The E3 ligases Itch and WWP2 regulate autoimmune neuroinflammation by controlling TH2 to TH17 cell conversion via interleukin-4-STAT5 axis in mice

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease primarily mediated by T helper 17 (T_H17) cells. We previously showed that Itch/WWP2 double knockout (DKO) T cells produce high levels of type 2 cytokines, driving spontaneous autoinflammation. Here, we report that DKO T_H2-high carrying autoantigen-specific TCR (2D2) develop atypical spontaneous experimental autoimmune encephalomyelitis (EAE), with CD4⁺ T cells simultaneously producing IL-4 and GM-CSF, directly causing neuroinflammation. Unexpectedly, IL-4 deletion in DKO T_H2-high 2D2 mice exacerbates T_H17-driven classical EAE, indicating a T_H2 to T_H17 conversion. Furthermore, we show that the JAK3/STAT5 signaling pathway is critical for maintaining T_H2 lineage stability by modulating Blimp1 and c-Maf thereby suppressing T_H17 differentiation. Importantly, we find that this phenomenon can also be observed in dupilumab-treated patients with atopic dermatitis who develop psoriasis. Thus, our findings uncover the molecular antagonism and plasticity in the T_H2 and T_H17 cell programs and identify potential therapeutic targets for modulating T_H2 and T_H17 cell responses in autoimmune diseases.