Spontaneous Intestinal Tumorigenesis in ApcMin+ Mice Requires Altered T Cell Development with IL-17A

Abstract EN

The control of inflammatory diseases requires functional regulatory T cells (Tregs) with significant Gata-3 expression.

Here we address the inhibitory role of Tregs on intestinal tumorigenesis in the Apc/Min+ mouse model that resembles human familial adenomatous polyposis (FAP).

Apc/Min+ mice had a markedly increased frequency of Foxp3+ Tregs and yet decreased Gata-3 expression in the lamina propria.

To address the role of heterozygous Apc gene mutation in Tregs, we generated Foxp3-Cre, Apcflox/+ mice.

Tregs from these mice effectively inhibited tumorigenesis comparable to wild type Tregs after adoptive transfer into Apc/Min+ mice, demonstrating that the heterozygous Apc gene mutation in Tregs does not induce the loss of control over tumor microenvironment.

Adoptive transfer of in vitro generated Apc/Min+ iTregs (inducible Tregs) failed to inhibit intestinal tumorigenesis, suggesting that naïve CD4 T cells generated from Apc/Min+ mice thymus were impaired.

We also showed that adoptively transferred IL-17A-deficient Apc/Min+ Tregs inhibited tumor growth, suggesting that IL-17A was critical to impair the tumor regression function of Apc/Min+ Tregs.

Taken together, our results suggest that both T cell development in a functional thymus and IL-17A control the ability of Treg to inhibit intestinal tumorigenesis in Apc/Min+ mice.