Elucidating the role of cytokine signaling in the homeostasis of innate immune cells with JAK inhibitors

Abstract The role of the JAK/STAT pathway in the function on innate lymphoid cells (ILCs) has been mostly investigated using genetically modified animals. While elegant, these studies present with the limitation of a complete loss of ILC populations. Therefore, pharmacological manipulation of this signaling cascade with JAK inhibitors (jakinibs) is an attractive alternative strategy. Here we investigated the effect of pan- and JAK-selective inhibitors on the development and functions of murine, IFN-γ producing, ILCs and iNKT cells after oral administration of tofacitinib (JAK1; JAK3 and JAK2), ruxolitinib (JAK1; JAK2), or PF-06651600 (JAK3). We observed a significant reduction in number and function (IFN-γ production) of both splenic and hepatic NKp46+ cells with either tofacitinib or PF- 006651600. The reduction appears to correlate with the number of proliferating Ki67+ NKp46+ cells. In addition, using an iNKT-dependent mouse model of acute liver inflammation, we observed a significant decreased production of IFN-γ by liver iNKT upon tofacitinib administration. Notably, we found that PF-06651600 selectively impairs the thymic development and the proliferation of IFN-γ-producing iNKT1 cells. Overall our data suggest that the transient inhibitory activity with jakinibs has strong impact on proliferation and activity of mouse IFN- γ producing innate cells. These preliminary findings bring us one step closer to elucidating mechanisms underlying innate cells homeostasis.