To analyse the function of T-bet and EOMES in effector T cells, the authors generated double-knockout mice that lack T-bet and EOMES expression in the T-cell compartment and infected them with lymphocytic choriomeningitis virus (LCMV). Unlike T-bet- or EOMES-deficient mice, double-knockout mice failed to control LCMV infection. Virus-specific CD8+ T cells from these mice produced lower levels of interferon-γ and exhibited defective cytotoxicity in vitro compared with cells from single-knockout or control mice. In addition, double-knockout mice developed a virus-induced wasting disease that was characterized by neutrophilia and multiple-organ pathology. However, mice that lack lymphocytes (Rag−/− mice)did not develop this wasting disease following LCMV infection, indicating that the immunopathology in double-knockout mice was lymphocyte dependent.
Because IL-17 induces the recruitment and activation of neutrophils and is an important mediator in inflammatory and autoimmune diseases, the authors investigated whether double-knockout virus-specific CD8+ T cells produced IL-17. Restimulation of these T cells in vitro with a viral antigen induced high levels of IL-17 production. In addition, double-deficient, but not single-deficient, CD8+ T cells expressed the T helper 17 (TH17)-lineage-specific transcription factor RORγt (retinoic-acid-receptor-related orphan receptor-γt), the signature cytokines IL-17A, IL-21 and IL-22 and the associated cytokine receptor IL-23R, indicating that CD8+ T cells differentiate into type 17 cells, reminiscent of TH17 cells, in the absence of T-bet and EOMES. Depletion of CD8+ T cells from double-knockout mice prevented LCMV-induced wasting disease, neutrophilia and multiple-organ pathology, indicating that these type 17 CD8+ T cells mediate the immunopathology that is observed in LCMV-infected double-knockout mice.
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