Webb Lauren M, Warner Lindsey M, Helm Eric Y, Mooney Bridget M, Sundaravaradan Pavithra, Matheson Macy K, Christopher Tighe, Lopez Espinoza Alejandra, Tait Wojno Elia D
Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
Mucosal Immunol. 2025 Aug;18(4):937-950. doi: 10.1016/j.mucimm.2025.05.004. Epub 2025 May 16.
Helminth infections affect billions of people worldwide and cause substantial morbidity. Intestinal helminth infection provokes Type 2 inflammation orchestrated by CD4 T helper type 2 (Th2) cells. Th2 cells cooperate with group 2 innate lymphoid cells (ILC2s) to produce interleukin (IL)-4 and IL-13 that prompt an epithelial "weep and sweep" response to drive parasite clearance. Tissue-specific cues optimize CD4 T cell responses, but the mechanisms regulating intestinal Th2 responses remain unclear. Previously, we identified that the Notch signaling pathway in basophils, rare granulocytes, drove effective parasite clearance and an optimal Th2 response during Trichuris muris infection, a mouse model of human whipworm infection. Here we report that basophil-intrinsic Notch was required for infection-elicited Th2 cytokine responses and a broader IL-4 production program across intestinal CD4 T cell subsets. In vitro, basophils supported CD4 T cell IL-4 production in a contact-dependent manner, independent of basophil-secreted factors and MHC class II, but dependent on autocrine IL-4 production from CD4 T cells. In vivo, basophil-intrinsic Notch mediated basophil-Th2 cell interactions in the cecum during infection. Thus, Notch-programmed basophils act in a contact-dependent manner to optimize intestinal CD4 T cell function during helminth infection. These findings improve our understanding of the tissue-specific mechanisms regulating intestinal CD4 T cell responses at inflamed mucosal barriers during Type 2 immunity.
蠕虫感染影响着全球数十亿人，并导致大量发病情况。肠道蠕虫感染引发由CD4辅助性T2型（Th2）细胞协调的2型炎症。Th2细胞与2型固有淋巴细胞（ILC2s）协作产生白细胞介素（IL）-4和IL-13，促使上皮细胞产生“哭泣与清扫”反应以推动寄生虫清除。组织特异性信号优化CD4 T细胞反应，但调节肠道Th2反应的机制仍不清楚。此前，我们发现嗜碱性粒细胞（一种罕见的粒细胞）中的Notch信号通路在小鼠鞭虫感染（人类鞭虫感染的小鼠模型）期间推动了有效的寄生虫清除和最佳的Th2反应。在此我们报告，嗜碱性粒细胞内在的Notch对于感染引发的Th2细胞因子反应以及整个肠道CD4 T细胞亚群更广泛的IL-4产生程序是必需的。在体外，嗜碱性粒细胞以接触依赖的方式支持CD4 T细胞产生IL-4，独立于嗜碱性粒细胞分泌的因子和MHC II类分子，但依赖于CD4 T细胞自分泌的IL-4产生。在体内，嗜碱性粒细胞内在的Notch在感染期间介导盲肠中的嗜碱性粒细胞与Th2细胞相互作用。因此，Notch编程的嗜碱性粒细胞以接触依赖的方式发挥作用，以优化蠕虫感染期间肠道CD4 T细胞功能。这些发现增进了我们对2型免疫期间炎症黏膜屏障处调节肠道CD4 T细胞反应的组织特异性机制的理解。
