Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations in DOCK8, a guanine exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans, Dock8^−/− mice have a profound type 2 CD4⁺ helper T (T_H2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-T_H2 stimuli. We found that recruited Dock8^−/−CX3CR1⁺ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1β that drives granulocyte−macrophage colony-stimulating factor (GM-CSF) production by CD4⁺ T cells. Blocking IL-1β, GM-CSF or caspase activation eliminated the type-2 skew in mice lacking Dock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and T_H2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4⁺ T cell responses in allergic disease.

影响免疫细胞迁移并导致免疫缺陷的突变说明了细胞运动在宿主防御中的重要性。在人类中， DOCK8 （一种参与造血细胞迁移的鸟嘌呤交换因子）的功能丧失突变会导致免疫缺陷，并且矛盾的是，会导致过敏性疾病。在这里，我们证明，与人类一样，Dock8 ^{-/−小鼠在肺部感染}新型隐球菌和其他非 T _H 2 刺激时具有深刻的 2 型 CD4 ⁺辅助 T (T _H 2) 细胞偏好。我们发现，招募的Dock8 ^−/− CX3CR1 ⁺单核吞噬细胞对迁移诱导的细胞破碎非常敏感，释放白细胞介素 (IL)-1β，驱动 CD4 + T 细胞产生粒细胞巨噬细胞集落刺激因子 (GM-CSF ⁾。阻断 IL-1β、GM-CSF 或 caspase 激活可消除缺乏Dock8的小鼠的 2 型偏斜。值得注意的是，用凋亡细胞治疗感染的野生型小鼠显着增加了 GM-CSF 的产生和 T _H 2 细胞的分化。这揭示了感染过程中细胞死亡在驱动 2 型信号中的重要作用，这可能对理解过敏性疾病中 2 型 CD4 ⁺ T 细胞反应的病因学具有重要意义。