Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells

CD1d-restricted invariant natural killer T (iNKT) cells are known as potent early regulatory cells of immune responses. Besides the established roles in the regulation of inflammation and autoimmune disease, studies have shown that iNKT cells have important roles in tumor surveillance and the control of tumor metastasis. Here we found that absence of iNKT cells dramatically decreased the total number of intestinal polyps in APC(Min/+) mice, a model for colorectal cancer. Polyp iNKT cells were enriched for IL-10 and IL-17 producing cells, showed a distinct phenotype being CD4(+), NK1.1(−) CD44(int) and PD-1(lo), and they were negative for the NKT cell transcription factor PLZF. Absence of iNKT cells was associated with a reduced frequency of Treg cells and lower expression levels of FoxP3 protein and transcript uniquely in the polyps, and a switch to an inflammatory macrophage phenotype. Moreover, in iNKT cell deficient APC(Min/+) mice, expression of T helper (TH) 1-associated genes, such as IFN-γ and Nos2, was increased in polyps, concomitantly with elevated frequencies of conventional CD4(+) and CD8(+) T cells in this tissue. The results suggest that a population of regulatory iNKT cells locally promote intestinal polyp formation by enhancing Treg cells and immunosuppression of anti-tumor TH1-immunity.