TYK2-deficient PBMC showed divergent responses to IFN-α/β/γ
Type I IFNs signal through IFNAR1 and IFNAR2, which associate with TYK2 and JAK1, respectively. STAT1 and STAT2 are the major signal transducing STATs in response to type I IFNs [10-12]. Nevertheless, also all other STATs can be activated and contribute to responses in a cell type-specific manner. IFN-γ signals through IFNGR1 and IFNGR2, which are associated with JAK1 and JAK2, respectively[13] and then STAT1 is activated. Often STAT3[14,15] and sometimes STAT5[16] are also activated by IFN-γ. To further investigate the functional effects of TYK2 deficiency, we tested the responses of PBMC from TYK2-deficient patients to type I and type II interferons. For P1, the phosphorylation of STAT1 and STAT3 induced by IFN-α and IFN-β were both abolished, while the phosphorylation of STAT1 induced by IFN-γ was comparable with that of healthy control (Fig. 2A). Reduced STAT1 expression is believed to be partially responsible for reduced phosphorylation of STAT1 in response to type I interferons in TYK2 deficient cells. Consistently, RT-qPCR showed decreased transcription of various ISGs (Fig. 2C). P2 also showed impaired responses to IFN-α/β but normal response to IFN-γ (Fig. 2B), which was also consistent with ISG expression (Fig. 2D). Taken together, our data indicates that TYK2 deficiency results in divergent responses to IFN-α/β/γ.