Inborn errors of Th17 immunity predispose patients to chronic and invasive fungal infections. The

IL-6/JAK2/STAT3 axis is recognized as a vital Th17 inducing signaling cascade and STAT3 mutations

are frequent in these patients. We identified a novel JAK2 mutation in a family with recurrent fungal

infections and a proven Th17 defect. Functional analysis revealed normal JAK2-STAT signaling. Based

on structural modeling, we hypothesize the mutant would hamper protein-protein interactions (PPI)

with non-STAT binding partners. Indeed, a proteome-wide MAPPIT screen revealed a loss of 65 PPI

with the mutant. Here we will focus on PIK3R1 and PIK3R3 since PI3K is activated downstream of

several JAK2-employing cytokines and the PI3K/AKT/mTOR pathway promotes Th17 induction.

To study how JAK2/PI3K interactions are involved in Th17 immunity and how this is impaired by the

mutant JAK2, we propose to study 1) JAK2-PI3K interactions and the effect of the mutation in HEK

cells and 2) JAK2-PI3K signaling in Th17 function in healthy control and patient cells, and by CRISPRCas9

knock-in of JAK2 F794S in healthy control cells.

Elucidation of the mechanism by which JAK2/PI3K interactions promote Th17 immunity, will shed

more light on the complex interactions of the JAK-STAT signaling network and on non-canonical

JAK2 signaling specifically towards PI3K/mTOR. Importantly, it may provide a rationale for

development of new treatment options for inborn errors of Th17 immunity