Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.

T helper type 2 (TH2) cells are critical for clearance of parasitic helminth infections. Their coordinated efforts harness cellular and molecular pathways to expel worms, resolve intestinal inflammation and drive tissue repair. Yet the mechanisms that control TH2 cell activation, maintenance, and downregulation remain unknown. We recently demonstrated that Leucine rich repeat and Ig domain containing 2 (LINGO2) can function as a receptor for the mucosal reparative cytokine, Trefoil factor 3, to limit epithelial damage, colitic disease and immunopathology. Because LINGO2 is broadly expressed in both hematopoietic and non-hematopoietic cell lineages, this study specifically addressed whether LINGO2 expression in the T cell compartment served a biologically important function in host protection against the parasitic helminth Trichuris muris. Data show that mice selectively deficient for LINGO2 in T lymphocytes (CD4Cre+ LINGO2flox/flox) had significantly higher numbers of adult worms in the cecum, parasite eggs in the stool and colon immunopathology compared to CD4Cre+ or LINGO2flox/flox controls. Intriguingly, after Trichuris infection, CD4Cre+ LINGO2flox/flox mice had significantly fewer GATA3+ TH2 cells and expressed significantly increased interferon gamma levels in the mesenteric lymph node. Taken together, this work highlights a previously unrecognized cell-intrinsic role for LINGO2 in controlling T cell responses that critically shapes the outcome of helminth infection.