CD44 v5 domain inhibition represses the polarization of Th2 cells by interfering with the IL-4/IL-4R signaling pathway,Immunology and Cell Biology

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CD44 v5 domain inhibition represses the polarization of Th2 cells by interfering with the IL-4/IL-4R signaling pathway
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2021-07-05 , DOI: 10.1111/imcb.12491
Chun Yang _{1,

2,

3} , Jianhong Lin _{2,

3} , Hongyan Liang ₁ , Li Xue _{1,

2,

3} , Ariel Kwart _{2,

3} , Meng Jiang _{2,

4} , Jianjun Zhao ₅ , Huan Ren ₆ , Xiaofeng Jiang ₁ , Nikhil C Munshi _{2,

3,

7}

Affiliation

The balance between T helper type 1 (Th1) and T helper type 2 (Th2) cells is critical for both innate and acquired immune reactions. However, the precise mechanisms of T helper-cell differentiation remain unclear. As an important T-cell activation molecule, CD44 participates in the differentiation of Th1 and Th2 cells. We demonstrated that CD44 variant exon v5 (CD44 v5) is highly expressed by induced human Th2 cells. To investigate the role of the CD44 v5 domain in Th2 cell differentiation, we treated human CD4⁺ T cells with anti-CD44v5 antibody and observed that the levels of phosphorylated STAT6 and GATA3 and the secretion of interleukin-4 (IL-4) were significantly decreased after the treatment. We also further found that the inhibition of Th2 differentiation was caused by the degradation of the alpha chain of IL-4 receptor (IL-4Rα), the CD44 v5 domain colocalized with IL-4Rα on cell surface and the degradation of IL-4Rα increased after CD44 v5 domain blocking or ablating. Our results indicated that CD44v5 antibody treatment interrupted the interaction between CD44 v5 domain and IL-4Rα, but the CD44 v5 domain blockage would not spoil the colocalization between IL-4R expression and T-cell receptor and the immunological synapse formation; similar results were also found in CD44v5-deficient CD4⁺ T cells. In conclusion, we revealed the function of the CD44 v5 domain in Th2 cell differentiation; blocking or ablating the CD44 v5 domain could accelerate IL-4Rα degradation and then induce the Th2 cell inhibition.

中文翻译：

CD44 v5 域抑制通过干扰 IL-4/IL-4R 信号通路抑制 Th2 细胞的极化

辅助性 T 细胞 1 (Th1) 和辅助性 T 细胞 2 (Th2) 之间的平衡对于先天性和获得性免疫反应都至关重要。然而，T辅助细胞分化的确切机制仍不清楚。CD44 作为重要的 T 细胞活化分子，参与 Th1 和 Th2 细胞的分化。我们证明了 CD44 变体外显子 v5（CD44 v5）由诱导的人类 Th2 细胞高度表达。为了研究 CD44 v5 结构域在 Th2 细胞分化中的作用，我们处理了人类 CD4 ⁺T细胞与抗CD44v5抗体并观察到磷酸化STAT6和GATA3的水平以及白细胞介素4（IL-4）的分泌在治疗后显着降低。我们还进一步发现，Th2分化的抑制是由IL-4受体（IL-4Rα）α链的降解引起的，细胞表面与IL-4Rα共定位的CD44 v5结构域和IL-4Rα的降解增加CD44 v5 域阻塞或消融后。我们的结果表明，CD44v5 抗体处理中断了 CD44 v5 域和 IL-4Rα 之间的相互作用，但 CD44 v5 域的阻断不会破坏 IL-4R 表达与 T 细胞受体之间的共定位以及免疫突触形成；在 CD44v5 缺陷的 CD4 ⁺中也发现了类似的结果T细胞。总之，我们揭示了 CD44 v5 结构域在 Th2 细胞分化中的功能；阻断或消除 CD44 v5 域可以加速 IL-4Rα 降解，然后诱导 Th2 细胞抑制。

更新日期：2021-07-05

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