Epidermal Growth Factor Receptor Expression Licenses Type-2 Helper T Cells to Function in a T Cell Receptor-Independent Fashion

• Published in: Immunity (Cambridge, Mass.) Vol. 47; no. 4; pp. 710 - 722.e6
• Main Authors: Minutti, Carlos M., Drube, Sebastian, Blair, Natalie, Schwartz, Christian, McCrae, Jame C., McKenzie, Andrew N., Kamradt, Thomas, Mokry, Michal, Coffer, Paul J., Sibilia, Maria, Sijts, Alice J., Fallon, Padraic G., Maizels, Rick M., Zaiss, Dietmar M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.10.2017; Elsevier Limited; Cell Press
• Subjects: Amphiregulin; Amphiregulin - immunology; Amphiregulin - metabolism; Animals; Antigen presentation; Antigens; Cell Line; Cells; Cells, Cultured; cytokine signaling; Cytokines; Effector cells; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - immunology; ErbB Receptors - metabolism; gastro-intestinal helminth infections; Gene Expression - genetics; Gene Expression - immunology; Gene Expression Profiling - methods; HEK293 Cells; Helper cells; Humans; Immune system; Infections; Interleukin 13; Interleukin-13 - genetics; Interleukin-13 - immunology; Interleukin-13 - metabolism; interleukin-33; Interleukin-33 - genetics; Interleukin-33 - immunology; Interleukin-33 - metabolism; Intestine; Licenses; Lymphocytes; Lymphocytes T; MAP Kinase Signaling System - immunology; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nematospiroides dubius - immunology; Nematospiroides dubius - physiology; Nocardia - immunology; Nocardia - physiology; Nocardia Infections - immunology; Nocardia Infections - metabolism; Nocardia Infections - microbiology; Parasites; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Signal transduction; Signaling; Strongylida Infections - immunology; Strongylida Infections - metabolism; Strongylida Infections - parasitology; T cell receptors; TCR-independent IL-13 secretion; Th2 Cells - immunology; Th2 Cells - metabolism; Tissues; type-2 helper T cells; cytokine signaling; type-2 helper T cells; interleukin-33; gastro-intestinal helminth infections; interleukin-13; TCR-independent IL-13 secretion
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.09.013

Gastro-intestinal helminth infections trigger the release of interleukin-33 (IL-33), which induces type-2 helper T cells (Th2 cells) at the site of infection to produce IL-13, thereby contributing to host resistance in a T cell receptor (TCR)-independent manner. Here, we show that, as a prerequisite for IL-33-induced IL-13 secretion, Th2 cells required the expression of the epidermal growth factor receptor (EGFR) and of its ligand, amphiregulin, for the formation of a signaling complex between T1/ST2 (the IL-33R) and EGFR. This shared signaling complex allowed IL-33 to induce the EGFR-mediated activation of the MAP-kinase signaling pathway and consequently the expression of IL-13. Lack of EGFR expression on T cells abrogated IL-13 expression in infected tissues and impaired host resistance. EGFR expression on Th2 cells was TCR-signaling dependent, and therefore, our data reveal a mechanism by which antigen presentation controls the innate effector function of Th2 cells at the site of inflammation. [Display omitted] •Mice lacking EGFR expression on T cells are more susceptible to worm infections•EGFR forms a complex with T1/ST2, allowing for IL-33 induced IL-13 expression•Amphiregulin-mediated EGFR activation is essential for complex formation with T1/ST2•EGFR expression is induced by TCR engagement and sustained by cytokines, such as TSLP At the site of infection, Th2 cells secrete IL-13 upon exposure to IL-33. Minutti et al. now show that TCR-induced expression of the EGFR and its ligand amphiregulin was essential for IL-33-induced IL-13 secretion, revealing a mechanism whereby antigen-specific activation controls the innate effector function of Th2 cells.