Type I interferon induces TCR-dependent and -independent antimicrobial responses in γδ intraepithelial lymphocytes

Abstract

Intraepithelial lymphocytes (IEL) expressing the {gamma}{delta} T cell receptor (TCR) survey the intestinal epithelium to limit the invasion of microbial pathogens. The production of type I interferon (IFN) is a central component of an antiviral immune response, yet how these pro-inflammatory cytokines contribute to {gamma}{delta} 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 {gamma}{delta} IEL function. Using an ex vivo culture model, we find that type I IFN alone is unable to drive IFN{gamma} production, yet low level TCR activation synergizes with type I IFN to induce IFN{gamma} production in murine {gamma}{delta} IELs. Further investigation into the underlying molecular mechanisms of co-stimulation revealed that TCR{gamma}{delta}-mediated activation of NFAT and JNK is required for type I IFN to promote IFN{gamma} expression in a STAT4- dependent manner. Whereas type I IFN rapidly upregulates antiviral gene expression independent of a basal TCR{gamma}{delta} signal, neither tonic TCR triggering nor the presence of a TCR agonist was sufficient to elicit type I IFN-induced IFN{gamma} production in vivo. However, bypassing proximal TCR signaling events synergized with IFNAR/STAT4 activation to induce {gamma}{delta} IEL IFN{gamma} production. These findings indicate that {gamma}{delta} IELs contribute to host defense in response to type I IFN by mounting a rapid antimicrobial response independent of TCR{gamma}{delta} signaling, and under permissive conditions, produce IFN{gamma} in a TCR-dependent manner.