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

## TL;DR

This study reveals how the E3 ligases Itch and WWP2 regulate immune cell behavior in autoimmune neuroinflammation, offering new insights into potential treatments for diseases like multiple sclerosis.

## Contribution

The study identifies a novel regulatory mechanism involving Itch and WWP2 in controlling TH2 to TH17 cell conversion via the IL-4-STAT5 axis.

## Key findings

- DKO TH2-high 2D2 mice develop neuroinflammation via CD4+ T cells producing IL-4 and GM-CSF.
- IL-4 deletion in DKO mice exacerbates TH17-driven EAE, indicating TH2 to TH17 conversion.
- The JAK3/STAT5 pathway maintains TH2 stability by modulating Blimp1 and c-Maf to suppress TH17 differentiation.

## Abstract

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease primarily mediated by T helper 17 (TH17) 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 TH2-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 TH2-high 2D2 mice exacerbates TH17-driven classical EAE, indicating a TH2 to TH17 conversion. Furthermore, we show that the JAK3/STAT5 signaling pathway is critical for maintaining TH2 lineage stability by modulating Blimp1 and c-Maf thereby suppressing TH17 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 TH2 and TH17 cell programs and identify potential therapeutic targets for modulating TH2 and TH17 cell responses in autoimmune diseases.

The contribution of T helper 2 (Th2) cells to the pathogenesis of neuroinflammation is underexplored. Here, the authors show that MOG35-55-specific 2D2-TCR transgenic mice lacking Itch and WWP2 in CD4 + T cells develop EAE symptoms primarily driven by Th2 trans-differentiation into pathogenic Th17 cells in the absence of IL-4. Furthermore, they identify a Jak3/STAT5/Blimp1/c-Maf axis required for the maintenance of Th2 stability by repressing Th17 genes.