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.