Type I IFN Induces TCR-dependent and -independent Antimicrobial Responses in γδ Intraepithelial Lymphocytes.

Abstract

Intraepithelial lymphocytes (IELs) expressing the TCRγδ survey the intestinal epithelium to limit the invasion of microbial pathogens. The production of type I IFN is a central component of an antiviral immune response, yet how these proinflammatory cytokines contribute to γδ IEL effector function remains unclear. Based on the unique activation status of IELs and their ability to bridge innate and adaptive immunity, we investigated the extent to which type I IFN signaling modulates γδ IEL function. Using an ex vivo culture model, we find that type I IFN alone is unable to drive IFN-γ production, yet low-level TCR activation synergizes with type I IFN to induce IFN-γ production in murine γδ IELs. Further investigation into the underlying molecular mechanisms of costimulation revealed that TCRγδ-mediated activation of NFAT and JNK is required for type I IFN to promote IFN-γ expression in a STAT4-dependent manner. Whereas type I IFN rapidly upregulates antiviral gene expression independent of a basal TCRγδ signal, neither tonic TCR triggering nor the presence of a TCR agonist was sufficient to elicit type I IFN-induced IFN-γ production in vivo. However, bypassing proximal TCR signaling events synergized with IFNAR/STAT4 activation to induce γδ IEL IFN-γ production. These findings indicate that γδ IELs contribute to host defense in response to type I IFN by mounting a rapid antimicrobial response independent of TCRγδ signaling, and may produce IFN-γ in a TCR-dependent manner under permissive conditions.