Control of TH2 and TH17 cell differentiation by Interleukin-4 during Neuroinflammation (PRJCA042880)
CD4+ T helper (TH) cells can polarize into different subsets and exhibit distinct immunological functions. It is generally acknowledged that TH2 cells orchestrate protective type 2 immune responses against helminth infection and contribute to the pathogenesis of allergic diseases, whereas TH17 cells participate in the defense against extracellular fungi and bacteria and are involved in the pathogenesis of autoimmune diseases. Whether TH2 cells play a role in autoimmunity remains elusive. We have previously shown that T cells lacking the E3 ligases Itch and WWP2 (DKO) produce high levels of type 2 cytokines and cause spontaneous autoinflammation. Here we found that the DKO 2D2 mice developed atypical spontaneous EAE, with CD4+ T cells simultaneously producing IL-4 and GM-CSF which intrinsically cause neuroinflammation. Notably, deletion of IL-4 in DKO mice showed exacerbated neuroinflammation and exhibited TH17-drived classical EAE symptoms. This phenomenon has also been observed in patients with atopic dermatitis treated with the IL-4Ra inhibitor dupilumab, which triggers the onset of psoriasis. Additionally, we revealed that the JAK3/STAT5 signaling pathway is critical for maintaining TH2 lineage stability by regulating the expression of key transcription factors such as Blimp1 and c-Maf, thereby preventing the differentiation of CD4+ T cells into pathogenic TH17 cells. The findings suggest potential therapeutic targets for modulating TH2 and TH17 cell responses in autoimmune diseases, highlighting the importance of cytokine signaling pathways in the regulation of immune cell function.