Abstract
BackgroundHost–microbiota interactions shape T-cell differentiation and promote tumour immunity. Although IL-9-producing T cells have been described as potent antitumour effectors, their role in microbiota-mediated tumour control remains unclear.MethodsWe analysed the impact of the intestinal microbiota on the differentiation of colonic lamina propria IL-9-producing T cells in germ-free and dysbiotic mice. Systemic effects of the intestinal microbiota on IL-9-producing T cells and the antitumour role of IL-9 were analysed in a model of melanoma-challenged dysbiotic mice.ResultsWe show that germ-free mice have lower frequency of colonic lamina propria IL-9-producing T cells when compared with conventional mice, and that intestinal microbiota reconstitution restores cell frequencies. Long-term antibiotic treatment promotes host dysbiosis, diminishes intestinal IL-4 and TGF-β gene expression, decreases the frequency of colonic lamina propria IL-9-producing T cells, increases the susceptibility to tumour development and reduces the frequency of IL-9-producing T cells in the tumour microenvironment. Faecal transplant restores intestinal microbiota diversity, and the frequency of IL-9-producing T cells in the lungs of dysbiotic animals, restraining tumour burden. Finally, recombinant IL-9 injection enhances tumour control in dysbiotic mice.ConclusionsHost–microbiota interactions are required for adequate differentiation and antitumour function of IL-9-producing T cells.
Highlights
Host–microbiota interactions shape T-cell differentiation and promote tumour immunity
Host microbiota play a key role in the differentiation of IL-9producing T cells It is well-established that host–microbiota interaction promotes the differentiation of many T-cell subsets.[5,8,11]
Flow cytometry analysis showed a significantly lower frequency of Th9 and Tc9 cells in the colonic lamina propria of ABX-treated animals (Fig. 2e–g). These results indicate that the host microbiota play a key role in the differentiation of IL-9producing T cells, and that the mechanism may rely on transforming growth factor-β (TGF-β) and IL-4 expression
Summary
Host–microbiota interactions shape T-cell differentiation and promote tumour immunity. METHODS: We analysed the impact of the intestinal microbiota on the differentiation of colonic lamina propria IL-9-producing T cells in germ-free and dysbiotic mice. Systemic effects of the intestinal microbiota on IL-9-producing T cells and the antitumour role of IL-9 were analysed in a model of melanoma-challenged dysbiotic mice. RESULTS: We show that germ-free mice have lower frequency of colonic lamina propria IL-9-producing T cells when compared with conventional mice, and that intestinal microbiota reconstitution restores cell frequencies. Faecal transplant restores intestinal microbiota diversity, and the frequency of IL-9-producing T cells in the lungs of dysbiotic animals, restraining tumour burden. Full intestinal microbial colonisation of GF mice was shown to drive expansion of peritoneal IL-17-producing γδ
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