-1b and IL-6, but not of TGF-b.
In conclusion, our data demonstrate that the ability of an APC to prime Th17 is dependent on the cytokines they secrete and that the cytokines that drive Th17 differentiation in humans are primarily IL-1b and IL-6 but not TGF-b.
