Gut T cell receptor-γδ⁺ intraepithelial lymphocytes are activated selectively by cholera toxin to break oral tolerance in mice

The gut immune system is usually tolerant to harmless foreign antigens such as food proteins. However, tolerance breakdown may occur and lead to food allergy. To study mechanisms underlying food allergy, animal models have been developed in mice by using cholera toxin (CT) to break tolerance. In this study, we identify T cell receptor (TCR)-γδ⁺ intraepithelial lymphocytes (IELs) as major targets of CT to break tolerance to food allergens. TCR-γδ⁺ IEL-enriched cell populations isolated from mice fed with CT and transferred to naive mice hamper tolerization to the food allergen β-lactoglobulin (BLG) in recipient mice which produce anti-BLG immunoglobulin (Ig)G1 antibodies. Furthermore, adoptive transfer of TCR-γδ⁺ cells from CT-fed mice triggers the production of anti-CT IgG1 antibodies in recipient mice that were never exposed to CT, suggesting antigen-presenting cell (APC)-like functions of TCR-γδ⁺ IELs. In contrast to TCR-αβ⁺ cells, TCR-γδ⁺ IELs bind and internalize CT both in vitro and in vivo. CT-activated TCR-γδ⁺ IELs express major histocompatibility complex (MHC) class II molecules, CD80 and CD86 demonstrating an APC phenotype. CT-activated TCR-γδ⁺ IELs migrate to the lamina propria, where they produce interleukin (IL)-10 and IL-17. These results provide in-vivo evidence for a major role of TCR-γδ⁺ IELs in the modulation of oral tolerance in the pathogenesis of food allergy.