生物
细胞生物学
关贸总协定3
T细胞
白细胞介素2受体
细胞因子
白细胞介素4
幼稚T细胞
下调和上调
细胞毒性T细胞
免疫学
免疫系统
T细胞受体
转录因子
生物化学
体外
基因
作者
Aydan C H Szeto,Ana Carolina Franco Ferreira,Jonathan Mannion,Paula A. Clark,Meera Sivasubramaniam,Morgan W D Heycock,Alastair Crisp,Helen E. Jolin,Patrycja Kozik,Martin Knolle,Andrew McKenzie
标识
DOI:10.1038/s41590-022-01378-w
摘要
Naive CD4+ T lymphocytes initially undergo antigen-specific activation to promote a broad-spectrum response before adopting bespoke cytokine expression profiles shaped by intercellular microenvironmental cues, resulting in pathogen-focused modular cytokine responses. Interleukin (IL)-4-induced Gata3 upregulation is important for the helper type 2 T cell (TH2 cell) polarization associated with anti-helminth immunity and misdirected allergic inflammation. Whether additional microenvironmental factors participate is unclear. Using whole mouse-genome CRISPR–Cas9 screens, we discovered a previously unappreciated role for αvβ3 integrin in TH2 cell differentiation. Low-level αvβ3 expression by naive CD4+ T cells contributed to pan-T cell activation by promoting T–T cell clustering and IL-2/CD25/STAT5 signaling. Subsequently, IL-4/Gata3-induced selective upregulation of αvβ3 licensed intercellular αvβ3–Thy1 interactions among TH2 cells, enhanced mammalian target of rapamycin (mTOR) signaling, supported differentiation and promoted IL-5/IL-13 production. In mice, αvβ3 was required for efficient, allergen-driven, antigen-specific lung TH2 cell responses. Thus, αvβ3-expressing TH2 cells form multicellular factories to propagate and amplify TH2 cell responses. Gata3 upregulation is required for TH2 cell polarization. McKenzie and colleagues find that integrin αvβ3 is upregulated by Gata3 and that this is crucial in inducing FAK–mTOR signaling required for TH2 cell differentiation.
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