The E3 ligases Itch and WWP2 regulate autoimmune neuroinflammation by controlling T<sub>H</sub>2 to T<sub>H</sub>17 cell conversion via interleukin-4-STAT5 axis in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41577662.
- Also identified by DOI 10.1038/s41467-025-67665-w and PMC identifier 12848126.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Multiple sclerosis (MS) is a neurodegenerative autoimmune disease primarily mediated by T helper 17 (T<sub>H</sub>17) 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<sub>H</sub>2-high carrying autoantigen-specific TCR (2D2) develop atypical spontaneous experimental autoimmune encephalomyelitis (EAE), with CD4<sup>+</sup> T cells simultaneously producing IL-4 and GM-CSF, directly causing neuroinflammation. Unexpectedly, IL-4 deletion in DKO T<sub>H</sub>2-high 2D2 mice exacerbates T<sub>H</sub>17-driven classical EAE, indicating a T<sub>H</sub>2 to T<sub>H</sub>17 conversion. Furthermore, we show that the JAK3/STAT5 signaling pathway is critical for maintaining T<sub>H</sub>2 lineage stability by modulating Blimp1 and c-Maf thereby suppressing T<sub>H</sub>17 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<sub>H</sub>2 and T<sub>H</sub>17 cell programs and identify potential therapeutic targets for modulating T<sub>H</sub>2 and T<sub>H</sub>17 cell responses in autoimmune diseases.
Medical subject headings
- Th17 Cells
- Encephalomyelitis, Autoimmune, Experimental
- Th2 Cells
- Interleukin-4
- Ubiquitin-Protein Ligases
- STAT5 Transcription Factor
- Neuroinflammatory Diseases