A Trefoil factor 3-Lingo2 axis restrains proliferative expansion of type-1 T helper cells during GI nematode infection

Abstract

Host defense at the mucosal interface requires collaborative interactions between diverse cell lineages. Epithelial cells damaged by microbial invaders release reparative proteins such as the Trefoil factor family (TFF) peptides that functionally restore barrier integrity. However, whether TFF peptides and their receptors also serve instructive roles for immune cell function during infection is incompletely understood. Here, we demonstrate that the intestinal trefoil factor, TFF3, restrains TH1 cell proliferation and promotes host protective Type 2 immunity against the gastrointestinal parasitic nematode Trichuris muris. Accordingly, T cell-specific deletion of the TFF3 receptor, Lingo2, impairs TH2 cell commitment, allows proliferative expansion of IFNγ+CD4+ TH1 cells and blocks normal worm expulsion through an IFNγ-dependent mechanism. This study indicates that TFF3, in addition to its known tissue reparative functions, drives anti-helminth immunity by controlling the balance between TH1/TH2 subsets.