Additional transcription factors have been implicated in the induction of IL-17+ CD8+ T cells including signal transducer and activator of transcription 3 (STAT3), interferon regulator factor 3 (IRF3) and interferon regulatory factor 4 (IRF4), at least in mice. Knockdown of STAT3 by siRNA in spleen or lymph node-derived CD8+ T cells resulted in a reduction of IL-17+ CD8+ T cell frequencies under IL-17+ CD8+ T cell differentiation conditions . A similar reduction in IL-17+ CD8+ T cells was seen under these conditions in an IRF4 knockout mouse, and this phenotype was partially reversed upon overexpression of RORγt in IRF4−/− cells . In contrast, CD8+ T cells derived from the spleen or lymph nodes of IRF3 knockout mice showed increased IL-17A production and upregulated Il23r gene expression under IL-17+ CD8+ T cell differentiation conditions. Interestingly, a direct interaction between IRF3 and RORγt transcription factors was identified in the cytoplasm under IL-17+ CD8+ T cell differentiation conditions indicating that IRF3 may act as a negative regulator of IL-17 induction in IL-17+ CD8+ T cells by antagonistically binding RORyt and therefore reducing downstream interactions .