024 Exposure of murine Langerhans cells (LCs) to IL-6 biases antigen (Ag) presentation toward an IL-17A response

Abstract

Exposure of endothelial cells (ECs) to the neuropeptide calcitonin gene-related peptide endows ECs with the ability, acting as bystanders, to bias the outcome of LC Ag presentation to T cells away from Th1 responses and toward Th17 responses, and IL-6 production by ECs appears to mediate most of this effect. To determine if IL-6 action on LCs alone, or T cells alone, is sufficient for this phenomenon, we exposed epidermal BALB/c LCs or, separately, T cells from DO11.10 mice (BALB/c background; DO11.10 mice have T cells that respond to a fragment of chicken ovalbumin, cOVA323339) to IL-6 or medium alone for 3 h. Then, all cells were washed x 4. IL-6-exposed or medium-exposed LC were cultured with DO11.10 T cells not exposed to IL-6 along with Ag. Supernatants were harvested 72 h later and analyzed by ELISA for cytokine content. Exposure of LCs to IL-6 led to significantly enhanced production of IL-6 and IL-17A with significantly reduced IFNγ production. When analogous experiments were set-up treating responding T cells with IL-6 instead of LCs, no effect was observed. Exposure of LCs to monoclonal anti-CD126 antibodies (Abs) before and during treatment with IL-6 significantly inhibited enhancement of IL-17A and IL-6 production, as well as decreased IFNγ production, by responding DO11.10 T cells, suggesting that presentation of IL-6 by the IL-6 receptor (IL-6R) alpha chain is important for this effect. Similar experiments exposing LCs to Abs against the type I cytokine receptor subunit CD130 instead of anti-CD126 Abs showed a much smaller, but still significant, effect on production of IL-6 and IFNγ and no significant effect on IL-17A. These experiments show that exposure of LCs to IL-6 polarizes the outcome of Ag presentation to T cells away from an IFNγ response and toward an IL-17A response and suggest that IL-6 must be presented by the IL-6R alpha chain for the effect observed. These findings may have implications for a greater understanding of the pathophysiology of inflammatory skin disorders.